WO2022082058A1 - Method of treatment by tryptamine alkaloids - Google Patents
Method of treatment by tryptamine alkaloids Download PDFInfo
- Publication number
- WO2022082058A1 WO2022082058A1 PCT/US2021/055301 US2021055301W WO2022082058A1 WO 2022082058 A1 WO2022082058 A1 WO 2022082058A1 US 2021055301 W US2021055301 W US 2021055301W WO 2022082058 A1 WO2022082058 A1 WO 2022082058A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tryptamine
- alkaloid
- minutes
- subject
- pharmaceutically acceptable
- Prior art date
Links
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical class C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 title claims abstract description 235
- 238000000034 method Methods 0.000 title claims abstract description 123
- 238000011282 treatment Methods 0.000 title claims abstract description 67
- 238000001802 infusion Methods 0.000 claims abstract description 166
- 238000001990 intravenous administration Methods 0.000 claims abstract description 74
- 238000002360 preparation method Methods 0.000 claims abstract description 61
- 208000002193 Pain Diseases 0.000 claims abstract description 52
- 229940049706 benzodiazepine Drugs 0.000 claims abstract description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims abstract description 47
- 201000010099 disease Diseases 0.000 claims abstract description 33
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims abstract description 26
- 229960004391 lorazepam Drugs 0.000 claims abstract description 26
- 231100000878 neurological injury Toxicity 0.000 claims abstract description 26
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 19
- 230000004968 inflammatory condition Effects 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 238000002483 medication Methods 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 101
- 239000012458 free base Substances 0.000 claims description 77
- 208000019901 Anxiety disease Diseases 0.000 claims description 61
- 230000036506 anxiety Effects 0.000 claims description 57
- ZSTKHSQDNIGFLM-UHFFFAOYSA-N 5-methoxy-N,N-dimethyltryptamine Chemical compound COC1=CC=C2NC=C(CCN(C)C)C2=C1 ZSTKHSQDNIGFLM-UHFFFAOYSA-N 0.000 claims description 54
- DMULVCHRPCFFGV-UHFFFAOYSA-N N,N-dimethyltryptamine Chemical compound C1=CC=C2C(CCN(C)C)=CNC2=C1 DMULVCHRPCFFGV-UHFFFAOYSA-N 0.000 claims description 39
- 230000036407 pain Effects 0.000 claims description 31
- 239000002111 antiemetic agent Substances 0.000 claims description 27
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 25
- RTLRUOSYLFOFHV-UHFFFAOYSA-N [3-[2-(dimethylamino)ethyl]-1h-indol-4-yl] acetate Chemical compound C1=CC(OC(C)=O)=C2C(CCN(C)C)=CNC2=C1 RTLRUOSYLFOFHV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002249 anxiolytic agent Substances 0.000 claims description 19
- 230000000949 anxiolytic effect Effects 0.000 claims description 15
- 230000001624 sedative effect Effects 0.000 claims description 15
- 229940125683 antiemetic agent Drugs 0.000 claims description 14
- 239000000932 sedative agent Substances 0.000 claims description 14
- 230000003444 anaesthetic effect Effects 0.000 claims description 13
- 230000003474 anti-emetic effect Effects 0.000 claims description 13
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 claims description 12
- 239000002160 alpha blocker Substances 0.000 claims description 12
- 239000002876 beta blocker Substances 0.000 claims description 12
- 229940097320 beta blocking agent Drugs 0.000 claims description 12
- 229960005343 ondansetron Drugs 0.000 claims description 12
- 208000006561 Cluster Headache Diseases 0.000 claims description 11
- 208000030814 Eating disease Diseases 0.000 claims description 11
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 11
- -1 acetate ester Chemical class 0.000 claims description 11
- 239000000739 antihistaminic agent Substances 0.000 claims description 11
- 230000001684 chronic effect Effects 0.000 claims description 11
- 235000014632 disordered eating Nutrition 0.000 claims description 11
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 10
- 230000001387 anti-histamine Effects 0.000 claims description 10
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 10
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims description 9
- 208000007777 paroxysmal Hemicrania Diseases 0.000 claims description 9
- 230000004044 response Effects 0.000 claims description 9
- 229960003529 diazepam Drugs 0.000 claims description 8
- 230000001667 episodic effect Effects 0.000 claims description 8
- 201000006417 multiple sclerosis Diseases 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 208000014637 trigeminal autonomic cephalalgia Diseases 0.000 claims description 7
- 208000001640 Fibromyalgia Diseases 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 231100000867 compulsive behavior Toxicity 0.000 claims description 6
- 235000021317 phosphate Nutrition 0.000 claims description 6
- 230000036470 plasma concentration Effects 0.000 claims description 6
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 5
- 208000007514 Herpes zoster Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 206010043269 Tension headache Diseases 0.000 claims description 5
- 208000008548 Tension-Type Headache Diseases 0.000 claims description 5
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 5
- 208000018912 cluster headache syndrome Diseases 0.000 claims description 5
- 208000017169 kidney disease Diseases 0.000 claims description 5
- 229960005181 morphine Drugs 0.000 claims description 5
- 208000020431 spinal cord injury Diseases 0.000 claims description 5
- 230000009529 traumatic brain injury Effects 0.000 claims description 5
- KBRYKXCBGISXQV-UHFFFAOYSA-N 3-[2-[di(propan-2-yl)amino]ethyl]-1h-indol-4-ol Chemical compound C1=CC(O)=C2C(CCN(C(C)C)C(C)C)=CNC2=C1 KBRYKXCBGISXQV-UHFFFAOYSA-N 0.000 claims description 4
- 206010012335 Dependence Diseases 0.000 claims description 4
- 208000008930 Low Back Pain Diseases 0.000 claims description 4
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 4
- LSSUMOWDTKZHHT-UHFFFAOYSA-N N,n-diethyltryptamine Chemical compound C1=CC=C2C(CCN(CC)CC)=CNC2=C1 LSSUMOWDTKZHHT-UHFFFAOYSA-N 0.000 claims description 4
- 208000004550 Postoperative Pain Diseases 0.000 claims description 4
- 208000008765 Sciatica Diseases 0.000 claims description 4
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 4
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 4
- 229960002428 fentanyl Drugs 0.000 claims description 4
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims description 4
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims description 4
- 229960000240 hydrocodone Drugs 0.000 claims description 4
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 4
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 4
- 229960001410 hydromorphone Drugs 0.000 claims description 4
- 229960000482 pethidine Drugs 0.000 claims description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 4
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims description 4
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical group N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 3
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical compound N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 claims description 3
- VCJCULBSFIZKLM-UHFFFAOYSA-N 1h-pyrido[3,2-c]diazepine Chemical compound N1N=CC=CC2=NC=CC=C12 VCJCULBSFIZKLM-UHFFFAOYSA-N 0.000 claims description 3
- ZHBFHRYOSBYWNS-UHFFFAOYSA-N 3,4,12-triazatetracyclo[9.8.0.02,8.014,19]nonadeca-1(11),2(8),9,12,14,16,18-heptaene Chemical compound C1CNNc2c(C1)ccc1ncc3ccccc3c21 ZHBFHRYOSBYWNS-UHFFFAOYSA-N 0.000 claims description 3
- OHHYMKDBKJPILO-UHFFFAOYSA-N 3-[2-(diethylamino)ethyl]-1h-indol-4-ol Chemical compound C1=CC(O)=C2C(CCN(CC)CC)=CNC2=C1 OHHYMKDBKJPILO-UHFFFAOYSA-N 0.000 claims description 3
- RQKDTQACQPHOQL-UHFFFAOYSA-N 3h-2,3-benzodiazepine Chemical compound C1=NNC=CC2=CC=CC=C21 RQKDTQACQPHOQL-UHFFFAOYSA-N 0.000 claims description 3
- CCDMBTCSHSROMD-UHFFFAOYSA-N 7h-thieno[3,2-c]diazepine Chemical compound C1=CN=NC2=CCSC2=C1 CCDMBTCSHSROMD-UHFFFAOYSA-N 0.000 claims description 3
- KSLDTUAYPLKPFS-UHFFFAOYSA-N 9h-[1,3]oxazolo[4,5-i][1,2]benzodiazepine Chemical compound N1=NC=CC=C2C=CC3=NCOC3=C21 KSLDTUAYPLKPFS-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010009094 Chronic paroxysmal hemicrania Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000007077 SUNCT syndrome Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- KLNFAMGHSZQYHR-UHFFFAOYSA-N imidazo[4,5-i][1,2]benzodiazepine Chemical compound C1=CC=NN=C2C3=NC=NC3=CC=C21 KLNFAMGHSZQYHR-UHFFFAOYSA-N 0.000 claims description 3
- 230000003959 neuroinflammation Effects 0.000 claims description 3
- 238000002638 palliative care Methods 0.000 claims description 3
- 229940002612 prodrug Drugs 0.000 claims description 3
- 239000000651 prodrug Substances 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 208000013223 septicemia Diseases 0.000 claims description 3
- KYTREVLPRJOBEM-UHFFFAOYSA-N triazolo[4,5-i][1,2]benzodiazepine Chemical compound C1=CC2=CC=CN=NC2=C2C1=NN=N2 KYTREVLPRJOBEM-UHFFFAOYSA-N 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- RXKGHZCQFXXWFQ-UHFFFAOYSA-N 4-ho-mipt Chemical compound C1=CC(O)=C2C(CCN(C)C(C)C)=CNC2=C1 RXKGHZCQFXXWFQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001773 anti-convulsant effect Effects 0.000 claims description 2
- 230000001430 anti-depressive effect Effects 0.000 claims description 2
- 230000002460 anti-migrenic effect Effects 0.000 claims description 2
- 230000000561 anti-psychotic effect Effects 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 239000000935 antidepressant agent Substances 0.000 claims description 2
- 229940005513 antidepressants Drugs 0.000 claims description 2
- 229960003965 antiepileptics Drugs 0.000 claims description 2
- 239000000939 antiparkinson agent Substances 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229940125688 antiparkinson agent Drugs 0.000 claims 1
- 208000024891 symptom Diseases 0.000 abstract description 43
- 230000002829 reductive effect Effects 0.000 abstract description 11
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 27
- 230000000694 effects Effects 0.000 description 19
- 208000020016 psychiatric disease Diseases 0.000 description 19
- 230000004054 inflammatory process Effects 0.000 description 17
- 206010061218 Inflammation Diseases 0.000 description 16
- 230000000472 traumatic effect Effects 0.000 description 16
- 208000035475 disorder Diseases 0.000 description 15
- 230000007423 decrease Effects 0.000 description 14
- 230000003247 decreasing effect Effects 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- 230000009429 distress Effects 0.000 description 10
- 238000012216 screening Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 206010019233 Headaches Diseases 0.000 description 9
- 230000006399 behavior Effects 0.000 description 9
- 208000024714 major depressive disease Diseases 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 206010026749 Mania Diseases 0.000 description 8
- 231100000869 headache Toxicity 0.000 description 8
- 230000006735 deficit Effects 0.000 description 7
- 208000024732 dysthymic disease Diseases 0.000 description 7
- 230000002085 persistent effect Effects 0.000 description 7
- 229940044551 receptor antagonist Drugs 0.000 description 7
- 239000002464 receptor antagonist Substances 0.000 description 7
- 208000020401 Depressive disease Diseases 0.000 description 6
- 208000030990 Impulse-control disease Diseases 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 230000003340 mental effect Effects 0.000 description 6
- 208000019906 panic disease Diseases 0.000 description 6
- 230000000306 recurrent effect Effects 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 206010048533 Hypervigilance Diseases 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 238000004088 simulation Methods 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 206010010219 Compulsions Diseases 0.000 description 4
- 206010012374 Depressed mood Diseases 0.000 description 4
- 206010029897 Obsessive thoughts Diseases 0.000 description 4
- 208000028017 Psychotic disease Diseases 0.000 description 4
- 206010041250 Social phobia Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 4
- 208000026345 acute stress disease Diseases 0.000 description 4
- 230000003542 behavioural effect Effects 0.000 description 4
- 150000001557 benzodiazepines Chemical class 0.000 description 4
- 230000036651 mood Effects 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 230000007958 sleep Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 3
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 3
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 3
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 3
- 108091005477 5-HT3 receptors Proteins 0.000 description 3
- 102000035037 5-HT3 receptors Human genes 0.000 description 3
- 206010016754 Flashback Diseases 0.000 description 3
- 208000011688 Generalised anxiety disease Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010022998 Irritability Diseases 0.000 description 3
- DIWRORZWFLOCLC-UHFFFAOYSA-N Lorazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-UHFFFAOYSA-N 0.000 description 3
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 3
- 206010033664 Panic attack Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 230000016571 aggressive behavior Effects 0.000 description 3
- 230000036528 appetite Effects 0.000 description 3
- 235000019789 appetite Nutrition 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000002996 emotional effect Effects 0.000 description 3
- 201000003104 endogenous depression Diseases 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 206010016256 fatigue Diseases 0.000 description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 3
- 208000029364 generalized anxiety disease Diseases 0.000 description 3
- 230000000147 hypnotic effect Effects 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 description 2
- 108091005482 5-HT4 receptors Proteins 0.000 description 2
- MIANLSMIRRRMJS-UHFFFAOYSA-N 5-meo-dmt Chemical compound [CH]1C(OC)=CC=C2N=CC(CCN(C)C)=C21 MIANLSMIRRRMJS-UHFFFAOYSA-N 0.000 description 2
- 229940121683 Acetylcholine receptor antagonist Drugs 0.000 description 2
- 208000000103 Anorexia Nervosa Diseases 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 206010006550 Bulimia nervosa Diseases 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- 206010011469 Crying Diseases 0.000 description 2
- 101150049660 DRD2 gene Proteins 0.000 description 2
- 206010011971 Decreased interest Diseases 0.000 description 2
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 2
- 229940121909 GABA receptor agonist Drugs 0.000 description 2
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 2
- 208000004547 Hallucinations Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 2
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 2
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 2
- 206010029412 Nightmare Diseases 0.000 description 2
- 208000001431 Psychomotor Agitation Diseases 0.000 description 2
- 206010038743 Restlessness Diseases 0.000 description 2
- 208000027520 Somatoform disease Diseases 0.000 description 2
- 102100037346 Substance-P receptor Human genes 0.000 description 2
- 206010042458 Suicidal ideation Diseases 0.000 description 2
- 208000012826 adjustment disease Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 229960004538 alprazolam Drugs 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 239000003420 antiserotonin agent Substances 0.000 description 2
- 230000037007 arousal Effects 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- UAHWPYUMFXYFJY-UHFFFAOYSA-N beta-myrcene Chemical compound CC(C)=CCCC(=C)C=C UAHWPYUMFXYFJY-UHFFFAOYSA-N 0.000 description 2
- 208000014679 binge eating disease Diseases 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000003554 cannabinoid 1 receptor agonist Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960002048 guanfacine Drugs 0.000 description 2
- 239000000938 histamine H1 antagonist Substances 0.000 description 2
- 229960000930 hydroxyzine Drugs 0.000 description 2
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 2
- 206010020765 hypersomnia Diseases 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 230000015654 memory Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 208000015238 neurotic disease Diseases 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 208000027753 pain disease Diseases 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229960001289 prazosin Drugs 0.000 description 2
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000003405 preventing effect Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 2
- 229960004134 propofol Drugs 0.000 description 2
- 229960003712 propranolol Drugs 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 1
- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002869 Anxiety symptoms Diseases 0.000 description 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 208000024254 Delusional disease Diseases 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 description 1
- 206010013496 Disturbance in attention Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 206010066482 Exaggerated startle response Diseases 0.000 description 1
- 206010016275 Fear Diseases 0.000 description 1
- 206010016374 Feelings of worthlessness Diseases 0.000 description 1
- 102000027484 GABAA receptors Human genes 0.000 description 1
- 108091008681 GABAA receptors Proteins 0.000 description 1
- 206010019075 Hallucination, visual Diseases 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000004356 Hysteria Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010021403 Illusion Diseases 0.000 description 1
- 206010022035 Initial insomnia Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 description 1
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000037490 Medically Unexplained Symptoms Diseases 0.000 description 1
- 206010027374 Mental impairment Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 206010027590 Middle insomnia Diseases 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010049816 Muscle tightness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 description 1
- 206010057342 Onychophagia Diseases 0.000 description 1
- 206010052794 Panic disorder with agoraphobia Diseases 0.000 description 1
- 206010033668 Panic disorder without agoraphobia Diseases 0.000 description 1
- 206010033864 Paranoia Diseases 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 206010034719 Personality change Diseases 0.000 description 1
- 208000037048 Prodromal Symptoms Diseases 0.000 description 1
- 206010071368 Psychological trauma Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 206010037213 Psychomotor retardation Diseases 0.000 description 1
- 208000020186 Schizophreniform disease Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 206010064805 Tachyphrenia Diseases 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 1
- 208000028911 Temporomandibular Joint disease Diseases 0.000 description 1
- 206010073746 Thumb sucking Diseases 0.000 description 1
- 208000023655 Tic Diseases 0.000 description 1
- 206010043903 Tobacco abuse Diseases 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 1
- UFLGIAIHIAPJJC-UHFFFAOYSA-N Tripelennamine Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CC=C1 UFLGIAIHIAPJJC-UHFFFAOYSA-N 0.000 description 1
- 208000001407 Vascular Headaches Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 1
- 229960002122 acebutolol Drugs 0.000 description 1
- 229960003792 acrivastine Drugs 0.000 description 1
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000006389 acute stress response Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 208000012761 aggressive behavior Diseases 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 229960004607 alfuzosin Drugs 0.000 description 1
- WNMJYKCGWZFFKR-UHFFFAOYSA-N alfuzosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(C)CCCNC(=O)C1CCCO1 WNMJYKCGWZFFKR-UHFFFAOYSA-N 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- VYBREYKSZAROCT-UHFFFAOYSA-N alpha-myrcene Natural products CC(=C)CCCC(=C)C=C VYBREYKSZAROCT-UHFFFAOYSA-N 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 210000003818 area postrema Anatomy 0.000 description 1
- 229940072698 ativan Drugs 0.000 description 1
- 208000025748 atypical depressive disease Diseases 0.000 description 1
- 229960004574 azelastine Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 238000013542 behavioral therapy Methods 0.000 description 1
- XDNQMQVXDKJOET-UHFFFAOYSA-N benzylbutylbarbiturate Chemical compound C=1C=CC=CC=1CC1(CCCC)C(=O)NC(=O)NC1=O XDNQMQVXDKJOET-UHFFFAOYSA-N 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 208000022266 body dysmorphic disease Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 229960000725 brompheniramine Drugs 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- UZVHFVZFNXBMQJ-UHFFFAOYSA-N butalbital Chemical compound CC(C)CC1(CC=C)C(=O)NC(=O)NC1=O UZVHFVZFNXBMQJ-UHFFFAOYSA-N 0.000 description 1
- 229960002546 butalbital Drugs 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000428 carbinoxamine Drugs 0.000 description 1
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960003564 cyclizine Drugs 0.000 description 1
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 1
- 208000026725 cyclothymic disease Diseases 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229960004253 dexmedetomidine Drugs 0.000 description 1
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960004993 dimenhydrinate Drugs 0.000 description 1
- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 206010013461 dissociative amnesia Diseases 0.000 description 1
- 208000018459 dissociative disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960001389 doxazosin Drugs 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 235000005686 eating Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229940037395 electrolytes Drugs 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- 229960000450 esketamine Drugs 0.000 description 1
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 1
- 229960003745 esmolol Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960001578 eszopiclone Drugs 0.000 description 1
- GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960001690 etomidate Drugs 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 210000004905 finger nail Anatomy 0.000 description 1
- QVNNONOFASOXQV-UHFFFAOYSA-N fospropofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1OCOP(O)(O)=O QVNNONOFASOXQV-UHFFFAOYSA-N 0.000 description 1
- 229960000239 fospropofol Drugs 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 206010021654 increased appetite Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229960003284 iron Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960005209 lofexidine Drugs 0.000 description 1
- KSMAGQUYOIHWFS-UHFFFAOYSA-N lofexidine Chemical compound N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl KSMAGQUYOIHWFS-UHFFFAOYSA-N 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 210000001767 medulla oblongata Anatomy 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 208000002851 paranoid schizophrenia Diseases 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000003236 psychic effect Effects 0.000 description 1
- 230000009430 psychological distress Effects 0.000 description 1
- 230000008433 psychological processes and functions Effects 0.000 description 1
- 230000037047 psychomotor activity Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000003237 recreational drug Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003989 repetitive behavior Effects 0.000 description 1
- 208000013406 repetitive behavior Diseases 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229960004953 silodosin Drugs 0.000 description 1
- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 230000003997 social interaction Effects 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000002630 speech therapy Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000024188 startle response Effects 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- AWLILQARPMWUHA-UHFFFAOYSA-M thiopental sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC([S-])=NC1=O AWLILQARPMWUHA-UHFFFAOYSA-M 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000009898 traumatic memory Effects 0.000 description 1
- 208000002271 trichotillomania Diseases 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 229940072690 valium Drugs 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 229960004010 zaleplon Drugs 0.000 description 1
- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 description 1
- 229940072018 zofran Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- 229960000820 zopiclone Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
Definitions
- tryptamine alkaloids Significant interest in the therapeutic application of tryptamine alkaloids has developed, based upon evidence of possible therapeutic effects in a wide array of clinical applications, including psychiatric conditions, pain disorders, and neurological conditions.
- harnessing the full therapeutic utility of tryptamine alkaloids requires new methods to mitigate side effects while enhancing safety and efficacy associated with tryptamine alkaloid administration.
- the invention features a method of treating a disease or condition in a subject in need thereof, the method including intravenously administering to the subject a continuous infusion of an aqueous solution including an pharmacologically effective amount of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, wherein the continuous infusion is administered at a rate of between 0.7 mg/hr and 30 mg/hr (e.g., 0.7 ⁇ 0.1 mg/hr, 0.8 ⁇ 0.1 mg/hr, 0.9 ⁇ 0.1 mg/hr, 1 ⁇ 0.1 mg/hr, 2 ⁇ 1 mg/hr, 3 ⁇ 1 mg/hr, 4 ⁇ 1 mg/hr, 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 1 mg/hr, 11 ⁇ 1 mg/hr, 12 ⁇ 1 mg/hr, 13 ⁇ 1 mg/hr, 14 ⁇ 1
- the pharmacologically effective amount of the tryptamine alkaloid is administered as a saline solution.
- the tryptamine alkaloid is selected from from N,N-dimethyl tryptamine (DMT), 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N, N-Diethyltryptamine (DET), 4-hydroxy-N, N- diethyltryptamine (4-HO-DET), 4-Hydroxy-N,N"diisopropyUryptamine (4-OH-DiPT), 4-hydroxy-N-methyi-N- isopropyl tryptamine (4-OH-MiPT), O-acetylpsilocin (4-AcO-DMT), and phosphates, acetate esters, or pharmaceutically acceptable salts thereof.
- the invention features a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject a free base equivalent of from 1 mg to 200 mg of a tryptamine alkaloid (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, over a period of between 1 and 60 minutes (e.g., a continuous in
- the invention features a method of treating a disease or condition in a subject in need thereof, the method comprising intranasally administering to the subject an aqueous solution including a free base equivalent of from 1 mg to 200 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.
- a tryptamine alkaloid or
- the tryptamine alkaloid is selected from N,N-dimethyl tryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N, N-Diethyltryptamine (DET), 4-hydroxy-N, N- diethyltryptamine (4-HO-DET), O-acetylpsilocin (4-AcO-DMT), and pharmaceutically acceptable salts thereof.
- DMT N,N-dimethyl tryptamine
- 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine
- DET N, N-Diethyltryptamine
- O-acetylpsilocin 4-AcO-DMT
- the tryptamine alkaloid is DMT or 5-MeO-DMT.
- a free base equivalent of from 30 mg to 200 mg e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg
- the tryptamine alkaloid is administered to the subject over a period of 20 to 60 minutes (e.g., a continuous infusion over about 20 minutes, 30 minutes, 45 minutes, 50 minutes, and 60 minutes).
- a free base equivalent of 56 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over a period of 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
- a free base equivalent of 70 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over a period of 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
- a free base equivalent of from 15 mg to 160 mg e.g., 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg. 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, and 160 ⁇ 10 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 2 to 20 minutes (e.g., a continuous infusion over a period of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- 15 mg to 160 mg e.g., 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg. 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg
- a free base equivalent of 28 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- a free base equivalent of 42 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- a free base equivalent of 56 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- the tryptamine alkaloid is DET, 4-OH-DET, or 4-AcO-DMT.
- a free base equivalent of from 4 mg to 15 mg e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg
- 4 mg to 15 mg e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg
- the tryptamine alkaloid is administered to the subject over a period of 20 to 60 minutes (e.g., a continuous infusion over about 25 minutes, 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
- a free base equivalent of 5.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
- a free base equivalent of 7.5 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
- a free base equivalent of 10.0 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
- a free base equivalent of from 1 mg to 5 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered to the subject over a period of 2 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- a free base equivalent of 4.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- a free base equivalent of 3.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- a free base equivalent of 2.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
- the invention features a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject a pharmacologically effective amount of (i) a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, and (ii) a benzodiazepine, each in an amount that together is effective for the treatment of the disease or condition.
- the invention features, a method of treating a disease or condition in a subject in need thereof, including administering to the subject a timed intravenous infusion of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, wherein (i) the timed intravenous infusion is administered at a free base equivalent rate of between 5 mg/hr and 250 mg/hr (e.g., 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 5 mg/hr, 15 ⁇ 5 mg/hr, 20 ⁇ 5 mg/hr, 25 ⁇ 5 mg/hr, 30 ⁇ 5 mg/hr, 40 ⁇ 5 mg/hr, 45 ⁇ 5 mg/hr, 50 ⁇ 10 mg/hr, 60 ⁇ 10 mg/hr, 70 ⁇ 10 mg/hr, 80 ⁇ 10 mg/hr, 90 ⁇ 10 mg/hr, 100 ⁇ 10 mg/hr, 1 10 ⁇ 10 mg/hr,
- the tryptamine alkaloid infusion or intranasal preparation may be administered in combination with an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic.
- additional agents such as an antiemetic, and/or benzodiazepine are also administered.
- described herein specifically are methods of treating a disease or condition where the disease or condition is chronic pain.
- the method includes administering to the subject a first preparation, the first preparation including a pharmacologically effective amount of an antiemetic agent.
- the antiemetic agent of the first preparation includes a non-selective 5-HT antagonist, 5- HT3 receptor antagonist, 5-HT4 receptor agonist, CB1 agonist, D2 receptor antagonist, D3 receptor antagonist, GABA receptor agonist, H1 receptor antagonist, muscarinic acetylcholine receptor antagonist, NK1 receptor antagonist, or a combination thereof.
- the first preparation includes an intravenous infusion or intranasal preparation of ondansetron.
- the intravenous infusion includes a pharmacologically effective amount of a benzodiazepine.
- the benzodiazepine is 1 ,4-benzodiazepine, 1 ,5- benzodiazepine, 2,3-benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine, pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, or a combination thereof.
- the benzodiazepine includes lorazepam.
- the benzodiazepine is administered in a dosage of between 2 mg and 40 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, 15 ⁇ 1 mg, 16 ⁇ 1 mg, 17 ⁇ 1 mg, 18 ⁇ 1 mg, 19 ⁇ 1 mg, 20 ⁇ 1 mg, 21 ⁇ 1 mg, 22 ⁇ 1 mg, 23 ⁇ 1 mg, 24 ⁇ 1 mg, 25 ⁇ 1 mg, 26 ⁇ 1 mg, 27 ⁇ 1 mg, 28 ⁇ 1 mg, 29 ⁇ 1 mg, 30 ⁇ 1 mg, 31 ⁇ 1 mg, 32 ⁇ 1 mg, 33 ⁇ 1 mg, 34 ⁇ 1 mg, 35 ⁇ 1 mg, 36 ⁇ 1 mg, 37 ⁇ 1 mg, 38 ⁇ 1 mg, and 39 ⁇ 1 mg).
- the lorazepam is administered in a dosage between 2 mg and 4 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, and 4 ⁇ 1 mg).
- the benzodiazepine is diazepam.
- the diazepam is administered in a dosage between 5 mg and 10 mg (e.g., 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, and 10 ⁇ 1 mg).
- the ratio of the tryptamine alkaloid to benzodiazepine is between 10:1 and 1 :5 by weight (e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight) by weight.
- the intravenous infusion or intranasal preparation includes a pharmacologically effective amount of an anesthetic, a sedative, an antiemetic, an anticonvulsant, an antidepressant, an antimigraine, an antipsychotic, an anxiolytic, and/or an antiparkinson.
- intravenous infusion or intranasal preparation includes ondansetron or a pharmaceutically acceptable salt thereof.
- the subject s plasma concentration of 5-MeO-DMT is monitored.
- the intravenous infusion or intranasal preparation including a pharmacologically effective amount of the tryptamine alkaloid is administered at least twice over the course of a month. In some embodiments, the intravenous infusion or intranasal preparation including a pharmacologically effective amount of the tryptamine alkaloid is administered between 2 and 10 times (e.g., 3, 4, 5, 6, 7, 8, and 9 times) over the course of a year.
- the disease or condition being treated a psychological condition.
- the psychological condition is evaluated 1 -8 weeks (e.g., 2, 3, 4, 5, 6, and 7 weeks) after treatment.
- the psychological condition is evaluated 1 week after treatment.
- the psychological condition is evaluated 4 weeks after treatment.
- the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder, an eating disorder, or compulsive behavior.
- the psychological condition is depression.
- the depression is evaluated using the Hamilton Depression Rating Scale (HAM-D).
- the HAM-D score decreases compared to the score before treatment. In particular embodiments, the HAM-D score decreases by 50% compared to the score before treatment.
- the depression is evaluated using the Beck Depression Inventory Scale (BDI).
- BDI Beck Depression Inventory Scale
- the BDI score decreases compared to the score before treatment.
- the BDI score decreases by 50% compared to the score before treatment.
- the depression is evaluated using the Quick Inventory of Depressive Symptomatology (QIDS) score.
- QIDS Quick Inventory of Depressive Symptomatology
- the QIDS score decreases compared to the score before treatment.
- the QIDS score decreases by 50% compared to the score before treatment.
- the depression is evaluated using a Montgomery-Asberg Depression Rating Scale.
- the Montgomery-Asberg Depression Rating Scale score decreases compared to the score before treatment.
- the Montgomery-Asberg Depression Rating Scale score decreases by 50% compared to the score before treatment. In particular embodiments, the Montgomery-Asberg Depression Rating Scale score is less than 10 after treatment.
- the psychological condition is anxiety. In certain embodiments, the anxiety is end of life anxiety, or anxiety of a subject receiving palliative care.
- the disease or condition is a neurological injury, an inflammatory condition, or chronic pain.
- the disease or condition is an inflammatory condition.
- the inflammatory condition is lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
- the inflammatory condition is chronic obstructive pulmonary disease (COPD)), or Alzheimer’s disease.
- the disease or condition is a neurological injury.
- the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury.
- the disease or condition is a chronic pain condition.
- the chronic pain condition results from postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica.
- the chronic pain condition results from trigeminal autonomic cephalalgia.
- trigeminal autonomic cephalalgia is selected from the group consisting of episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).
- the trigeminal autonomic cephalalgia is episodic or chronic CH.
- the method further includes administering to the subject one or more medications for pain relief, including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
- the tryptamine alkaloid is DMT, or a pharmaceutically acceptable salt thereof.
- the tryptamine alkaloid is 4-AcO-DMT, or a pharmaceutically acceptable salt thereof.
- the tryptamine alkaloid is 5-MeO-DMT, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, the tryptamine alkaloid is 4-OH-DiPT or 4- OH-MiPT, or a phosphate, acetate ester, or pharmaceutically acceptable salt thereof.
- the method further includes monitoring the intensity rating by the subject, and in response to the intensity rating further administering to the subject a benzodiazepine to reduce the intensity rating.
- the benzodiazepine can be lorazepam, or any other benzodiazepine described herein.
- the term “about” refers to a value that is within 10% above or below the value being described.
- acute stress disorder and “ASD” refer to a condition that arises as a response to a stressful event or situation of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime).
- acute stress disorder is an anxiety disorder that involves a very specific reaction following exposure to a traumatic event or stressor.
- the duration of acute stress disorder is shorter than that for PTSD, such that the symptoms are present for at least one, two, or three days, but no more than four, five, or six weeks. For individuals exhibiting symptoms persisting for a longer period of time, a diagnosis of PTSD may be warranted.
- administering refers to a method of giving a dosage of a compound or pharmaceutical composition to a subject.
- tryptamine alkaloid refers to N,N-dimethyl tryptamine (DMT), and its derivatives, including O-acetylpsilocin (4-AcO-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), diethyltryptamine (4-OH-DET), 4-hydroxy-N-methyl-N-isopropyltryptamine (4OH-MiPT), and 4-hydroxy- N,N-di-isopropyltryptamine (4-OH-DIPT) as phosphates or acetate esters or as a pharmaceutically acceptable salts thereof.
- continuous infusion refers to an infusion of a drug (e.g., the tryptamine alkaloid or a pharmaceutically acceptable salt thereof) such that the plasma concentration of the drug and/or metabolite does not vary by more than ⁇ 10% for at least 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, or 15 minutes unless the rate of infusion is altered in response to the subject’s intensity rating.
- a drug e.g., the tryptamine alkaloid or a pharmaceutically acceptable salt thereof
- the terms “dosage” and “unit dose” when used in reference to a therapeutic composition refer to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent, i.e., carrier, or vehicle.
- dysthymia or “dysthymic disorder” is meant a chronically depressed mood that occurs for most of the day, more days than not, for at least two years. In children and adolescents, the mood may be irritable rather than depressed, and the required minimum duration is one year. During the two year period (one year for children or adolescents), any symptom-free intervals last no longer than 2 months.
- dysthymia During periods of depressed mood, at least two of the following additional symptoms are present: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration, or difficulty making decisions, and feelings of hopelessness.
- the symptoms cause clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning.
- the diagnosis of dysthymia is not made if: the individual has ever had a manic episode, a mixed episode, a hypomanic episode; has ever met the criteria for a cyclothymic disorder; the depressive symptoms occur exclusively during the course of a chronic psychotic disorder (e.g., schizophrenia); or if the disturbance is due to the direct physiological effects of a substance or a general medical condition.
- a chronic psychotic disorder e.g., schizophrenia
- free base equivalent an amount corresponding to a free base equivalent in a mass of a tryptamine alkaloid salt form.
- a free base equivalent of 1 mg of N,N-dimethyl- tryptamine is equal to 1 mg of N,N-dimethyl-tryptamine in its free base form and equal to 1 .28 mg of N,N- dimethyl-tryptamine in its hydrochloride salt form (e.g., 1 ,0x(240.728/188.269) to account for the mass contribution of the hydrochloride).
- generalized anxiety disorder refers to a condition characterized by excessive anxiety and worry (i.e., apprehensive expectation). Typically, the excessive anxiety and worry occur on more days than not for a period of time (e.g., one, two, three, or four months or more).
- the anxiety and worry can be associated with (i) restlessness, feeling keyed up, or on edge; and/or (ii) muscle tension.
- the anxiety and worry can be associated with (a) a marked avoidance of situations in which a negative outcome could occur; (b) a marked time and effort preparing for situations in which a negative outcome could occur; (c) a marked procrastination in behavior or decision-making due to worries; and (d) repeatedly seeking reassurance due to worries.
- the anxiety, worry, or physical symptoms can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in many, but not necessarily all individuals with GAD.
- the term “intensity rating,” “intensity of experience,” and “intensity of acute subjective effects” refer to the intensity of an experience a subject has after being administered a particular drug measured on a scale from 1 to 10 by subjects. An intensity rating of less than 2 may indicate that it is safe for a subject to leave the clinic. The intensity rating described by the subject is used to determine whether the infusion rate of a drug should be increased, decreased, or remain the same.
- intranasal preparation refers to a tryptamine alkaloid, or pharmaceutically acceptable salt thereof, which may be formulated as a pharmaceutical composition for administration by way of the nasal cavity.
- Obsessive compulsive disorder As used herein, the terms “obsessive compulsive disorder,” “OCD,” and “anxiety and obsessive- compulsive spectrum disorders” refer to a condition characterized by obsessions and/or compulsions. Obsessions are recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that usually cause marked anxiety or distress in which the appetite individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e. , by performing a compulsion).
- Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly.
- the behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive.
- the obsessions or compulsions are time consuming (for example, take more than 1 hour a day), or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
- the term “pharmaceutically acceptable salt” refers to those salts of the compounds described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
- the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic or inorganic acid.
- panic disorder refers to a condition characterized by recurrent and unexpected panic attacks.
- Panic disorder includes both panic disorder with agoraphobia and panic disorder without agoraphobia.
- Subjects with this condition can exhibit one or both of the following: (i) a persistent concern or worry about additional panic attacks or their consequences (e.g., losing control, having a heart attack, going crazy); and/or (ii) significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks), which may include agoraphobic avoidance.
- the terms "pharmacologically effective amount,” “therapeutically effective amount,” and the like, when used in reference to a therapeutic composition refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, such as clinical results.
- these terms refer to an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition.
- the quantity of a given composition described herein that will correspond to such an amount may vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like.
- an “effective amount,” "pharmacologically effective amount,” or the like, of a composition of the present disclosure also include an amount that results in a beneficial or desired result in a subject as compared to a control (e.g., a decrease in the score on the Montgomery-Asberg Depression Rating Scale).
- post traumatic stress disorder and “PTSD” refer to a condition that arises as a delayed and/or protracted response to a stressful event or situation (either short- or long- lasting) of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime).
- Predisposing factors such as personality traits (e.g., compulsive, asthenic) or previous history of neurotic illness may lower the threshold for the development of the condition or aggravate its course, but they are neither necessary nor sufficient to explain its occurrence.
- PTSD is a less frequent and more enduring consequence of psychological trauma than the more frequently seen acute stress response.
- PTSD has been recognized in the past as railway spine, stress syndrome, shell shock, battle fatigue, traumatic war neurosis, and post-traumatic stress syndrome.
- Diagnostic symptoms include re-experiencing original trauma(s), by means of flashbacks or nightmares; avoidance of stimuli associated with the trauma; and increased arousal, such as difficulty falling or staying asleep, anger, and hypervigilance.
- Formal diagnostic criteria DSM-V, DSM-IV, and/or ICD-9 require that the symptoms last more than one month and cause significant impairment in social, occupational, or other important areas of functioning (e.g., problems with work and/or relationships).
- Formal diagnostic criteria can include: (i) intrusion symptoms that are associated with the traumatic event (e.g., (a) spontaneous or cued recurrent, involuntary, and intrusive distressing memories of the traumatic event; (b) recurrent distressing dreams in which the content and/or effect of the dream is related to the event; (c) dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event were recurring (such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings; (d) intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event; and/or (e) marked physiological reactions to reminders of the traumatic event); (ii) persistent avoidance of stimuli associated with the traumatic event (e.g., (a) thoughts, feelings, or physical sensations that arouse recollections of the traumatic event; (b) activities, places, physical reminders, or times (
- Formal diagnostic criteria can further include that the duration of disturbance is more than a certain period of time (e.g., one month, three months, or six months) and that the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
- the condition may show a chronic course over many years and a transition to an enduring personality change.
- the three main symptoms associated with PTSD are (1 ) “reliving” the traumatic event, such as flashbacks, nightmares, intrusive thoughts and recollections, (2) avoidance behaviors and emotional numbing, and (3) hypersensitivity such as an inability to sleep, anxious feelings, overactive startle response, hyperarousal, hypervigilance, irritability, and outbursts of anger.
- psychological disorder and “psychological condition” refer to a condition characterized by a disturbance in one’s emotional or behavioral regulation that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental function.
- Psychological disorders include, but are not limited to depressive disorders (major depression, treatment resistant depression, melancholic depression, atypical depression, or dysthymia), anxiety disorders (end of life anxiety, generalized anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, or social phobia), addictions (e.g., substance abuse, e.g., alcoholism, tobacco abuse, or drug abuse)), eating disorders (e.g., anorexia nervosa, bulimia nervosa, and binge eating disorder) and compulsive behavior disorders (e.g., primary impulse-control disorders or obsessive-compulsive disorder).
- depressive disorders major depression, treatment resistant depression, melancholic depression, atypical depression,
- Psychological disorders can be any psychological condition associated with one or more symptoms, e.g., somatic symptoms (e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause), or psychosomatic symptoms (e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome).
- somatic symptoms e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause
- psychosomatic symptoms e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome.
- Psychological disorders also include repetitive body-focused behaviors, such as tic disorders (e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder).
- tic disorders e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder.
- development of a psychological disorder is associated with or characterized by a prodromal symptom, such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self-esteem, irritability, dependency, self-pity, somatic complaints, decreased effectiveness, helplessness, and decreased initiation of voluntary responses.
- a prodromal symptom such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self-esteem, irritability, dependency
- social phobia and “social anxiety disorder” refer to a condition characterized by fear or anxiety associated with one or more social situations. Subjects with this condition typically exhibit a marked fear or anxiety about one or more social situations in which the person is exposed to possible scrutiny by others. Examples include social interactions (e.g., having a conversation), being observed (e.g., eating or drinking), or performance in front of others (e.g., giving a speech).
- an individual with this condition (i) fears that he or she will act in a way, or show anxiety symptoms that will be negatively evaluated (i.e., be humiliating, embarrassing, lead to rejection, or offend others); (ii) the social situations almost invariably provoke immediate fear or anxiety; (iii) the social situations are avoided or endured with intense fear or anxiety; and (iv) the fear or anxiety is out of proportion to the danger posed by the social situation.
- the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking or refusal to speak in social situations.
- the fear, anxiety, and avoidance can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
- the terms “treat,” “treating,” or “treatment” refer to administration of a compound or pharmaceutical composition for a therapeutic purpose.
- To “treat a disorder” or use for “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease to ameliorate the disease or one or more symptoms thereof to improve the subject’s condition (e.g., by reducing one or more symptoms of inflammation).
- the term “therapeutic” includes the effect of mitigating deleterious clinical effects of certain inflammatory processes (i.e., consequences of the inflammation, rather than the symptoms of inflammation).
- the methods of the invention can be used as a primary prevention measure, i.e., to prevent a condition or to reduce the risk of developing a condition.
- Prevention refers to prophylactic treatment of a subject who may not have fully developed a condition or disorder, but who is susceptible to, or otherwise at risk of, the condition.
- the methods of the invention can be used either for therapeutic or prophylactic purposes.
- unipolar depression or “major depressive disorder” is meant a clinical course that is characterized by one or more major depressive episodes in an individual without a history of manic, mixed, or hypomanic episodes.
- the diagnosis of unipolar depression is not made if: manic, mixed, or hypomanic episodes develop during the course of depression; if the depression is due to the direct physiological effects of a substance; if the depression is due to the direct physiological effects of a general medical condition; if the depression is due to a bereavement or other significant loss (“reactive depression”); or if the episodes are better accounted for by schizoaffective disorder and are not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder.
- depression may be associated with chronic general medical conditions (e.g., diabetes, myocardial infarction, carcinoma, and stroke). Generally, unipolar depression is more severe than dysthymia.
- the essential feature of a major depressive episode is a period of at least two15 weeks during which there is either depressed mood or loss of interest or pleasure in nearly all activities. In children and adolescents, the mood may be irritable rather than sad. The episode may be a single episode or may be recurrent.
- the individual also experiences at least four additional symptoms drawn from a list that includes changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts.
- Each symptom must be newly present or must have clearly worsened compared with the person's pre-episode status.
- the symptoms must persist for most of the day, nearly every day, for at least two consecutive weeks, and the episode must be accompanied by clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, 1994).
- FIG. 1 is a graph showing a simulation for pharmacokinetic data measured as the concentration of N,N-dimethyl tryptamine (DMT) in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 15 minute infusion.
- FIG. 2 is a graph showing a simulation for pharmacokinetic data measured as the concentration of DMT in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 30 minute infusion.
- DMT N,N-dimethyl tryptamine
- FIG. 3 is a graph showing a simulation for pharmacokinetic data measured as the concentration of DMT in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 45 minute infusion.
- the disclosure provides new methods of treating psychological conditions, neurological injuries, pain, cephalic pain (e.g., headache), inflammatory conditions, and anxiety in a subject by utilizing intravenous tryptamine alkaloid infusion formulations or intranasal tryptamine alkaloid preparations.
- the tryptamine alkaloid infusion or intranasal formulation is administered in combination with another therapeutic agent, such as an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic.
- additional agents such as an antiemetic, and/or benzodiazepine can also be administered.
- tryptamine alkaloid Treatment with an infusion or intranasal administration of tryptamine alkaloid can cause profound changes in consciousness that may cause acute transient anxiety and subsequent discomfort to the subject during treatment.
- the psychoactivity of tryptamine alkaloids can include: visual hallucinations and illusions, distortion of the spatial perception and body image, disturbances of the thought and speech, and euphoria.
- the combination therapies of the invention can ameliorate unwanted side effects associated with tryptamine alkaloid therapy, and permit therapies with increased, reduced, or prolonged treatment times that may be required to achieve a therapeutic effect, or an improved therapeutic effect, in a given subject for a given condition.
- the psychological condition may be any psychological condition described herein.
- the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder (PTSD), an eating disorder, or compulsive behavior.
- the psychological condition may be depression.
- the psychological condition may also be anxiety.
- the anxiety may be experienced by a subject who is receiving palliative care or is enrolled in a hospice program.
- the subject who is experiencing anxiety has symptoms such as hypervigilance, fatigue, racing thoughts, irritability, excessive worry, and/or fear.
- a subject may be diagnosed with a psychological condition by a clinician, a physician, or a therapist.
- the subject may be diagnosed with a psychological condition by evaluation of the subject’s symptoms by a physician, clinician, or therapist, based on a physical examination.
- a blood test may be used to evaluate blood concentration levels of certain biomarkers such as hormones, calcium, vitamin D, electrolytes, and iron in diagnosing depression.
- a depression screening test may be performed by the physician, clinician, or therapist to aid in the diagnosis of depression.
- the depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self- Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), or the Montgomery-Asberg Depression Rating Scale (MADRS-C).
- the methods described herein may be used to treat psychosomatic pain conditions.
- the psychosomatic pain condition may be fibromyalgia, chronic fatigue, migraines, or back pain.
- the subject is being treated for depression with the intravenous infusion of the tryptamine alkaloid.
- the subject is being treated for depression with the intranasal preparation of the tryptamine alkaloid.
- the subject may have their symptoms of depression evaluated using a depression screening test.
- the symptoms of depression may be evaluated by a clinician using the Clinical Global Impression (CGI) rating.
- the depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS).
- the subject being treated for depression with the intravenous infusion or intranasal preparation of the tryptamine alkaloid may have their symptoms of depression evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS-C).
- the subject may be evaluated using the MADRS-C by a clinician, physician, or third party rater.
- the subject may self-evaluate using the MADRS.
- the subject’s score obtained using the MADRS-C may be decreased compared to the score before treatment.
- the subject’s score may decreased by at least 50% compared to the score before treatment.
- the subject’s score obtained using the MADRS-C may be less than 10.
- the decrease in the subject’s score using the MADRS-C is decreased for 1 week after treatment.
- the decrease in the subject’s score using the MADRS-C is decreased for 4 weeks after treatment.
- the subject’s score using the MADRS-C is decreased for more than 4 weeks after treatment.
- the subject is being treated for anxiety with an intravenous infusion of the tryptamine alkaloid. In some embodiments, the subject is being treated for anxiety with an intranasal preparation of the tryptamine alkaloid.
- the subject may have their symptoms of anxiety evaluated using an anxiety screening test.
- the anxiety screening test may be the Zung Self-Rating Anxiety Scale, the Hamilton Anxiety Scale, the Beck Anxiety Inventory, the Social Phobia Inventory, the Penn State Worry Questionnaire, the Yale-Brown Obsessive-Compulsive Scale, or the - General Anxiety Disorder-7.
- the subject’s anxiety score using any one of these screening tests decreases in comparison to the subject’s score before receiving treatment.
- the subject’s anxiety score using any one of the above screening tests decreases by 50% in comparison to the subject’s score before receiving treatment.
- the subject meets fewer criteria for anxiety as described by the Diagnostic and Statistical Manual of Mental Disorders in comparison before receiving treatment.
- the methods of the invention are used to treat psychological conditions, e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior, by administering an infusion of the tryptamine alkaloid as needed to treat the symptoms associated with the psychological condition.
- the methods of the invention are used to treat psychological conditions, e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior, by administering an intranasal preparation of the tryptamine alkaloid as needed to treat the symptoms associated with the psychological condition.
- An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloids e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloids over a period of time of between 10 minutes and 1 hour, spaced at least three days, five days, 10 days, or two weeks apart.
- the intensity and/or frequency of the symptoms associated with the psychological disorder can be reduced following treatment with the infused tryptamine alkaloids.
- Another example of this method of treatment is when a subject is being treated with four intranasal administrations of the tryptamine alkaloids, e.g., each administration with a dose of between 1 mg and 200 mg spaced at least two days, five days, seven days, 10 days, or two weeks apart.
- the intensity and/or frequency of the symptoms associated with the psychological disorder can be reduced following treatment with the intranasal tryptamine alkaloids.
- the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
- the neurological injury may be any neurological injury.
- the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury.
- the methods of treating a neurological injury described herein may reduce acute inflammation.
- hippocampal hyperactivity is reduced.
- the methods described herein for treating a neurological injury may be administered in combination with a behavioral, physical, or speech therapy.
- the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury, by administering an infusion of the tryptamine alkaloid as needed to treat pain, inflammation, and/or other symptoms associated with the neurological injury.
- a neurological injury e.g., stroke, traumatic brain injury, and spinal cord injury
- an infusion of the tryptamine alkaloid as needed to treat pain, inflammation, and/or other symptoms associated with the neurological injury.
- An example of this method of treatment is when a subject is being treated with five infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid over a period of time of between 10 minutes and 1 hour, spaced at least two days, five days, seven days, 10 days, or two weeks apart.
- the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
- the intensity and/or frequency of the symptoms associated with the neurological injury can be reduced following treatment with infused the tryptamine alkaloid.
- the treatment can be used to promote neurogenesis and improve cognitive function following a neurological injury.
- the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury, by administering an intranasal preparation of the tryptamine alkaloid as needed to pain, inflammation, and/or other symptoms associated with the neurological injury.
- this method of treatment is when a subject is being treated with four intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage of between 1 mg and 200 mg, spaced at least two days, five days, seven days, 10 days, or two weeks apart.
- the intensity and/or frequency of the symptoms associated with the neurological injury can be reduced following treatment with the intranasal tryptamine alkaloid.
- An inflammatory condition in a subject can be treated with an infusion or intranasal administration of the tryptamine alkaloid using the methods of the invention.
- the inflammatory condition to be treated can be a lung inflammation (e.g., chronic obstructive pulmonary disease (COPD)), neuroinflammation (e.g., Alzheimer’s disease), chronic inflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
- COPD chronic obstructive pulmonary disease
- neuroinflammation e.g., Alzheimer’s disease
- chronic inflammation e.g., rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
- inflammation is treated by administering an infusion of the tryptamine alkaloid as needed to treat (i) acute attacks of inflammation (e.g., inflammatory bowel disease), or (ii) chronic inflammatory conditions (e.g., arthritis).
- An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid or an over a period of time of between 30 minutes and 4 hours, spaced at least three days, five days, 10 days, or two weeks apart.
- the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
- the intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the infused tryptamine alkaloid.
- inflammation is treated by administering an intranasal preparation of the tryptamine alkaloid as needed to treat (i) acute attacks of inflammation (e.g., inflammatory bowel disease), or (ii) chronic inflammatory conditions (e.g., arthritis).
- this method of treatment is when a subject is being treated with three intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage between 1 mg and 200 mg of the tryptamine alkaloid, spaced at least three days, five days, 10 days, or two weeks apart.
- the intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the intranasal tryptamine alkaloid.
- a disorder or condition associated with pain can be treated with an infusion or intranasal preparation of the tryptamine alkaloid using the methods of the invention.
- the pain can be chronic pain, which may result, e.g., from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica.
- the chronic pain may arise from an operation.
- the chronic pain may also be pain associated with a particular disease or condition such as nephropathy, multiple sclerosis, shingles, or complex regional pain syndrome.
- a disorder or condition associated with cephalic pain can be treated with an infusion of the tryptamine alkaloid using the methods of the invention.
- a disorder or condition associated with cephalic pain is a disorder or condition which has as one of its symptoms cephalic/head pain (e.g., headache).
- examples of such disorders or conditions include trigeminal autonomic cephalalgias such as episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).
- CH episodic and chronic cluster headache
- PH episodic and chronic paroxysmal hemicrania
- SUNCT short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing
- vascular headaches e.g., migraine headaches
- tension headaches e.g., headaches associated with the use of a substance (e.g., triptans such as sumatriptan, benzodiazepines such as alprazolam, analgesics such as ibuprofen, ergots such as ergotamine, opioids such as morphine, recreational drugs such as caffeine, nicotine, alcohol, and hormone replacement therapy containing, for example, estrogen) or its
- disorders or conditions associated with cephalic pain include miscellaneous headache unassociated with a structural lesion, headache associated with a nonvascular intracranial disorder, headache associated with a non-cephalic infection, headache associated with a metabolic disorder, headache associated with a disorder of the cranium, neck, eyes, nose, sinuses, teeth, mouth, or other facial or cranial structure, nerve trunk pain and deafferentiation pain.
- the methods of the invention are used to treat chronic pain, e.g., postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica, by administering an infusion or intranasal preparation of the tryptamine alkaloid as needed to treat acute attacks of cephalic pain during the period in which the tryptamine alkaloid is being administered.
- chronic pain e.g., postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica
- An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid over a period of time of between 30 minutes and 1 hour, spaced at least three days, five days, 10 days, or two weeks apart.
- the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
- the intensity and/or frequency of the chronic pain can be reduced following treatment with infused the tryptamine alkaloid.
- the subject being treated for chronic pain is also administered a medication for pain relief including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
- a medication for pain relief including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
- Another example of this method of treatment is when a subject is being treated with three intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage between 1 mg and 200 mg of the tryptamine alkaloid, spaced at least three days, five days, 10 days, or two weeks apart.
- the intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the intranasal tryptamine alkaloid.
- the tryptamine alkaloids that can be used in the methods of the invention include DMT, 4-AcO- DMT, 5-MeO-DMT, 4-OH-DET, 4-OH-DIPT and phosphates, acetate esters, or pharmaceutically acceptable salts thereof.
- Tryptamine alkaloids have a high affinity for 5-HT2A receptor, also known as the serotonin 2A receptor, which plays a key role in regulating mood, sexual behavior, aggression, impulsivity, cognitive function, appetite, pain, sleep, and memory along with other behaviors. As result, tryptamine alkaloids bind to the 5-HT2A receptor mimicking the binding of serotonin.
- This disclosure provides methods for treating a subject having a psychological condition or a neurological injury using an intravenous infusion or intranasal preparation of the tryptamine alkaloid.
- the disclosure provides a method for treating a subject with a psychological condition using an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof.
- the tryptamine alkaloid may be administered as an infusion described herein.
- the rate of infusion may be adjusted so as to minimize adverse side effects and maximize the effectiveness of treatment on the subject’s psychological condition.
- the subject’s plasma concentration of 5- MeO-DMT may be monitored over the course of the infusion.
- the disclosure provides a method for treating a subject with a neurological injury, inflammation, or pain using an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof.
- the tryptamine alkaloid may be administered as an infusion described herein.
- the rate of infusion may be adjusted so as to minimize adverse side effects and maximize the effectiveness of treatment on the subject’s psychological condition.
- the subject’s plasma concentration of 5-MeO-DMT may be monitored over the course of the infusion.
- the disclosure provides a method for treating a subject with a psychological condition using an intranasal preparation of tryptamine alkaloid.
- the tryptamine alkaloid may be administered at a dosage of between 5 mg/hr and 600 mg/hr (e.g., 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 1 mg/hr, 11 ⁇ 1 mg/hr, 12 ⁇ 1 mg/hr, 13 ⁇ 1 mg/hr, 14 ⁇ 1 mg/hr, 15 ⁇ 5 mg/hr, 20 ⁇ 5 mg/hr, 25 ⁇ 5 mg/hr, 30 ⁇ 5 mg/hr, 40 ⁇ 20 mg/hr, 60 ⁇ 20 mg/hr, 80 ⁇ 20 mg/hr, 100 ⁇ 50 mg/hr, 150 ⁇ 50 mg/hr, 200 ⁇ 50 mg/hr, 250 ⁇ 50 mg/hr, 300 ⁇ 50 mg/hr, 350 ⁇ 50 mg/hr
- the tryptamine alkaloid may be administered in a dosage of the free base equivalent of between 1 mg and 200 mg (e.g., (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg).
- 1 mg and 200 mg e.g., (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 30 mg and 200 mg (e.g., (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) over a period of 20 to 60 minutes.
- 30 mg and 200 mg e.g., (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 30 mg and 100 mg (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, and 100 ⁇ 10 mg) over a period of 20 to 60 minutes.
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 100 mg and 200 mg (e.g., 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) over a period of 20 to 60 minutes.
- 100 mg and 200 mg e.g., 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 15 mg and 160 mg (e.g., 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, and 160 ⁇ 10 mg) over a period of 10 to 20 minutes.
- 15 mg and 160 mg e.g., 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, and 160 ⁇ 10 mg
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 15 mg and 50 mg (e.g., 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, and 50 ⁇ 10 mg) over a period of 10 to 20 minutes.
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 50 mg and 100 mg (e.g., 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, and 100 ⁇ 10 mg) over a period of 10 to 20 minutes.
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 4 mg and 15 mg (e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg) over a period of 20 to 60 minutes.
- 4 mg and 15 mg e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 4 mg and 10 mg (e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, and 10 ⁇ 1 mg) over a period of 20 to 60 minutes.
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 10 mg and 15 mg (e.g., 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg) over a period of 20 to 60 minutes.
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 1 mg and 5 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) over a period of 10 to 20 minutes.
- the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 1 mg and 3 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) over a period of 10 to 20 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 3 mg and 5 mg (e.g., 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) over a period of 10 to 20 minutes.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid for the treatment of a disease or condition may be administered at once or twice.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered between 2 and 10 times (e.g., 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, and 10 times).
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered weekly.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered multiple times in one week (e.g., 2 times a week, 3 times a week, 4 times a week, and 5 times a week).
- the infusion or intranasal preparation of tryptamine alkaloid may be administered 2 times a week.
- the infusion or intranasal preparation of tryptamine alkaloid may be administered 3 times a week.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered every two weeks.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered monthly.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may also be administered every 3 months and the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered every 4 months.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered once a year.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered until the subject’s symptoms of their disease or condition are improved compared the subject’s symptoms of depression before being administered treatment.
- the methods for treating a disease or condition described herein include administering to a subject an intravenous infusion or intranasal preparation of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.
- the tryptamine alkaloid infusion or intranasal may be administered in combination with an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic.
- additional agents such as an antiemetic, and/or benzodiazepine are also administered.
- described herein specifically are methods of treating a disease or condition where the disease or condition is chronic pain.
- the subject When the subject is being treated for chronic pain with the tryptamine alkaloid infusion or intranasal the subject may also be administered one or more medications for pain relief, including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
- medications for pain relief including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
- the intravenous tryptamine alkaloid infusion may be administered to a subject in combination with a pharmacologically effective amount of an anxiolytic (e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine).
- anxiolytic e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine
- the intranasal tryptamine alkaloid preparation may be administered to a subject in combination with a pharmacologically effective amount of an anxiolytic (e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine).
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a benzodiazepine.
- the benzodiazepine may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the benzopiazepine may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
- the benzodiazepine and the tryptamine alkaloid infusion or intranasal are administered concurrently.
- the tryptamine alkaloid infusion or intranasal and the benzodiazepine are administered separately.
- the benzodiazepine may be 1 ,4-benzodiazepine, 1 ,5-benzodiazepine, 2,3-benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine, pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, diazepam, midazolam, alprazolam, temazepam, clonazepam or a combination thereof.
- the benzodiazepine is lorazepam.
- Lorazepam is a benzodiazepine medication sold under various trade names including ATIVAN®, ALMAZINE®, and TAVOR®. Lorazepam has various properties, including acting as a sedative, a hypnotic, an amnesiac, and an anxiolytic. Like other benzodiazepines, lorazepam is generally understood to act primarily by enhancing the effect of gamma-aminobutyric acid (GABA) at the GABAA receptor. As the primary inhibitory neurotransmitter, GABA acts to reduce neuronal excitability throughout the nervous system. Compared to other benzodiazepines such as diazepam (valium), lorazepam is substantially more potent and longer acting.
- GABA gamma-aminobutyric acid
- the benzodiazepine is administered in combination with the tryptamine alkaloid infusion or intranasal preparation such that the ratio of tryptamine alkaloid to benzodiazepine is between 10:1 and 1 :5 by weight (e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight).
- 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1
- the benzodiazepine may be administered in a dosage of between 2 mg and 40 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, 10 ⁇ 1 mg, 11 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, 15 ⁇ 1 mg, 16 ⁇ 1 mg, 17 ⁇ 1 mg, 18 ⁇ 1 mg, 19 ⁇ 1 mg, 20 ⁇ 1 mg, 21 ⁇ 1 mg, 22 ⁇ 1 mg, 23 ⁇ 1 mg, 24 ⁇ 1 mg, 25 ⁇ 1 mg, 26 ⁇ 1 mg, 27 ⁇ 1 mg, 28 ⁇ 1 mg, 29 ⁇ 1 mg, 30 ⁇ 1 mg, 31 ⁇ 1 mg, 32 ⁇ 1 mg, 33 ⁇ 1 mg, 34 ⁇ 1 mg, 35 ⁇ 1 mg, 36 ⁇ 1 mg, 37 ⁇ 1 mg, 38 ⁇ 1 mg, and 39 ⁇ 1 mg) in combination with the tryptamine alkaloid infusion or intranasal preparation.
- the benzodiazepine administered may be lorazepam.
- the lorazepam may be administered in a dosage between 2 mg and 4 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, and 4 ⁇ 1 mg).
- the benzodiazepine administered in combination with the tryptamine alkaloid may be diazepam.
- the diazepam may be administered in a dosage between 5 mg and 10 mg (e.g., 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, and 10 ⁇ 1 mg).
- the benzodiazepine may be administered orally, transmucosally (e.g. nasally, buccally, sublingually, vaginally, ocularly, rectally, etc.) intravenously, by inhalation, intramuscular injection, and any other form of delivery
- the benzodiazepine may be administered to the subject to dampen the effects of the tryptamine alkaloid. As a result, the benzodiazepine may decrease the intensity of the experience of the subject being administered the tryptamine alkaloid. Therefore, benzodiazepine may be administered in order to limited, stop, or prevent any negative side effects (such as tryptamine alkaloid-induced anxiety) from the tryptamine alkaloid that the subject may experience.
- any negative side effects such as tryptamine alkaloid-induced anxiety
- the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an antihistamine, which produce sedative effects by blocking the H1 receptor.
- the antihistamine may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the antihistamine may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
- the antihistamine and the tryptamine alkaloid infusion or intranasal are administered concurrently.
- the tryptamine alkaloid infusion or intranasal and the antihistamine are administered separately.
- the antihistamine used in combination with the intravenous tryptamine alkaloid infusion or intranasal may be carbinoxamine, clemastine, dimenhydrinate, pyrilamine, tripelennamine, chlorpheniramine, brompheniramine, hydroxyzine, cyclizine, acrivastine, cetririzine, azelastine, loratadine, fexofenadine, doxepin, diphenhydramine, or a combination thereof, or a pharmaceutically acceptable salt thereof.
- the benzodiazepine is hydroxyzine or a pharmaceutically acceptable salt thereof.
- the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a beta-blocker (e.g., an amount that ameliorates anxiety).
- a beta-blocker e.g., an amount that ameliorates anxiety.
- the beta-blocker may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the beta-blocker may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
- the beta-blocker and the tryptamine alkaloid infusion or intranasal are administered concurrently.
- the tryptamine alkaloid infusion or intranasal and the beta-blocker are administered separately.
- the beta-blocker used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be propranolol, nadolol, timolol, pindolol, labetalol, metroprolol, atenolol, esmolol, and acebutolol, or a combination thereof, or a pharmaceutically acceptable salt thereof.
- the beta-blocker is propranolol, atenolol, or a pharmaceutically acceptable salt thereof.
- the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an alpha blocker (e.g., an amount that ameliorates hypertension).
- the alpha blocker may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the alpha blocker may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
- the alpha blocker and the tryptamine alkaloid infusion or intranasal are administered concurrently.
- the tryptamine alkaloid infusion or intranasal and the alpha blocker are administered separately.
- the alpha blocker used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, clonidine, lofexidine, dexmedetomidine, guanfacine, myrcene, or a combination thereof, or a pharmaceutically acceptable salt thereof.
- the alpha blocker is prazosin, clonidine, guanfacine, or a pharmaceutically acceptable salt thereof.
- the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a sedative (e.g., a sedating amount of a barbiturate, a hypnotic, or a benzodiazepine (described above)).
- a sedative e.g., a sedating amount of a barbiturate, a hypnotic, or a benzodiazepine (described above)
- the sedative may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the sedative may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
- the sedative and the tryptamine alkaloid infusion or intranasal are administered concurrently.
- the sedative used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be a barbituate selected from benzylbutylbarbiturate, butalbital, amobarbital, pentobarbital, secobarbital, sodium thiopental, or phenobarbital; or a hypnotic selected from eszopiclone, zaleplon, zolpidem, or zopiclone, or a combination thereof, or a pharmaceutically acceptable salt thereof.
- the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an anesthetic (e.g., an amount that produces anesthesia).
- the anesthetic may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the anesthetic may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
- the anesthetic and the tryptamine alkaloid infusion or intranasal are administered concurrently.
- the tryptamine alkaloid infusion or intranasal and the anesthetic are administered separately.
- the anesthetic used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be chloral hydrate, ketamine, esketamine, etomidate, propofol, fospropofol, chlorobutanol, or a combination thereof, or a pharmaceutically acceptable salt thereof.
- the anesthetic is propofol or a pharmaceutically acceptable salt thereof.
- the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject having a disease or condition in need of treatment in combination with a pharmacologically effective amount of an antiemetic agent.
- the antiemetic agent may be administered to the subject prior to the tryptamine alkaloid infusion or intranasal.
- the antiemetic agent may be a non-selective 5-HT antagonist, 5-HT3 receptor antagonist, 5-HT4 receptor agonist, CB1 agonist, D2 receptor antagonist, D3 receptor antagonist, GABA receptor agonist, H1 receptor antagonist, muscarinic acetylcholine receptor antagonist, NK1 receptor antagonist, or a combination thereof.
- the antiemetic agent is ondansetron.
- Ondansetron is an antiemetic medication sold under the trade names ZOFRAN® and ONDISSOLVE® in various markets.
- Ondansetron is a 5-HT3 receptor antagonist (a “setron”) generally used in controlling nausea and vomiting in post-operative conditions and in chemotherapy subjects, and as well as for various off-label uses.
- 5-HT3 receptor antagonists bind to and block the 5-HT3 receptor, which is a ligand-gated ion channel found in the vagus nerve and in the area postrema, as well as the in the vomiting center in the medulla oblongata of the brainstem. Synaptic transmission initiated via the 5- HT3 receptor directly mediates the nausea and vomiting reflex.
- a pharmacologically effective amount of an antiemetic agent may be administered to the subject.
- the antiemetic agent may be ondansetron.
- the ondansetron may be administered in a dosage between 4 mg and 8 mg.
- the antiemetic agent is administered as a 4 mg intravenous infusion of ondansetron prior to the tryptamine alkaloid infusion.
- the ondansetron may be administered as a 4 mg intranasal dosage prior to the tryptamine alkaloid intranasal preparation.
- other preparations may be administered to the subject which may vary in dosage form.
- methods of delivery of the antiemetic agent other than intravenous infusion may be utilized, including but not limited to oral delivery, transmucosal (e.g. nasal, buccal, sublingual, vaginal, ocular, rectal, etc.) delivery, inhalatory delivery, intramuscular injection, and any other form of delivery that may achieve administration to the subject of a pharmacologically effective amount of the antiemetic agent.
- transmucosal e.g. nasal, buccal, sublingual, vaginal, ocular, rectal, etc.
- inhalatory delivery e.g., intramuscular injection
- intramuscular injection e.g., intramuscular injection
- antiemetic agents other than ondansetron may be utilized, including but not limited to other setrons, or other antiemetic compounds or preparations.
- the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be contained in any appropriate amount in any suitable carrier substance formulated for intravenous infusion or intranasal administration and is generally present in an amount of 1 -95% by weight of the total weight of the composition. In particular embodiments, the tryptamine alkaloid is present in an amount of 65-95% by weight of the of the total weight of the composition.
- the tryptamine alkaloid for intravenous infusion may be formulated in a saline solution. In certain embodiments, the tryptamine alkaloid for intranasal administration may be formulated in a saline solution.
- compositions for infusion or intranasal use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added.
- the composition may be in the form of a solution, a suspension, an emulsion, an infusion device, a dropper, a pipette, a spray, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
- dosing may be achieved by the subject administering an appropriate, predetermined volume of the solution.
- a spray this may be achieved, for example, by means of a metering atomizing spray pump.
- the composition may include suitable carriers and/or excipients.
- the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release.
- the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents.
- the pharmaceutical compositions of tryptamine alkaloid according to the invention may be in a form suitable for sterile infusion.
- the pharmaceutical compositions of tryptamine alkaloid according to the invention may be in the form of a suitable intranasal preparation.
- the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is dissolved or suspended in a parenterally acceptable liquid vehicle.
- acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution, and isotonic sodium chloride solution.
- the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate).
- preservatives e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate.
- a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like.
- Administration of an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be controlled by a rate of infusion.
- administration of an intranasal preparation of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be controlled by a spray device. This is especially preferred in cases in which the subject receives a dosing regimen that at peak plasma levels can result in side effects.
- the rate of tryptamine alkaloid infusion may be between 5 mg/hr and 600 mg/hr (e.g., 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 1 mg/hr, 11 ⁇ 1 mg/hr, 12 ⁇ 1 mg/hr, 13 ⁇ 1 mg/hr, 14 ⁇ 1 mg/hr, 15 ⁇ 5 mg/hr, 20 ⁇ 5 mg/hr, 25 ⁇ 5 mg/hr, 30 ⁇ 5 mg/hr, 40 ⁇ 20 mg/hr, 60 ⁇ 20 mg/hr, 80 ⁇ 20 mg/hr, 100 ⁇ 50 mg/hr, 150 ⁇ 50 mg/hr, 200 ⁇ 50 mg/hr, 250 ⁇ 50 mg/hr, 300 ⁇ 50 mg/hr, 350 ⁇ 50 mg/hr, 400 ⁇ 50 mg/hr, 450 ⁇ 50 mg/hr, 500 ⁇ 50
- the tryptamine alkaloid infusion may administered in an amount of between from 30 mg to 200 mg (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, over a period of 20 to 60 minutes (e.g., a continuous infusion over about 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
- 30 mg to 200 mg e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg,
- the free base equivalent of the tryptamine alkaloid may be administered to the subject in an amount of between 30 mg and 100 mg (30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, and 100 ⁇ 10 mg) over a period of 30 to 60 minutes.
- the intravenous infusion or intranasal preparation of tryptamine alkaloid is administered in combination with an anxiolytic agent (e.g., benzodiazepine) which may result in a dampening and/or shortening of the intensity of the experience of the subject in comparison to when tryptamine alkaloid alone is administered.
- an anxiolytic agent e.g., benzodiazepine
- the intravenous tryptamine alkaloid infusion is administered in combination with an anxiolytic agent (e.g., benzodiazepine) which may result in intensity rating falling below 2 more quickly than the time the intensity rating takes to fall below 2 when only the tryptamine alkaloid is administered.
- the antiemetic, anxiolytic agent, or pharmaceutically acceptable salt thereof which may be administered in combination with the tryptamine alkaloid infusion may be formulated in any suitable carrier substance and is generally present in an amount of 1 -95% by weight of the total weight of the composition.
- the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof are formulated in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
- the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
- Pharmaceutical compositions according to the invention may be formulated to release the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof, substantially immediately upon administration or at any predetermined time or time period after administration.
- any of the antiemetic and anxiolytic agents described herein may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
- the antiemetic and anxiolytic agents may also be administered parenterally by injection, infusion, or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
- Example 1 Treatment of patients having depression with intravenous infusion of DMT in combination with lorazepam
- Subjects suffering from depression are treated with an intravenous infusion of N,N- dimethyltryptamine (DMT) and lorazepam.
- DMT N,N- dimethyltryptamine
- the subject is first diagnosed with depression by a clinician by using a physical exam, using the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), or conducting an depression screening test such as the Patient Health Questionnaire- 9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS).
- PHQ-9 Patient Health Questionnaire- 9
- BDI Beck Depression Inventory
- CES-D the Zung Self-Rating Depression Scale
- CES-D Center for Epidemiological Studies Depression Scale
- HRSD Hamilton Rating Scale for Depression
- MADRS Montgomery-Asberg Depression Rating Scale
- the subjects are administered a continuous intravenous dosage of DMT with an infusion rate of between 5 mg/hr and 250 mg/hr over a time period of no more than one hour.
- the DMT is co-infused with lorazepam at an infusion rate of between 75 mg/hr and 115 mg/hr.
- the subject is administered a dosage of the DMT and lorazepam combination up to 3 to 4 times a week for a period of 2 weeks.
- DMT/lorazepam infusions can reduce depression in subjects suffering from depression or a condition associated with depression.
- Example 2 Administration of Acetylpsilocin to treat post-traumatic stress disorder with lorazepam
- Subjects suffering from post-traumatic stress disorder are treated with an intravenous infusion of acetylpsilocin (4-AcO-DMT) and lorazepam.
- the subject is first diagnosed by a clinician with post-traumatic stress disorder using a physical exam and the criteria listed in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).
- the subjects are administered a continuous intravenous dosage of 4-AcO-DMT.
- the intensity of the 4-AcO-DMT experienced by the subject is rated by the subject and is monitored throughout administration of the tryptamine alkaloid infusion using the Drug Effects Questionnaire (DEQ).
- DEQ Drug Effects Questionnaire
- the subjects are simultaneously administered the benzodiazepine lorazepam in the same intravenous formulation as the 4-AcO-DMT in a dosage of 2 mg to 4 mg. In other embodiments, the subjects are simultaneously administered the benzodiazepine diazepam in the same intravenous formulation as the 4-AcO-DMT in a dosage of 5 mg to 10 mg.
- the subject is administered the intravenous infusion of 4-AcO-DMT and lorazepam up to 3 times a week for one week.
- the subject’s symptoms associated with post-traumatic stress disorder are evaluated by a clinician using the criteria listed in the DSM-5.
- the subject’s anxiety level is assessed using an anxiety screening test such as the Zung Self-Rating Anxiety Scale, the Hamilton Anxiety Scale, the Beck Anxiety Inventory, or the General Anxiety Disorder-7.
- the subject is capable of adaptive reconsolidation of the subject’s traumatic memory, resulting in a reduction in anxiety, depression, aggression, and/or hypervigilance.
- the subject can experience less anxiety in comparison the amount of anxiety experienced before treatment.
- the clinician may recommend continued treatment.
- the 4-AcO-DMT infusions can reduce the intensity and frequency of PTSD symptoms (e.g., anxiety or depression) in subjects suffering from PTSD.
- Example 3 Administration of 5-methoxy-N,N-dimethyltryptamine to treat eating disorders
- Subjects suffering from an eating disorder are treated with an intravenous infusion of 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT) in combination with the anxiolytic lorazepam.
- the subjects are first diagnosed by a clinician with an eating disorder including anorexia nervosa, bulimia nervosa, and binge eating disorder as having met the criteria listed in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).
- the subjects are administered an intravenous dosage of 5-MeO-DMT.
- the intensity of the 5-MeO-DMT experienced by the subject is rated by the subject and is monitored throughout administration of the 5-MeO-DMT infusion.
- the 5-MeO-DMT infusion is stopped when the patient experiences a negative side effect including vomiting, muscle weakness, dizziness, paranoia, or frightening hallucinations.
- a negative side effect including vomiting, muscle weakness, dizziness, paranoia, or frightening hallucinations.
- the intensity experienced by the subject drops quickly resulting in ending the negative side effects in less than 10 minutes.
- intravenous administration of 5-MeO-DMT is restarted but now with co-administration of an anxiolytic (e.g., lorazepam).
- the subject is administered the intravenous infusion of 5-MeO-DMT and lorazepam up to 3 times a week for two weeks.
- the subject is evaluated by a clinician to identify any changes in the subject’s symptoms associated with an eating disorder.
- the subject may experience fewer of the symptoms described by the criteria for being diagnosed with an eating disorder as described in the DSM- 5 in comparison to the subject’s symptoms before receiving treatment.
- the subject may experience weight gain, fewer purging events per week, fewer binging events per week, or an increase in daily caloric intake as a result of receiving the intravenous 5-MeO-DMT infusion.
- the mean concentration-time profiles of dimethyltryptamine (DMT) was determined from 10 subjects administered an intravenous bolus dose of DMT ranging from 0.05 mg/kg to 0.2 mg/kg and placebo (see, e.g., Strassman RJ and Qualls CR. Arch Gen Psychiatry. 1994; 51 : 85-97). These concentration time profiles were used to simulate concentration-time profiles of several doses of DMT administered as an intravenous infusion at concentrations of 0.2 mg, 0.4 mg, and 0.8 mg over an intravenous infusion time of 15 minutes (FIG. 1 ), 30 minutes (FIG. 2), or 45 minutes (FIG. 3). The relationship between DMT concentration and subjective effects were also derived from this publication. The simulated dosing regimens were selected to maintain concentrations between minimum and maximum efficacious DMT concentration.
- DMT dimethyltryptamine
- Analogous simulations can be performed for other tryptamine alkaloids to assess appropriate dosing levels based upon the PK and PD performance of a particular tryptamine alkaloid.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Methods for treatment for subjects suffering from disease or condition are contemplated as including an administration of an intravenous infusion or intranasal preparation of a pharmaceutically effective amount of a tryptamine alkaloid in combination with a second agent. For example, the intravenous infusion or intranasal preparation of the tryptamine alkaloid may include an additional compound such as a benzodiazepine, preferably lorazepam, administered via a continuous intravenous infusion. Such methods may be seen to better alleviate the symptoms of psychological conditions, neurological injuries, chronic pain, or inflammatory condition, and may result in reduced need for other medications.
Description
METHOD OF TREATMENT BY TRYPTAMINE ALKALOIDS
BACKGROUND OF THE INVENTION
Significant interest in the therapeutic application of tryptamine alkaloids has developed, based upon evidence of possible therapeutic effects in a wide array of clinical applications, including psychiatric conditions, pain disorders, and neurological conditions. However, harnessing the full therapeutic utility of tryptamine alkaloids requires new methods to mitigate side effects while enhancing safety and efficacy associated with tryptamine alkaloid administration. As a result, there remains a need for new methods of administering tryptamine alkaloids along with adjunctive treatments.
SUMMARY OF THE INVENTION
In a first aspect the invention features a method of treating a disease or condition in a subject in need thereof, the method including intravenously administering to the subject a continuous infusion of an aqueous solution including an pharmacologically effective amount of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, wherein the continuous infusion is administered at a rate of between 0.7 mg/hr and 30 mg/hr (e.g., 0.7±0.1 mg/hr, 0.8±0.1 mg/hr, 0.9±0.1 mg/hr, 1 ±0.1 mg/hr, 2±1 mg/hr, 3±1 mg/hr, 4±1 mg/hr, 5±1 mg/hr, 6±1 mg/hr, 7±1 mg/hr, 8±1 mg/hr, 9±1 mg/hr, 10±1 mg/hr, 11 ±1 mg/hr, 12±1 mg/hr, 13±1 mg/hr, 14±1 mg/hr, 15±1 mg/hr, 16±1 mg/hr, 17±1 mg/hr, 18±1 mg/hr, 19±1 mg/hr, 20±1 mg/hr, 21 ±1 mg/hr, 22±1 mg/hr, 23±1 mg/hr, 24±1 mg/hr, 25±1 mg/hr, 26±1 mg/hr, 27±1 mg/hr, 28±1 mg/hr, 29±1 mg/hr, and 30±1 mg/hr) of the tryptamine alkaloid for period of time between 15 minutes and 4 hours (e.g., a continuous infusion for about 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours). In preferred embodiments, the pharmacologically effective amount of the tryptamine alkaloid is administered as a saline solution. In certain embodiments, the tryptamine alkaloid is selected from from N,N-dimethyl tryptamine (DMT), 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N, N-Diethyltryptamine (DET), 4-hydroxy-N, N- diethyltryptamine (4-HO-DET), 4-Hydroxy-N,N"diisopropyUryptamine (4-OH-DiPT), 4-hydroxy-N-methyi-N- isopropyl tryptamine (4-OH-MiPT), O-acetylpsilocin (4-AcO-DMT), and phosphates, acetate esters, or pharmaceutically acceptable salts thereof..
In a related aspect, the invention features a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject a free base equivalent of from 1 mg to 200 mg of a tryptamine alkaloid (e.g., 2±1 mg, 3±1 mg, 4±1 mg, 5±1 mg, 6±1 mg, 7±1 mg, 8±1 mg, 9±1 mg, 10±5 mg, 15±5 mg, 20±5 mg, 25±5 mg, 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 1 10±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, 160±10 mg, 170±10 mg, 180±10 mg, 190±10 mg, and 200±10 mg) or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, over a period of between 1 and 60 minutes (e.g., a continuous infusion for about 5 minutes, 15 minutes, 25 minutes, 35 minutes, 45 minutes, 55 minutes, and 60 minutes).
In another aspect, the invention features a method of treating a disease or condition in a subject in need thereof, the method comprising intranasally administering to the subject an aqueous solution including a free base equivalent of from 1 mg to 200 mg (e.g., 2±1 mg, 3±1 mg, 4±1 mg, 5±1 mg, 6±1 mg, 7±1 mg, 8±1 mg, 9±1 mg, 10±5 mg, 15±5 mg, 20±5 mg, 25±5 mg, 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 110±10 mg, 120±10 mg, 130±10 mg, 140±10
mg, 150±10 mg, 160±10 mg, 170±10 mg, 180±10 mg, 190±10 mg, and 200±10 mg) of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.
In some embodiments, the tryptamine alkaloid is selected from N,N-dimethyl tryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N, N-Diethyltryptamine (DET), 4-hydroxy-N, N- diethyltryptamine (4-HO-DET), O-acetylpsilocin (4-AcO-DMT), and pharmaceutically acceptable salts thereof.
In particular embodiments, the tryptamine alkaloid is DMT or 5-MeO-DMT. In some embodiments, a free base equivalent of from 30 mg to 200 mg (e.g., 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 110±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, 160±10 mg, 170±10 mg, 180±10 mg, 190±10 mg, and 200±10 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 20 to 60 minutes (e.g., a continuous infusion over about 20 minutes, 30 minutes, 45 minutes, 50 minutes, and 60 minutes). In certain embodiments, a free base equivalent of 56±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over a period of 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes). In certain embodiments, a free base equivalent of 70±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over a period of 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes). In some embodiments, a free base equivalent of from 15 mg to 160 mg (e.g., 10±5 mg, 15±5 mg, 20±5 mg. 25±5 mg, 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 1 10±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, and 160±10 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 2 to 20 minutes (e.g., a continuous infusion over a period of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes). In certain embodiments, a free base equivalent of 28±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes). In certain embodiments, a free base equivalent of 42±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes). In some embodiments, a free base equivalent of 56±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
In particular embodiments, the tryptamine alkaloid is DET, 4-OH-DET, or 4-AcO-DMT. In some embodiments, a free base equivalent of from 4 mg to 15 mg (e.g., 4±1 mg, 5±1 mg, 6±1 mg , 7±1 mg, 8±1 mg, 9±1 mg, 10±1 mg, 1 1 ±1 mg, 12±1 mg, 13±1 mg, 14±1 mg, and 15±1 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 20 to 60 minutes (e.g., a continuous infusion over about 25 minutes, 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes). In certain embodiments, a free base equivalent of 5.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes). In certain embodiments, a free base equivalent of 7.5±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over
a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes). In certain embodiments, a free base equivalent of 10.0±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes). In some embodiments, a free base equivalent of from 1 mg to 5 mg (e.g., 2±1 mg, 3±1 mg, 4±1 mg, and 5±1 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 2 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes). In certain embodiments, a free base equivalent of 4.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes). In certain embodiments, a free base equivalent of 3.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes). In certain embodiments, a free base equivalent of 2.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
In another aspect, the invention features a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject a pharmacologically effective amount of (i) a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, and (ii) a benzodiazepine, each in an amount that together is effective for the treatment of the disease or condition. In another aspect, the invention features, a method of treating a disease or condition in a subject in need thereof, including administering to the subject a timed intravenous infusion of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, wherein (i) the timed intravenous infusion is administered at a free base equivalent rate of between 5 mg/hr and 250 mg/hr (e.g., 5±1 mg/hr, 6±1 mg/hr, 7±1 mg/hr, 8±1 mg/hr, 9±1 mg/hr, 10±5 mg/hr, 15±5 mg/hr, 20±5 mg/hr, 25±5 mg/hr, 30±5 mg/hr, 40±5 mg/hr, 45±5 mg/hr, 50±10 mg/hr, 60±10 mg/hr, 70±10 mg/hr, 80±10 mg/hr, 90±10 mg/hr, 100±10 mg/hr, 1 10±10 mg/hr, 120±10 mg/hr, 130±10 mg/hr, 140±10 mg/hr, 150±10 mg/hr, 160±10 mg/hr, 170±10 mg/hr, 180±10 mg/hr, 190±10 mg/hr, 200±10 mg/hr, 210±10 mg/hr, 220±10 mg/hr, 230±10 mg/hr, 240±10 mg/hr, and 250±10 mg/hr) of the tryptamine alkaloid for a period of time between 10 minutes and 60 minutes (e.g., a continuous infusion of about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, and 60 minutes); or (ii) the timed intravenous infusion is administered at a free base equivalent rate of between 10 mg/hr and 600 mg/hr (e.g., 10±1 mg/hr, 1 1 ±1 mg/hr, 12±1 mg/hr, 13±1 mg/hr, 14±1 mg/hr, 15±5 mg/hr, 20±5 mg/hr, 25±5 mg/hr, 30±5 mg/hr, 40±20 mg/hr, 60±20 mg/hr, 80±20 mg/hr, 100±50 mg/hr, 150±50 mg/hr, 200±50 mg/hr, 250±50 mg/hr, 300±50 mg/hr, 350±50 mg/hr, 400±50 mg/hr, 450±50 mg/hr, 500±50 mg/hr, 550±50 mg/hr, and 600±50 mg/hr) of the tryptamine alkaloid for a period of time between 2 minutes and 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
The tryptamine alkaloid infusion or intranasal preparation may be administered in combination with an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic. In certain methods additional agents, such as an antiemetic, and/or benzodiazepine are also administered.
Additionally, described herein specifically are methods of treating a disease or condition where the disease or condition is chronic pain.
In some embodiments, the method includes administering to the subject a first preparation, the first preparation including a pharmacologically effective amount of an antiemetic agent. In certain embodiments, the antiemetic agent of the first preparation includes a non-selective 5-HT antagonist, 5- HT3 receptor antagonist, 5-HT4 receptor agonist, CB1 agonist, D2 receptor antagonist, D3 receptor antagonist, GABA receptor agonist, H1 receptor antagonist, muscarinic acetylcholine receptor antagonist, NK1 receptor antagonist, or a combination thereof. In particular embodiments, the first preparation includes an intravenous infusion or intranasal preparation of ondansetron.
In some embodiments, wherein the intravenous infusion includes a pharmacologically effective amount of a benzodiazepine. In certain embodiments, the benzodiazepine is 1 ,4-benzodiazepine, 1 ,5- benzodiazepine, 2,3-benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine, pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, or a combination thereof. In particular embodiments, the benzodiazepine includes lorazepam. In some embodiments, the benzodiazepine is administered in a dosage of between 2 mg and 40 mg (e.g., 2±1 mg, 3±1 mg, 4±1 mg, 5±1 mg, 6±1 mg, 7±1 mg, 8±1 , 9±1 mg, 10±1 mg, 1 1 ±1 mg, 12±1 mg, 13 ±1 mg, 14±1 mg, 15±1 mg, 16±1 mg, 17±1 mg, 18±1 mg, 19±1 mg, 20±1 mg, 21 ±1 mg, 22±1 mg, 23±1 mg, 24±1 mg, 25±1 mg, 26±1 mg, 27±1 mg, 28±1 mg, 29±1 mg, 30±1 mg, 31 ±1 mg, 32±1 mg, 33±1 mg, 34±1 mg, 35±1 mg, 36±1 mg, 37±1 mg, 38±1 mg, and 39±1 mg). In particular embodiments, the lorazepam is administered in a dosage between 2 mg and 4 mg (e.g., 2±1 mg, 3±1 mg, and 4±1 mg). In certain embodiments, the benzodiazepine is diazepam. In particular embodiments, the diazepam is administered in a dosage between 5 mg and 10 mg (e.g., 5±1 mg, 6±1 mg, 7±1 mg, 8±1 , 9±1 mg, and 10±1 mg). In certain embodiments, the ratio of the tryptamine alkaloid to benzodiazepine is between 10:1 and 1 :5 by weight (e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight) by weight.
In some embodiments, the intravenous infusion or intranasal preparation includes a pharmacologically effective amount of an anesthetic, a sedative, an antiemetic, an anticonvulsant, an antidepressant, an antimigraine, an antipsychotic, an anxiolytic, and/or an antiparkinson. In particular embodiments, intravenous infusion or intranasal preparation includes ondansetron or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject’s plasma concentration of 5-MeO-DMT is monitored.
In some embodiments, the intravenous infusion or intranasal preparation including a pharmacologically effective amount of the tryptamine alkaloid is administered at least twice over the course of a month. In some embodiments, the intravenous infusion or intranasal preparation including a pharmacologically effective amount of the tryptamine alkaloid is administered between 2 and 10 times (e.g., 3, 4, 5, 6, 7, 8, and 9 times) over the course of a year.
In some embodiments, the disease or condition being treated a psychological condition. In certain embodiments, the psychological condition is evaluated 1 -8 weeks (e.g., 2, 3, 4, 5, 6, and 7 weeks) after treatment. In some embodiments, the psychological condition is evaluated 1 week after treatment. In some embodiments, the psychological condition is evaluated 4 weeks after treatment. In certain embodiments, the psychological condition is depression, anxiety, addiction, post-traumatic stress
disorder, an eating disorder, or compulsive behavior. In particular embodiments, the psychological condition is depression. In some embodiments, the depression is evaluated using the Hamilton Depression Rating Scale (HAM-D). In certain embodiments, the HAM-D score decreases compared to the score before treatment. In particular embodiments, the HAM-D score decreases by 50% compared to the score before treatment. In some embodiments, the depression is evaluated using the Beck Depression Inventory Scale (BDI). In certain embodiments, the BDI score decreases compared to the score before treatment. In particular embodiments, the BDI score decreases by 50% compared to the score before treatment. In some embodiments, the depression is evaluated using the Quick Inventory of Depressive Symptomatology (QIDS) score. In certain embodiments, the QIDS score decreases compared to the score before treatment. In some embodiments, the QIDS score decreases by 50% compared to the score before treatment. In certain embodiments, the depression is evaluated using a Montgomery-Asberg Depression Rating Scale. In some embodiments, the Montgomery-Asberg Depression Rating Scale score decreases compared to the score before treatment. In certain embodiments, the Montgomery-Asberg Depression Rating Scale score decreases by 50% compared to the score before treatment. In particular embodiments, the Montgomery-Asberg Depression Rating Scale score is less than 10 after treatment. In some embodiments, the psychological condition is anxiety. In certain embodiments, the anxiety is end of life anxiety, or anxiety of a subject receiving palliative care.
In certain embodiments, the disease or condition is a neurological injury, an inflammatory condition, or chronic pain. In particular embodiments, the disease or condition is an inflammatory condition. In certain embodiments, the inflammatory condition is lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia. In certain embodiments, the inflammatory condition is chronic obstructive pulmonary disease (COPD)), or Alzheimer’s disease. In some embodiments, the disease or condition is a neurological injury. In particular embodiments, the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury. In some embodiments, the disease or condition is a chronic pain condition. In particular embodiments, the chronic pain condition results from postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica. In some embodiments, the chronic pain condition results from trigeminal autonomic cephalalgia. In certain embodiments, trigeminal autonomic cephalalgia is selected from the group consisting of episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). In particular embodiments, the trigeminal autonomic cephalalgia is episodic or chronic CH. In certain embodiments, the method further includes administering to the subject one or more medications for pain relief, including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
In one embodiment of any of the above methods, the tryptamine alkaloid is DMT, or a pharmaceutically acceptable salt thereof.
In particular embodiments of any of the above methods, the tryptamine alkaloid is 4-AcO-DMT, or a pharmaceutically acceptable salt thereof.
In certain embodiments of any of the above methods, the tryptamine alkaloid is 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the above methods, the tryptamine alkaloid is 4-OH-DiPT or 4- OH-MiPT, or a phosphate, acetate ester, or pharmaceutically acceptable salt thereof.
In an embodiment of any of the above aspects, the method further includes monitoring the intensity rating by the subject, and in response to the intensity rating further administering to the subject a benzodiazepine to reduce the intensity rating. The benzodiazepine can be lorazepam, or any other benzodiazepine described herein.
Definitions
To facilitate the understanding of this invention, a number of terms are defined below and throughout the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims.
Terms such as "a", "an," and "the" are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration.
As used herein, the term “about” refers to a value that is within 10% above or below the value being described.
As used herein, the terms “acute stress disorder” and “ASD” refer to a condition that arises as a response to a stressful event or situation of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime). Like PTSD, acute stress disorder is an anxiety disorder that involves a very specific reaction following exposure to a traumatic event or stressor. However, the duration of acute stress disorder is shorter than that for PTSD, such that the symptoms are present for at least one, two, or three days, but no more than four, five, or six weeks. For individuals exhibiting symptoms persisting for a longer period of time, a diagnosis of PTSD may be warranted.
The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a subject.
As used herein, the term “tryptamine alkaloid” refers to N,N-dimethyl tryptamine (DMT), and its derivatives, including O-acetylpsilocin (4-AcO-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), diethyltryptamine (4-OH-DET), 4-hydroxy-N-methyl-N-isopropyltryptamine (4OH-MiPT), and 4-hydroxy- N,N-di-isopropyltryptamine (4-OH-DIPT) as phosphates or acetate esters or as a pharmaceutically acceptable salts thereof.
As used herein, the term “continuous infusion” refers to an infusion of a drug (e.g., the tryptamine alkaloid or a pharmaceutically acceptable salt thereof) such that the plasma concentration of the drug and/or metabolite does not vary by more than ±10% for at least 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, or 15 minutes unless the rate of infusion is altered in response to the subject’s intensity rating.
As used herein, the terms “dosage” and “unit dose” when used in reference to a therapeutic composition refer to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent, i.e., carrier, or vehicle.
By "dysthymia" or "dysthymic disorder" is meant a chronically depressed mood that occurs for most of the day, more days than not, for at least two years. In children and adolescents, the mood may be irritable rather than depressed, and the required minimum duration is one year. During the two year period (one year for children or adolescents), any symptom-free intervals last no longer than 2 months. During periods of depressed mood, at least two of the following additional symptoms are present: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration, or difficulty making decisions, and feelings of hopelessness. The symptoms cause clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning. The diagnosis of dysthymia is not made if: the individual has ever had a manic episode, a mixed episode, a hypomanic episode; has ever met the criteria for a cyclothymic disorder; the depressive symptoms occur exclusively during the course of a chronic psychotic disorder (e.g., schizophrenia); or if the disturbance is due to the direct physiological effects of a substance or a general medical condition. After the initial two-years of dysthymic disorder, major depressive episodes may be superimposed on the dysthymic disorder ("double depression"). Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, I 994. Diagnostic guidance for psychological disorders can be found, for example, in the ICD-10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and the DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).
By "free base equivalent" is meant an amount corresponding to a free base equivalent in a mass of a tryptamine alkaloid salt form. For example, a free base equivalent of 1 mg of N,N-dimethyl- tryptamine is equal to 1 mg of N,N-dimethyl-tryptamine in its free base form and equal to 1 .28 mg of N,N- dimethyl-tryptamine in its hydrochloride salt form (e.g., 1 ,0x(240.728/188.269) to account for the mass contribution of the hydrochloride).
As used herein, the term “generalized anxiety disorder” refers to a condition characterized by excessive anxiety and worry (i.e., apprehensive expectation). Typically, the excessive anxiety and worry occur on more days than not for a period of time (e.g., one, two, three, or four months or more). The anxiety and worry can be associated with (i) restlessness, feeling keyed up, or on edge; and/or (ii) muscle tension. The anxiety and worry can be associated with (a) a marked avoidance of situations in which a negative outcome could occur; (b) a marked time and effort preparing for situations in which a negative outcome could occur; (c) a marked procrastination in behavior or decision-making due to worries; and (d) repeatedly seeking reassurance due to worries. The anxiety, worry, or physical symptoms can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in many, but not necessarily all individuals with GAD.
As used herein, the term “intensity rating,” “intensity of experience,” and “intensity of acute subjective effects” refer to the intensity of an experience a subject has after being administered a particular drug measured on a scale from 1 to 10 by subjects. An intensity rating of less than 2 may indicate that it is safe for a subject to leave the clinic. The intensity rating described by the subject is used to determine whether the infusion rate of a drug should be increased, decreased, or remain the same.
As used herein, the term “intranasal preparation” refers to a tryptamine alkaloid, or pharmaceutically acceptable salt thereof, which may be formulated as a pharmaceutical composition for administration by way of the nasal cavity.
As used herein, the terms “obsessive compulsive disorder,” “OCD,” and “anxiety and obsessive- compulsive spectrum disorders” refer to a condition characterized by obsessions and/or compulsions. Obsessions are recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that usually cause marked anxiety or distress in which the obsessed individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e. , by performing a compulsion). Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly. The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive. Typically, the obsessions or compulsions are time consuming (for example, take more than 1 hour a day), or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts of the compounds described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic or inorganic acid.
As used herein, the term “panic disorder” refers to a condition characterized by recurrent and unexpected panic attacks. Panic disorder includes both panic disorder with agoraphobia and panic disorder without agoraphobia. Subjects with this condition can exhibit one or both of the following: (i) a persistent concern or worry about additional panic attacks or their consequences (e.g., losing control, having a heart attack, going crazy); and/or (ii) significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks), which may include agoraphobic avoidance.
As used herein, the terms "pharmacologically effective amount," "therapeutically effective amount," and the like, when used in reference to a therapeutic composition, refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, such as clinical results. For example, in the context of treating depression, described herein, these terms refer to an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition. The quantity of a given composition described herein that will correspond to such an amount may vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like.
An “effective amount,” "pharmacologically effective amount," or the like, of a composition of the present disclosure, also include an amount that results in a beneficial or desired result in a subject as compared to a control (e.g., a decrease in the score on the Montgomery-Asberg Depression Rating Scale).
As used herein, the terms “post traumatic stress disorder” and “PTSD” refer to a condition that arises as a delayed and/or protracted response to a stressful event or situation (either short- or long- lasting) of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime). Predisposing factors such as personality traits (e.g., compulsive, asthenic) or previous history of neurotic illness may lower the threshold for the development of the condition or aggravate its course, but they are neither necessary nor sufficient to explain its occurrence. PTSD is a less frequent and more enduring consequence of psychological trauma than the more frequently seen acute stress response. PTSD has been recognized in the past as railway spine, stress syndrome, shell shock, battle fatigue, traumatic war neurosis, and post-traumatic stress syndrome. Diagnostic symptoms include re-experiencing original trauma(s), by means of flashbacks or nightmares; avoidance of stimuli associated with the trauma; and increased arousal, such as difficulty falling or staying asleep, anger, and hypervigilance. Formal diagnostic criteria (DSM-V, DSM-IV, and/or ICD-9) require that the symptoms last more than one month and cause significant impairment in social, occupational, or other important areas of functioning (e.g., problems with work and/or relationships). Formal diagnostic criteria can include: (i) intrusion symptoms that are associated with the traumatic event (e.g., (a) spontaneous or cued recurrent, involuntary, and intrusive distressing memories of the traumatic event; (b) recurrent distressing dreams in which the content and/or effect of the dream is related to the event; (c) dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event were recurring (such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings; (d) intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event; and/or (e) marked physiological reactions to reminders of the traumatic event); (ii) persistent avoidance of stimuli associated with the traumatic event (e.g., (a) thoughts, feelings, or physical sensations that arouse recollections of the traumatic event; (b) activities, places, physical reminders, or times (e.g., anniversary reactions) that arouse recollections of the traumatic event; and/or (c) people, conversations, or interpersonal situations that arouse recollections of the traumatic event); (iii) negative alterations in cognitions and mood that are associated with the traumatic event (e.g., (a) inability to remember an important aspect of the traumatic event (typically dissociative amnesia); (b) persistent and exaggerated negative expectations about one’s self, others, or the world; (c) persistent distorted blame of self or others about the cause or consequences of the traumatic event; (d) pervasive negative emotional state (e.g., fear, horror, anger, guilt, or shame); (e) markedly diminished interest or participation in significant activities; (f) feeling of detachment or estrangement from others; and/or (g) persistent inability to experience positive emotions (e.g., unable to have loving feelings, psychic numbing); and (iv) alterations in arousal (i.e., hyperarousal) and reactivity that are associated with the traumatic event (e.g., (a) irritable, angry, or aggressive behavior; (b) reckless or self-destructive behavior; (c) hypervigilance; (d) exaggerated startle response; (e) problems with concentration; and/or (f) sleep disturbance (e.g., difficulty falling or staying asleep, or restless sleep)). Formal diagnostic criteria can further include that the duration of disturbance is more than a certain period
of time (e.g., one month, three months, or six months) and that the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. In a small proportion of subjects, the condition may show a chronic course over many years and a transition to an enduring personality change. The three main symptoms associated with PTSD are (1 ) “reliving” the traumatic event, such as flashbacks, nightmares, intrusive thoughts and recollections, (2) avoidance behaviors and emotional numbing, and (3) hypersensitivity such as an inability to sleep, anxious feelings, overactive startle response, hyperarousal, hypervigilance, irritability, and outbursts of anger.
As used herein, the terms “psychological disorder” and “psychological condition” refer to a condition characterized by a disturbance in one’s emotional or behavioral regulation that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental function. Psychological disorders include, but are not limited to depressive disorders (major depression, treatment resistant depression, melancholic depression, atypical depression, or dysthymia), anxiety disorders (end of life anxiety, generalized anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, or social phobia), addictions (e.g., substance abuse, e.g., alcoholism, tobacco abuse, or drug abuse)), eating disorders (e.g., anorexia nervosa, bulimia nervosa, and binge eating disorder) and compulsive behavior disorders (e.g., primary impulse-control disorders or obsessive-compulsive disorder). Psychological disorders can be any psychological condition associated with one or more symptoms, e.g., somatic symptoms (e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause), or psychosomatic symptoms (e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome). Psychological disorders also include repetitive body-focused behaviors, such as tic disorders (e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder). In some cases, development of a psychological disorder is associated with or characterized by a prodromal symptom, such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self-esteem, irritability, dependency, self-pity, somatic complaints, decreased effectiveness, helplessness, and decreased initiation of voluntary responses.
As used herein, the terms “social phobia” and “social anxiety disorder” refer to a condition characterized by fear or anxiety associated with one or more social situations. Subjects with this condition typically exhibit a marked fear or anxiety about one or more social situations in which the person is exposed to possible scrutiny by others. Examples include social interactions (e.g., having a conversation), being observed (e.g., eating or drinking), or performance in front of others (e.g., giving a speech). Typically, an individual with this condition (i) fears that he or she will act in a way, or show anxiety symptoms that will be negatively evaluated (i.e., be humiliating, embarrassing, lead to rejection, or offend others); (ii) the social situations almost invariably provoke immediate fear or anxiety; (iii) the social situations are avoided or endured with intense fear or anxiety; and (iv) the fear or anxiety is out of proportion to the danger posed by the social situation. In children, the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking or refusal to speak in social situations. The fear, anxiety,
and avoidance can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
As used herein, the terms “treat,” “treating,” or “treatment” refer to administration of a compound or pharmaceutical composition for a therapeutic purpose. To “treat a disorder” or use for “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease to ameliorate the disease or one or more symptoms thereof to improve the subject’s condition (e.g., by reducing one or more symptoms of inflammation). The term “therapeutic” includes the effect of mitigating deleterious clinical effects of certain inflammatory processes (i.e., consequences of the inflammation, rather than the symptoms of inflammation). The methods of the invention can be used as a primary prevention measure, i.e., to prevent a condition or to reduce the risk of developing a condition. Prevention refers to prophylactic treatment of a subject who may not have fully developed a condition or disorder, but who is susceptible to, or otherwise at risk of, the condition. Thus, in the claims and embodiments, the methods of the invention can be used either for therapeutic or prophylactic purposes.
By "unipolar depression" or "major depressive disorder" is meant a clinical course that is characterized by one or more major depressive episodes in an individual without a history of manic, mixed, or hypomanic episodes. The diagnosis of unipolar depression is not made if: manic, mixed, or hypomanic episodes develop during the course of depression; if the depression is due to the direct physiological effects of a substance; if the depression is due to the direct physiological effects of a general medical condition; if the depression is due to a bereavement or other significant loss ("reactive depression"); or if the episodes are better accounted for by schizoaffective disorder and are not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder. If manic, mixed, or hypomanic episodes develop, then the diagnosis is changed to a bipolar disorder. Depression may be associated with chronic general medical conditions (e.g., diabetes, myocardial infarction, carcinoma, and stroke). Generally, unipolar depression is more severe than dysthymia. The essential feature of a major depressive episode is a period of at least two15 weeks during which there is either depressed mood or loss of interest or pleasure in nearly all activities. In children and adolescents, the mood may be irritable rather than sad. The episode may be a single episode or may be recurrent. The individual also experiences at least four additional symptoms drawn from a list that includes changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. Each symptom must be newly present or must have clearly worsened compared with the person's pre-episode status. The symptoms must persist for most of the day, nearly every day, for at least two consecutive weeks, and the episode must be accompanied by clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, 1994). Diagnostic guidance for psychological disorders can be found, for example, in the ICD-10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and the DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).
Other features and advantages of the invention will be apparent from the following Detailed
Description, Examples, Figure, and Claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
FIG. 1 is a graph showing a simulation for pharmacokinetic data measured as the concentration of N,N-dimethyl tryptamine (DMT) in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 15 minute infusion. FIG. 2 is a graph showing a simulation for pharmacokinetic data measured as the concentration of DMT in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 30 minute infusion.
FIG. 3 is a graph showing a simulation for pharmacokinetic data measured as the concentration of DMT in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 45 minute infusion.
DETAILED DESCRIPTION
The disclosure provides new methods of treating psychological conditions, neurological injuries, pain, cephalic pain (e.g., headache), inflammatory conditions, and anxiety in a subject by utilizing intravenous tryptamine alkaloid infusion formulations or intranasal tryptamine alkaloid preparations. The tryptamine alkaloid infusion or intranasal formulation is administered in combination with another therapeutic agent, such as an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic. In certain methods additional agents, such as an antiemetic, and/or benzodiazepine can also be administered.
Treatment with an infusion or intranasal administration of tryptamine alkaloid can cause profound changes in consciousness that may cause acute transient anxiety and subsequent discomfort to the subject during treatment. The psychoactivity of tryptamine alkaloids can include: visual hallucinations and illusions, distortion of the spatial perception and body image, disturbances of the thought and speech, and euphoria.
The combination therapies of the invention can ameliorate unwanted side effects associated with tryptamine alkaloid therapy, and permit therapies with increased, reduced, or prolonged treatment times that may be required to achieve a therapeutic effect, or an improved therapeutic effect, in a given subject for a given condition.
Psychological Conditions
Disclosed herein are methods of treating psychological conditions. The psychological condition may be any psychological condition described herein. In some embodiments the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder (PTSD), an eating disorder, or compulsive behavior. In some embodiments, the psychological condition may be depression. The psychological condition may also be anxiety. The anxiety may be experienced by a subject who is receiving palliative care or is enrolled in a hospice program. In certain embodiments, the subject who is experiencing anxiety has symptoms such as hypervigilance, fatigue, racing thoughts, irritability, excessive worry, and/or fear.
A subject may be diagnosed with a psychological condition by a clinician, a physician, or a therapist. The subject may be diagnosed with a psychological condition by evaluation of the subject’s symptoms by a physician, clinician, or therapist, based on a physical examination. For example, a blood test may be used to evaluate blood concentration levels of certain biomarkers such as hormones, calcium, vitamin D, electrolytes, and iron in diagnosing depression. Additionally, or alternatively, for subjects with a possible depression condition a depression screening test may be performed by the physician, clinician, or therapist to aid in the diagnosis of depression. The depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self- Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), or the Montgomery-Asberg Depression Rating Scale (MADRS-C). In some embodiments, the methods described herein may be used to treat psychosomatic pain conditions. In some embodiments, the psychosomatic pain condition may be fibromyalgia, chronic fatigue, migraines, or back pain.
In particular embodiments, the subject is being treated for depression with the intravenous infusion of the tryptamine alkaloid. In certain embodiments, the subject is being treated for depression with the intranasal preparation of the tryptamine alkaloid. The subject may have their symptoms of depression evaluated using a depression screening test. The symptoms of depression may be evaluated by a clinician using the Clinical Global Impression (CGI) rating. The depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS). The subject being treated for depression with the intravenous infusion or intranasal preparation of the tryptamine alkaloid may have their symptoms of depression evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS-C). In some embodiments, the subject may be evaluated using the MADRS-C by a clinician, physician, or third party rater. In certain embodiments, the subject may self-evaluate using the MADRS. The subject’s score obtained using the MADRS-C may be decreased compared to the score before treatment. The subject’s score may decreased by at least 50% compared to the score before treatment. The subject’s score obtained using the MADRS-C may be less than 10. In some embodiments, the decrease in the subject’s score using the MADRS-C is decreased for 1 week after treatment. In certain embodiments, the decrease in the subject’s score using the MADRS-C is decreased for 4 weeks after treatment. In particular embodiments, the subject’s score using the MADRS-C is decreased for more than 4 weeks after treatment.
In certain embodiments, the subject is being treated for anxiety with an intravenous infusion of the tryptamine alkaloid. In some embodiments, the subject is being treated for anxiety with an intranasal preparation of the tryptamine alkaloid. The subject may have their symptoms of anxiety evaluated using an anxiety screening test. The anxiety screening test may be the Zung Self-Rating Anxiety Scale, the Hamilton Anxiety Scale, the Beck Anxiety Inventory, the Social Phobia Inventory, the Penn State Worry Questionnaire, the Yale-Brown Obsessive-Compulsive Scale, or the - General Anxiety Disorder-7. In some embodiments, the subject’s anxiety score using any one of these screening tests decreases in comparison to the subject’s score before receiving treatment. In certain embodiments, the subject’s anxiety score using any one of the above screening tests decreases by 50% in comparison to the subject’s score before receiving treatment. In particular embodiments, the subject meets fewer criteria
for anxiety as described by the Diagnostic and Statistical Manual of Mental Disorders in comparison before receiving treatment.
In one embodiment, the methods of the invention are used to treat psychological conditions, e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior, by administering an infusion of the tryptamine alkaloid as needed to treat the symptoms associated with the psychological condition. In other embodiments, the methods of the invention are used to treat psychological conditions, e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior, by administering an intranasal preparation of the tryptamine alkaloid as needed to treat the symptoms associated with the psychological condition. An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloids e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloids over a period of time of between 10 minutes and 1 hour, spaced at least three days, five days, 10 days, or two weeks apart. The intensity and/or frequency of the symptoms associated with the psychological disorder can be reduced following treatment with the infused tryptamine alkaloids. Another example of this method of treatment is when a subject is being treated with four intranasal administrations of the tryptamine alkaloids, e.g., each administration with a dose of between 1 mg and 200 mg spaced at least two days, five days, seven days, 10 days, or two weeks apart. The intensity and/or frequency of the symptoms associated with the psychological disorder can be reduced following treatment with the intranasal tryptamine alkaloids. For example, the subject can be treated with a free base equivalent of 10.0±1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
Neurological Injuries
Also disclosed herein are methods of treating a neurological injury. The neurological injury may be any neurological injury. In some embodiments, the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury. The methods of treating a neurological injury described herein may reduce acute inflammation. In certain embodiments, hippocampal hyperactivity is reduced. Also, the methods described herein for treating a neurological injury may be administered in combination with a behavioral, physical, or speech therapy.
In particular embodiments, the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury, by administering an infusion of the tryptamine alkaloid as needed to treat pain, inflammation, and/or other symptoms associated with the neurological injury. An example of this method of treatment is when a subject is being treated with five infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid over a period of time of between 10 minutes and 1 hour, spaced at least two days, five days, seven days, 10 days, or two weeks apart. For example, the subject can be treated with a free base equivalent of 10.0±1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes. The intensity and/or frequency of the symptoms associated with the neurological injury can be reduced following treatment with infused the tryptamine alkaloid. Furthermore, the treatment can be used to promote neurogenesis and improve cognitive function following a neurological injury. In some embodiments, the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury, by administering an intranasal preparation of the tryptamine alkaloid as needed to pain, inflammation, and/or other symptoms
associated with the neurological injury. For example, this method of treatment is when a subject is being treated with four intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage of between 1 mg and 200 mg, spaced at least two days, five days, seven days, 10 days, or two weeks apart. The intensity and/or frequency of the symptoms associated with the neurological injury can be reduced following treatment with the intranasal tryptamine alkaloid.
Inflammatory Conditions
An inflammatory condition in a subject can be treated with an infusion or intranasal administration of the tryptamine alkaloid using the methods of the invention. The inflammatory condition to be treated can be a lung inflammation (e.g., chronic obstructive pulmonary disease (COPD)), neuroinflammation (e.g., Alzheimer’s disease), chronic inflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
In one embodiment, inflammation is treated by administering an infusion of the tryptamine alkaloid as needed to treat (i) acute attacks of inflammation (e.g., inflammatory bowel disease), or (ii) chronic inflammatory conditions (e.g., arthritis). An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid or an over a period of time of between 30 minutes and 4 hours, spaced at least three days, five days, 10 days, or two weeks apart. For example, the subject can be treated with a free base equivalent of 10.0±1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes. The intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the infused tryptamine alkaloid.
In another embodiment, inflammation is treated by administering an intranasal preparation of the tryptamine alkaloid as needed to treat (i) acute attacks of inflammation (e.g., inflammatory bowel disease), or (ii) chronic inflammatory conditions (e.g., arthritis). For example, this method of treatment is when a subject is being treated with three intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage between 1 mg and 200 mg of the tryptamine alkaloid, spaced at least three days, five days, 10 days, or two weeks apart. The intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the intranasal tryptamine alkaloid.
Pain
A disorder or condition associated with pain (e.g., acute or chronic pain of known or unknown origin) can be treated with an infusion or intranasal preparation of the tryptamine alkaloid using the methods of the invention. The pain can be chronic pain, which may result, e.g., from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica. The chronic pain may arise from an operation. The chronic pain may also be pain associated with a particular disease or condition such as nephropathy, multiple sclerosis, shingles, or complex regional pain syndrome. One particular disorder or condition associated with cephalic pain can be treated with an infusion of the tryptamine alkaloid using the methods of the invention. As used herein, a disorder or condition
associated with cephalic pain is a disorder or condition which has as one of its symptoms cephalic/head pain (e.g., headache). Examples of such disorders or conditions include trigeminal autonomic cephalalgias such as episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). Other examples of disorders or conditions that can be treated according to the present invention include vascular headaches (e.g., migraine headaches), tension headaches, headaches associated with the use of a substance (e.g., triptans such as sumatriptan, benzodiazepines such as alprazolam, analgesics such as ibuprofen, ergots such as ergotamine, opioids such as morphine, recreational drugs such as caffeine, nicotine, alcohol, and hormone replacement therapy containing, for example, estrogen) or its withdrawal. Yet additional examples of disorders or conditions associated with cephalic pain include miscellaneous headache unassociated with a structural lesion, headache associated with a nonvascular intracranial disorder, headache associated with a non-cephalic infection, headache associated with a metabolic disorder, headache associated with a disorder of the cranium, neck, eyes, nose, sinuses, teeth, mouth, or other facial or cranial structure, nerve trunk pain and deafferentiation pain.
In one embodiment, the methods of the invention are used to treat chronic pain, e.g., postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica, by administering an infusion or intranasal preparation of the tryptamine alkaloid as needed to treat acute attacks of cephalic pain during the period in which the tryptamine alkaloid is being administered. An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid over a period of time of between 30 minutes and 1 hour, spaced at least three days, five days, 10 days, or two weeks apart. For example, the subject can be treated with a free base equivalent of 10.0±1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes. The intensity and/or frequency of the chronic pain can be reduced following treatment with infused the tryptamine alkaloid. In certain embodiments, the subject being treated for chronic pain is also administered a medication for pain relief including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl. Another example of this method of treatment is when a subject is being treated with three intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage between 1 mg and 200 mg of the tryptamine alkaloid, spaced at least three days, five days, 10 days, or two weeks apart. The intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the intranasal tryptamine alkaloid.
T yptamine Alkaloids
The tryptamine alkaloids that can be used in the methods of the invention include DMT, 4-AcO- DMT, 5-MeO-DMT, 4-OH-DET, 4-OH-DIPT and phosphates, acetate esters, or pharmaceutically acceptable salts thereof.
4-OH-MIPT
Tryptamine alkaloids have a high affinity for 5-HT2A receptor, also known as the serotonin 2A receptor, which plays a key role in regulating mood, sexual behavior, aggression, impulsivity, cognitive function, appetite, pain, sleep, and memory along with other behaviors. As result, tryptamine alkaloids bind to the 5-HT2A receptor mimicking the binding of serotonin. This disclosure provides methods for treating a subject having a psychological condition or a neurological injury using an intravenous infusion or intranasal preparation of the tryptamine alkaloid.
In one aspect, the disclosure provides a method for treating a subject with a psychological condition using an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof. The tryptamine alkaloid may be administered as an infusion described herein. The rate of infusion may be adjusted so as to minimize adverse side effects and maximize the effectiveness of treatment on the subject’s psychological condition. As a result, the subject’s plasma concentration of 5- MeO-DMT may be monitored over the course of the infusion.
In another aspect, the disclosure provides a method for treating a subject with a neurological injury, inflammation, or pain using an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof. The tryptamine alkaloid may be administered as an infusion described herein. The rate of infusion may be adjusted so as to minimize adverse side effects and maximize the
effectiveness of treatment on the subject’s psychological condition. As a result, the subject’s plasma concentration of 5-MeO-DMT may be monitored over the course of the infusion.
In another aspect, the disclosure provides a method for treating a subject with a psychological condition using an intranasal preparation of tryptamine alkaloid. The tryptamine alkaloid may be administered at a dosage of between 5 mg/hr and 600 mg/hr (e.g., 5±1 mg/hr, 6±1 mg/hr, 7±1 mg/hr, 8±1 mg/hr, 9±1 mg/hr, 10±1 mg/hr, 11 ±1 mg/hr, 12±1 mg/hr, 13±1 mg/hr, 14±1 mg/hr, 15±5 mg/hr, 20±5 mg/hr, 25±5 mg/hr, 30±5 mg/hr, 40±20 mg/hr, 60±20 mg/hr, 80±20 mg/hr, 100±50 mg/hr, 150±50 mg/hr, 200±50 mg/hr, 250±50 mg/hr, 300±50 mg/hr, 350±50 mg/hr, 400±50 mg/hr, 450±50 mg/hr, 500±50 mg/hr, 550±50 mg/hr, and 600±50 mg/hr). In some embodiments, the tryptamine alkaloid may be administered in a dosage of the free base equivalent of between 1 mg and 200 mg (e.g., (e.g., 2±1 mg, 3±1 mg, 4±1 mg, 5±1 mg, 6±1 mg, 7±1 mg, 8±1 mg, 9±1 mg, 10±5 mg, 15±5 mg, 20±5 mg, 25±5 mg, 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 110±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, 160±10 mg, 170±10 mg, 180±10 mg, 190±10 mg, and 200±10 mg). In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 30 mg and 200 mg (e.g., (e.g., 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 110±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, 160±10 mg, 170±10 mg, 180±10 mg, 190±10 mg, and 200±10 mg) over a period of 20 to 60 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 30 mg and 100 mg (e.g., 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, and 100±10 mg) over a period of 20 to 60 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 100 mg and 200 mg (e.g., 100±10 mg, 1 10±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, 160±10 mg, 170±10 mg, 180±10 mg, 190±10 mg, and 200±10 mg) over a period of 20 to 60 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 15 mg and 160 mg (e.g., 15±5 mg, 20±5 mg, 25±5 mg, 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 1 10±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, and 160±10 mg) over a period of 10 to 20 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 15 mg and 50 mg (e.g., 15±5 mg, 20±5 mg, 25±5 mg, 30±10 mg, 40±10 mg, and 50±10 mg) over a period of 10 to 20 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 50 mg and 100 mg (e.g., 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, and 100±10 mg) over a period of 10 to 20 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 4 mg and 15 mg (e.g., 4±1 mg, 5±1 mg, 6±1 mg , 7±1 mg, 8±1 mg, 9±1 mg, 10±1 mg, 1 1 ±1 mg, 12±1 mg, 13±1 mg, 14±1 mg, and 15±1 mg) over a period of 20 to 60 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 4 mg and 10 mg (e.g., 4±1 mg, 5±1 mg, 6±1 mg, 7±1 mg, 8±1 mg, 9±1 mg, and 10±1 mg) over a
period of 20 to 60 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 10 mg and 15 mg (e.g., 10±1 mg, 1 1 ±1 mg, 12±1 mg, 13±1 mg, 14±1 mg, and 15±1 mg) over a period of 20 to 60 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 1 mg and 5 mg (e.g., 2±1 mg, 3±1 mg, 4±1 mg, and 5±1 mg) over a period of 10 to 20 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 1 mg and 3 mg (e.g., 2±1 mg, 3±1 mg, 4±1 mg, and 5±1 mg) over a period of 10 to 20 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 3 mg and 5 mg (e.g., 3±1 mg, 4±1 mg, and 5±1 mg) over a period of 10 to 20 minutes.
The intravenous infusion or intranasal preparation of tryptamine alkaloid for the treatment of a disease or condition may be administered at once or twice. In some embodiments, the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered between 2 and 10 times (e.g., 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, and 10 times). In certain embodiments, the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered weekly. In particular embodiments, the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered multiple times in one week (e.g., 2 times a week, 3 times a week, 4 times a week, and 5 times a week). The infusion or intranasal preparation of tryptamine alkaloid may be administered 2 times a week. Also, the infusion or intranasal preparation of tryptamine alkaloid may be administered 3 times a week. In some embodiments, the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered every two weeks. In other embodiments, the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered monthly. The intravenous infusion or intranasal preparation of tryptamine alkaloid may also be administered every 3 months and the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered every 4 months. In particular embodiments, the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered once a year. The intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered until the subject’s symptoms of their disease or condition are improved compared the subject’s symptoms of depression before being administered treatment.
Combination Therapies
The methods for treating a disease or condition described herein include administering to a subject an intravenous infusion or intranasal preparation of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents. The tryptamine alkaloid infusion or intranasal may be administered in combination with an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic. In certain methods additional agents, such as an antiemetic, and/or benzodiazepine are also administered. Additionally, described herein specifically are methods of treating a disease or condition where the disease or condition is chronic pain. When the subject is being treated for chronic pain with the tryptamine alkaloid infusion or intranasal the
subject may also be administered one or more medications for pain relief, including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
Anxiolytics
The intravenous tryptamine alkaloid infusion may be administered to a subject in combination with a pharmacologically effective amount of an anxiolytic (e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine). Furthermore, the intranasal tryptamine alkaloid preparation may be administered to a subject in combination with a pharmacologically effective amount of an anxiolytic (e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine).
The intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a benzodiazepine. The benzodiazepine may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the benzopiazepine may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal. In some embodiments, the benzodiazepine and the tryptamine alkaloid infusion or intranasal are administered concurrently. In certain embodiments, the tryptamine alkaloid infusion or intranasal and the benzodiazepine are administered separately.
The benzodiazepine may be 1 ,4-benzodiazepine, 1 ,5-benzodiazepine, 2,3-benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine, pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, diazepam, midazolam, alprazolam, temazepam, clonazepam or a combination thereof. In some embodiments, the benzodiazepine is lorazepam.
Lorazepam is a benzodiazepine medication sold under various trade names including ATIVAN®, ALMAZINE®, and TAVOR®. Lorazepam has various properties, including acting as a sedative, a hypnotic, an amnesiac, and an anxiolytic. Like other benzodiazepines, lorazepam is generally understood to act primarily by enhancing the effect of gamma-aminobutyric acid (GABA) at the GABAA receptor. As the primary inhibitory neurotransmitter, GABA acts to reduce neuronal excitability throughout the nervous system. Compared to other benzodiazepines such as diazepam (valium), lorazepam is substantially more potent and longer acting.
It may be seen however that other benzodiazepines may be utilized. In some embodiments described herein, the benzodiazepine is administered in combination with the tryptamine alkaloid infusion or intranasal preparation such that the ratio of tryptamine alkaloid to benzodiazepine is between 10:1 and 1 :5 by weight (e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight). The benzodiazepine may be administered in a dosage of between 2 mg and 40 mg (e.g., 2±1 mg, 3±1 mg, 4±1 mg, 5±1 mg, 6±1 mg, 7±1 mg, 8±1 , 9±1 mg, 10±1 mg, 11 ±1 mg, 12±1 mg, 13 ±1 mg, 14±1 mg, 15±1 mg, 16±1 mg, 17±1 mg, 18±1 mg, 19±1 mg, 20±1 mg, 21 ±1 mg, 22±1 mg, 23±1 mg, 24±1 mg, 25±1 mg, 26±1 mg, 27±1 mg, 28±1 mg, 29±1 mg, 30±1 mg, 31 ±1 mg, 32±1 mg, 33±1 mg, 34±1 mg, 35±1 mg, 36±1 mg, 37±1 mg, 38±1 mg, and 39±1 mg) in combination with the tryptamine alkaloid infusion or intranasal preparation. The benzodiazepine administered may be lorazepam. The lorazepam may be administered in a dosage between 2 mg and 4 mg (e.g., 2±1 mg, 3±1 mg, and 4±1 mg). The benzodiazepine administered in combination with the tryptamine alkaloid may be diazepam. The diazepam may be administered in a dosage between 5 mg and 10 mg (e.g., 5±1 mg, 6±1 mg, 7±1 mg, 8±1 , 9±1 mg, and
10±1 mg). The benzodiazepine may be administered orally, transmucosally (e.g. nasally, buccally, sublingually, vaginally, ocularly, rectally, etc.) intravenously, by inhalation, intramuscular injection, and any other form of delivery
The benzodiazepine may be administered to the subject to dampen the effects of the tryptamine alkaloid. As a result, the benzodiazepine may decrease the intensity of the experience of the subject being administered the tryptamine alkaloid. Therefore, benzodiazepine may be administered in order to limited, stop, or prevent any negative side effects (such as tryptamine alkaloid-induced anxiety) from the tryptamine alkaloid that the subject may experience.
Antihistamines
The intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an antihistamine, which produce sedative effects by blocking the H1 receptor. The antihistamine may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the antihistamine may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal. In some embodiments, the antihistamine and the tryptamine alkaloid infusion or intranasal are administered concurrently. In certain embodiments, the tryptamine alkaloid infusion or intranasal and the antihistamine are administered separately. The antihistamine used in combination with the intravenous tryptamine alkaloid infusion or intranasal may be carbinoxamine, clemastine, dimenhydrinate, pyrilamine, tripelennamine, chlorpheniramine, brompheniramine, hydroxyzine, cyclizine, acrivastine, cetririzine, azelastine, loratadine, fexofenadine, doxepin, diphenhydramine, or a combination thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the benzodiazepine is hydroxyzine or a pharmaceutically acceptable salt thereof.
Beta-blockers
The intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a beta-blocker (e.g., an amount that ameliorates anxiety). The beta-blocker may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the beta-blocker may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal. In some embodiments, the beta-blocker and the tryptamine alkaloid infusion or intranasal are administered concurrently. In certain embodiments, the tryptamine alkaloid infusion or intranasal and the beta-blocker are administered separately.
The beta-blocker used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be propranolol, nadolol, timolol, pindolol, labetalol, metroprolol, atenolol, esmolol, and acebutolol, or a combination thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the beta-blocker is propranolol, atenolol, or a pharmaceutically acceptable salt thereof.
Alpha-blockers
The intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an alpha blocker (e.g., an amount that ameliorates hypertension). The alpha blocker may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the alpha blocker may be formulated in a separate
compositon from the tryptamine alkaloid infusion or intranasal. In some embodiments, the alpha blocker and the tryptamine alkaloid infusion or intranasal are administered concurrently. In certain embodiments, the tryptamine alkaloid infusion or intranasal and the alpha blocker are administered separately.
The alpha blocker used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, clonidine, lofexidine, dexmedetomidine, guanfacine, myrcene, or a combination thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the alpha blocker is prazosin, clonidine, guanfacine, or a pharmaceutically acceptable salt thereof.
Sedatives
The intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a sedative (e.g., a sedating amount of a barbiturate, a hypnotic, or a benzodiazepine (described above)). The sedative may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the sedative may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal. In some embodiments, the sedative and the tryptamine alkaloid infusion or intranasal are administered concurrently. In certain embodiments, the tryptamine alkaloid infusion or intranasal and the sedative are administered separately.
The sedative used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be a barbituate selected from benzylbutylbarbiturate, butalbital, amobarbital, pentobarbital, secobarbital, sodium thiopental, or phenobarbital; or a hypnotic selected from eszopiclone, zaleplon, zolpidem, or zopiclone, or a combination thereof, or a pharmaceutically acceptable salt thereof.
Anesthetics
The intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an anesthetic (e.g., an amount that produces anesthesia). The anesthetic may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the anesthetic may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal. In some embodiments, the anesthetic and the tryptamine alkaloid infusion or intranasal are administered concurrently. In certain embodiments, the tryptamine alkaloid infusion or intranasal and the anesthetic are administered separately.
The anesthetic used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be chloral hydrate, ketamine, esketamine, etomidate, propofol, fospropofol, chlorobutanol, or a combination thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the anesthetic is propofol or a pharmaceutically acceptable salt thereof.
Antiemetic Agent
In some embodiments described herein, the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject having a disease or condition in need of treatment in combination with a pharmacologically effective amount of an antiemetic agent. The antiemetic agent may be administered to the subject prior to the tryptamine alkaloid infusion or intranasal. The antiemetic agent may be a non-selective 5-HT antagonist, 5-HT3 receptor antagonist, 5-HT4 receptor agonist, CB1
agonist, D2 receptor antagonist, D3 receptor antagonist, GABA receptor agonist, H1 receptor antagonist, muscarinic acetylcholine receptor antagonist, NK1 receptor antagonist, or a combination thereof. In a preferred embodiment, the antiemetic agent is ondansetron.
Ondansetron is an antiemetic medication sold under the trade names ZOFRAN® and ONDISSOLVE® in various markets. Ondansetron is a 5-HT3 receptor antagonist (a “setron”) generally used in controlling nausea and vomiting in post-operative conditions and in chemotherapy subjects, and as well as for various off-label uses. 5-HT3 receptor antagonists bind to and block the 5-HT3 receptor, which is a ligand-gated ion channel found in the vagus nerve and in the area postrema, as well as the in the vomiting center in the medulla oblongata of the brainstem. Synaptic transmission initiated via the 5- HT3 receptor directly mediates the nausea and vomiting reflex.
According to a presently contemplated method of treating a subject, a pharmacologically effective amount of an antiemetic agent may be administered to the subject. The antiemetic agent may be ondansetron. The ondansetron may be administered in a dosage between 4 mg and 8 mg. In some embodiments, the antiemetic agent is administered as a 4 mg intravenous infusion of ondansetron prior to the tryptamine alkaloid infusion. In particular embodiments, the ondansetron may be administered as a 4 mg intranasal dosage prior to the tryptamine alkaloid intranasal preparation. However, it may be seen that in other embodiments, other preparations may be administered to the subject which may vary in dosage form. For example, methods of delivery of the antiemetic agent other than intravenous infusion may be utilized, including but not limited to oral delivery, transmucosal (e.g. nasal, buccal, sublingual, vaginal, ocular, rectal, etc.) delivery, inhalatory delivery, intramuscular injection, and any other form of delivery that may achieve administration to the subject of a pharmacologically effective amount of the antiemetic agent. Likewise, it may also be seen that antiemetic agents other than ondansetron may be utilized, including but not limited to other setrons, or other antiemetic compounds or preparations.
Pharmaceutical Compositions
For use in the methods and compositions of the invention, the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be contained in any appropriate amount in any suitable carrier substance formulated for intravenous infusion or intranasal administration and is generally present in an amount of 1 -95% by weight of the total weight of the composition. In particular embodiments, the tryptamine alkaloid is present in an amount of 65-95% by weight of the of the total weight of the composition. In some embodiments, the tryptamine alkaloid for intravenous infusion may be formulated in a saline solution. In certain embodiments, the tryptamine alkaloid for intranasal administration may be formulated in a saline solution.
Formulation of infusions and intranasal administration are well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). Compositions for infusion or intranasal use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added. The composition may be in the form of a solution, a suspension, an emulsion, an infusion device, a dropper, a pipette, a spray, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. In the case of a dropper or pipette,
dosing may be achieved by the subject administering an appropriate, predetermined volume of the solution. In the case of a spray, this may be achieved, for example, by means of a metering atomizing spray pump.
Apart from the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, the composition may include suitable carriers and/or excipients. The tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release. Furthermore, the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents.
As indicated above, the pharmaceutical compositions of tryptamine alkaloid according to the invention may be in a form suitable for sterile infusion. Also, as indicated above, the pharmaceutical compositions of tryptamine alkaloid according to the invention may be in the form of a suitable intranasal preparation. To prepare such a composition, the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution, and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate). In cases where one of the compounds is only sparingly or slightly soluble in water, a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like.
Administration of an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be controlled by a rate of infusion. Likewise, administration of an intranasal preparation of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be controlled by a spray device. This is especially preferred in cases in which the subject receives a dosing regimen that at peak plasma levels can result in side effects. For the treatment of psychological conditions, neurological injury, pain, or an inflammatory condition, the rate of tryptamine alkaloid infusion may be between 5 mg/hr and 600 mg/hr (e.g., 5±1 mg/hr, 6±1 mg/hr, 7±1 mg/hr, 8±1 mg/hr, 9±1 mg/hr, 10±1 mg/hr, 11 ±1 mg/hr, 12±1 mg/hr, 13±1 mg/hr, 14±1 mg/hr, 15±5 mg/hr, 20±5 mg/hr, 25±5 mg/hr, 30±5 mg/hr, 40±20 mg/hr, 60±20 mg/hr, 80±20 mg/hr, 100±50 mg/hr, 150±50 mg/hr, 200±50 mg/hr, 250±50 mg/hr, 300±50 mg/hr, 350±50 mg/hr, 400±50 mg/hr, 450±50 mg/hr, 500±50 mg/hr, 550±50 mg/hr, and 600±50 mg/hr). In some embodiments, for the treatment of psychological conditions, neurological injury, pain, or an inflammatory condition, the tryptamine alkaloid infusion may administered in an amount of between from 30 mg to 200 mg (e.g., 30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, 100±10 mg, 110±10 mg, 120±10 mg, 130±10 mg, 140±10 mg, 150±10 mg, 160±10 mg, 170±10 mg, 180±10 mg, 190±10 mg, and 200±10 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, over a period of 20 to 60 minutes (e.g., a continuous infusion over about 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes). For example, the free base equivalent of the tryptamine alkaloid may be administered to the subject in an amount of between 30 mg and 100 mg (30±10 mg, 40±10 mg, 50±10 mg, 60±10 mg, 70±10 mg, 80±10 mg, 90±10 mg, and 100±10 mg) over a period of 30 to 60 minutes.
In some embodiments, the intravenous infusion or intranasal preparation of tryptamine alkaloid is administered in combination with an anxiolytic agent (e.g., benzodiazepine) which may result in a dampening and/or shortening of the intensity of the experience of the subject in comparison to when
tryptamine alkaloid alone is administered. In certain embodiments, the intravenous tryptamine alkaloid infusion is administered in combination with an anxiolytic agent (e.g., benzodiazepine) which may result in intensity rating falling below 2 more quickly than the time the intensity rating takes to fall below 2 when only the tryptamine alkaloid is administered.
The antiemetic, anxiolytic agent, or pharmaceutically acceptable salt thereof which may be administered in combination with the tryptamine alkaloid infusion may be formulated in any suitable carrier substance and is generally present in an amount of 1 -95% by weight of the total weight of the composition. In some embodiments, the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof are formulated in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route. The antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof, may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. Pharmaceutical compositions according to the invention may be formulated to release the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof, substantially immediately upon administration or at any predetermined time or time period after administration.
Any of the antiemetic and anxiolytic agents described herein may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
The antiemetic and anxiolytic agents may also be administered parenterally by injection, infusion, or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.
Example 1 : Treatment of patients having depression with intravenous infusion of DMT in combination with lorazepam
Subjects suffering from depression are treated with an intravenous infusion of N,N- dimethyltryptamine (DMT) and lorazepam. The subject is first diagnosed with depression by a clinician by using a physical exam, using the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), or conducting an depression screening test such as the Patient Health Questionnaire- 9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS). The subjects are administered a continuous intravenous dosage of DMT with an infusion rate of between 5 mg/hr and 250 mg/hr over a time period of no more than one hour. The DMT is co-infused with lorazepam at an infusion rate of
between 75 mg/hr and 115 mg/hr. The subject is administered a dosage of the DMT and lorazepam combination up to 3 to 4 times a week for a period of 2 weeks. After 2 weeks, the subject’s symptoms associated with depression are evaluated using the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), or the score received on the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS). The DMT/lorazepam infusions can reduce depression in subjects suffering from depression or a condition associated with depression.
Example 2: Administration of Acetylpsilocin to treat post-traumatic stress disorder with lorazepam
Subjects suffering from post-traumatic stress disorder (PTSD) are treated with an intravenous infusion of acetylpsilocin (4-AcO-DMT) and lorazepam. The subject is first diagnosed by a clinician with post-traumatic stress disorder using a physical exam and the criteria listed in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5). The subjects are administered a continuous intravenous dosage of 4-AcO-DMT. The intensity of the 4-AcO-DMT experienced by the subject is rated by the subject and is monitored throughout administration of the tryptamine alkaloid infusion using the Drug Effects Questionnaire (DEQ). The subjects are simultaneously administered the benzodiazepine lorazepam in the same intravenous formulation as the 4-AcO-DMT in a dosage of 2 mg to 4 mg. In other embodiments, the subjects are simultaneously administered the benzodiazepine diazepam in the same intravenous formulation as the 4-AcO-DMT in a dosage of 5 mg to 10 mg. The subject is administered the intravenous infusion of 4-AcO-DMT and lorazepam up to 3 times a week for one week.
One week after the first administration of 4-AcO-DMT MT with lorazepam, the subject’s symptoms associated with post-traumatic stress disorder are evaluated by a clinician using the criteria listed in the DSM-5. In particular, the subject’s anxiety level is assessed using an anxiety screening test such as the Zung Self-Rating Anxiety Scale, the Hamilton Anxiety Scale, the Beck Anxiety Inventory, or the General Anxiety Disorder-7. Additionally, as a result of receiving treatment, the subject is capable of adaptive reconsolidation of the subject’s traumatic memory, resulting in a reduction in anxiety, depression, aggression, and/or hypervigilance. As a result of the administration of the 4-AcO-DMT infusion in combination with lorazepam, the subject can experience less anxiety in comparison the amount of anxiety experienced before treatment. Based on the subject’s symptoms associated with post- traumatic stress disorder after receiving treatment in comparison to before receiving treatment, the clinician may recommend continued treatment. The 4-AcO-DMT infusions can reduce the intensity and frequency of PTSD symptoms (e.g., anxiety or depression) in subjects suffering from PTSD.
Example 3: Administration of 5-methoxy-N,N-dimethyltryptamine to treat eating disorders
Subjects suffering from an eating disorder are treated with an intravenous infusion of 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT) in combination with the anxiolytic lorazepam. The subjects are first diagnosed by a clinician with an eating disorder including anorexia nervosa, bulimia nervosa, and binge eating disorder as having met the criteria listed in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5). The subjects are administered an intravenous dosage of 5-MeO-DMT. The intensity of the 5-MeO-DMT experienced by the subject is rated by the subject and is monitored throughout
administration of the 5-MeO-DMT infusion. The 5-MeO-DMT infusion is stopped when the patient experiences a negative side effect including vomiting, muscle weakness, dizziness, paranoia, or frightening hallucinations. As a result of the stopping the infusion of 5-MEO-DMT, the intensity experienced by the subject drops quickly resulting in ending the negative side effects in less than 10 minutes. After the negative side effects have subsided, intravenous administration of 5-MeO-DMT is restarted but now with co-administration of an anxiolytic (e.g., lorazepam). The subject is administered the intravenous infusion of 5-MeO-DMT and lorazepam up to 3 times a week for two weeks. Two weeks after beginning treatment with 5-MeO-DMT the subject is evaluated by a clinician to identify any changes in the subject’s symptoms associated with an eating disorder. The subject may experience fewer of the symptoms described by the criteria for being diagnosed with an eating disorder as described in the DSM- 5 in comparison to the subject’s symptoms before receiving treatment. The subject may experience weight gain, fewer purging events per week, fewer binging events per week, or an increase in daily caloric intake as a result of receiving the intravenous 5-MeO-DMT infusion.
Example 4: Simulations of pharmacokinetic and pharmacodynamic results of dimethyltryptamine infusion
The mean concentration-time profiles of dimethyltryptamine (DMT) was determined from 10 subjects administered an intravenous bolus dose of DMT ranging from 0.05 mg/kg to 0.2 mg/kg and placebo (see, e.g., Strassman RJ and Qualls CR. Arch Gen Psychiatry. 1994; 51 : 85-97). These concentration time profiles were used to simulate concentration-time profiles of several doses of DMT administered as an intravenous infusion at concentrations of 0.2 mg, 0.4 mg, and 0.8 mg over an intravenous infusion time of 15 minutes (FIG. 1 ), 30 minutes (FIG. 2), or 45 minutes (FIG. 3). The relationship between DMT concentration and subjective effects were also derived from this publication. The simulated dosing regimens were selected to maintain concentrations between minimum and maximum efficacious DMT concentration.
Analogous simulations can be performed for other tryptamine alkaloids to assess appropriate dosing levels based upon the PK and PD performance of a particular tryptamine alkaloid.
OTHER EMBODIMENTS
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. This application claims the benefit of U.S. provisional serial no. 63/092,883, filed on October 16, 2020, which is incorporated herein by reference in its entirety.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.
Other embodiments are within the claims.
Claims
1 . A method of treating a disease or condition in a subject in need thereof, the method comprising intravenously administering to the subject a free base equivalent of from 1 mg to 200 mg of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, over a period of between 1 and 60 minutes
2. A method of treating a disease or condition in a subject in need thereof, the method comprising intranasally administering to the subject an aqueous solution including a free base equivalent of from 1 mg to 200 mg of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.
3. The method of claim 1 or claim 2, wherein the tryptamine alkaloid is selected from N,N-dimethyl tryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N, N-Diethyltryptamine (DET), 4- hydroxy-N, N-diethyltryptamine (4-HO-DET), 4-Hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), 4- hydroxy-N-methyl-N-isopropyltryptamine (4-OH-MiPT), O-acetylpsilocin (4-AcO-DMT), and phosphates, acetate esters, or pharmaceutically acceptable salts thereof.
4. The method of claim 3, wherein the tryptamine alkaloid is DMT or 5-MeO-DMT.
5. The method of claim 4, wherein a free base equivalent of from 30 mg to 200 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 20 to 60 minutes.
6. The method of claim 5, wherein a free base equivalent of 56±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes.
7. The method of claim 5, wherein a free base equivalent of 70±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes.
8. The method of claim 4, wherein a free base equivalent of from 15 mg to 160 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 2 to 20 minutes.
9. The method of claim 8, wherein a free base equivalent of 28±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes.
10. The method of claim 8, wherein a free base equivalent of 42±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes.
28
11 . The method of claim 8, wherein a free base equivalent of 56±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes.
12. The method of claim 3, wherein the tryptamine alkaloid is DET, 4-OH-DET, or 4-AcO-DMT.
13. The method of claim 12, wherein a free base equivalent of from 4 mg to 15 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 20 to 60 minutes.
14. The method of claim 13, wherein a free base equivalent of 5.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes.
15. The method of claim 13, wherein a free base equivalent of 7.5±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes.
16. The method of claim 13, wherein a free base equivalent of 10.0±2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 30 to 60 minutes.
17. The method of claim 12, wherein a free base equivalent of from 1 mg to 5 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 2 to 20 minutes.
18. The method of claim 17, wherein a free base equivalent of 4.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes.
19. The method of claim 17, wherein a free base equivalent of 3.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes.
20. The method of claim 17, wherein a free base equivalent of 2.0±1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered over a period of 5 to 20 minutes.
21 . A method of treating a disease or condition in a subject in need thereof, the method comprising intravenously administering to the subject a pharmacologically effective amount of (i) a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, and (ii) a benzodiazepine, each in an amount that together is effective for the treatment of the disease or condition.
22. A method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a timed intravenous infusion of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, wherein (i) the timed intravenous infusion is administered at a free base equivalent rate of between 5 mg/hr and 250 mg/hr of tryptamine alkaloid for a period of time betweenl O minutes and 60 minutes; or (ii) the timed intravenous infusion is administered at a free base equivalent
rate of between 10 mg/hr and 600 mg/hr of tryptamine alkaloid for a period of time between 2 minutes and 20 minutes.
23. The method of any one of claims 1 -20, further comprising to the subject a second therapeutic agent selected from an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic or a combination thereof.
24. The method of any one of claims 1 -23, wherein the method comprises further administering to the subject a pharmacologically effective amount of an antiemetic agent.
25. The method of claim 24, wherein the antiemetic ondansetron is intravenously infused or intranasally administered.
26. The method of any one of claims 1 -25, wherein the intravenous infusion or intranasal preparation comprises a pharmacologically effective amount of a benzodiazepine.
27. The method of claim 26, wherein the benzodiazepine is 1 ,4-benzodiazepine, 1 ,5-benzodiazepine, 2,3-benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine,pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, or a combination thereof.
28. The method of claim 27, wherein the benzodiazepine is lorazepam or diazepam.
29. The method of any one of claims 26-28, wherein the benzodiazepine is administered in a dosage between 2 mg and 10 mg.
30. The method of any one of claims 1 -29, wherein the intravenous infusion or intranasal administration comprises a pharmacologically effective amount of an anesthetic, a sedative, an antiemetic, an anticonvulsant, an antidepressant, an antimigraine, an antipsychotic, an anxiolytic, and/or an antiparkinson agent.
31 . The method of any one of claims 1 -30, wherein the intravenous infusion or intranasal preparation comprises ondansetron or a pharmaceutically acceptable salt thereof.
32. The method of any one of claims 1 -31 , wherein the subject’s plasma concentration of 5-MeO-DMT is monitored.
33. The method of any one of claims 1 -32, wherein the intravenous infusion or intranasal preparation comprising a pharmacologically effective amount of the tryptamine alkaloid is administered at least twice over the course of a month.
34. The method of claim 33, wherein the intravenous infusion or intranasal preparation comprising a pharmacologically effective amount of the tryptamine alkaloid is administered between 2 and 10 times over the course of a year.
35. The method of any one of claims 1 -34, wherein the condition is a psychological condition.
36. The method of claim 35, wherein the psychological condition is evaluated 1 -8 weeks after treatment.
37. The method of claim 36, wherein the psychological condition is evaluated 1 week after treatment.
38. The method of any one of claims 35-37, wherein the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder, an eating disorder, or compulsive behavior.
39. The method of claim 38, wherein the psychological condition is depression.
40. The method of claim 38, wherein the psychological condition is anxiety.
41 . The method of claim 40, wherein the anxiety is of a subject receiving palliative care.
42. The method of any one of claims 1 -34, wherein the disease or condition is a neurological injury, an inflammatory condition, or chronic pain.
43. The method of claim 42, wherein the disease or condition is an inflammatory condition.
44. The method of claim 43, wherein the inflammatory condition is lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
45. The method of claim 43, wherein the inflammatory condition is chronic obstructive pulmonary disease (COPD), or Alzheimer’s disease.
46. The method of claim 43, wherein the disease or condition is a neurological injury.
47. The method of claim 46, wherein the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury.
48. The method of claim 42, wherein the disease or condition is chronic pain.
49. The method of claim 48, wherein the chronic pain results from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica.
50. The method of claim 49, wherein the chronic pain condition results from trigeminal autonomic cephalalgia.
51 . The method of claim 50, wherein the trigeminal autonomic cephalalgia is selected from the group consisting of episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).
52. The method of claim 51 , wherein the trigeminal autonomic cephalalgia is episodic or chronic CH.
53. The method of any one of claims 48-52, further comprising administering to the subject one or more medications for pain relief, comprising morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
54. The method of any one of claims 1 -53, wherein the tryptamine alkaloid is DMT, or a pharmaceutically acceptable salt thereof.
55. The method of any one of claims 1 -53, wherein the tryptamine alkaloid is 4-AcO-DMT, or a pharmaceutically acceptable salt thereof.
56. The method of any one of claims 1 -53, wherein the tryptamine alkaloid is 4-OH-DiPT or 4-OH-MiPT, or a phosphate, acetate ester, or pharmaceutically acceptable salt thereof.
57. The method of any one of claims 1 -53, wherein the tryptamine alkaloid is 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
58. The method of any one of claims 1 -57, further comprising monitoring the intensity rating by the subject, and in response to the intensity rating further administering to the subject a benzodiazepine to reduce the intensity rating.
32
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063092883P | 2020-10-16 | 2020-10-16 | |
US63/092,883 | 2020-10-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022082058A1 true WO2022082058A1 (en) | 2022-04-21 |
Family
ID=81209396
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2021/055301 WO2022082058A1 (en) | 2020-10-16 | 2021-10-15 | Method of treatment by tryptamine alkaloids |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022082058A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023230303A1 (en) * | 2022-05-27 | 2023-11-30 | Lerer Leonard | Treatment of cognitive decline related to anesthesia and sedation |
US11905535B2 (en) | 2019-10-01 | 2024-02-20 | Empyrean Nueroscience, Inc. | Genetic engineering of fungi to modulate tryptamine expression |
US12012381B2 (en) | 2021-12-30 | 2024-06-18 | Atai Therapeutics, Inc. | Dimethyltryptamine analogues as nitric oxide delivery drugs |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4571395A (en) * | 1980-01-21 | 1986-02-18 | Burroughs Wellcome Co. | Lorazepam and bupropion, compositions and methods |
US20130302357A1 (en) * | 2009-02-05 | 2013-11-14 | Wei Li | Novel benzodiazepine derivatives |
US20190350949A1 (en) * | 2017-01-18 | 2019-11-21 | Procare Beheer B.V. | Psilocybin and/or psilocin in combination with cannabinoids and/or terpenes |
WO2020169850A1 (en) * | 2019-02-22 | 2020-08-27 | Gh Research Limited | 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) for treating depression |
-
2021
- 2021-10-15 WO PCT/US2021/055301 patent/WO2022082058A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4571395A (en) * | 1980-01-21 | 1986-02-18 | Burroughs Wellcome Co. | Lorazepam and bupropion, compositions and methods |
US20130302357A1 (en) * | 2009-02-05 | 2013-11-14 | Wei Li | Novel benzodiazepine derivatives |
US20190350949A1 (en) * | 2017-01-18 | 2019-11-21 | Procare Beheer B.V. | Psilocybin and/or psilocin in combination with cannabinoids and/or terpenes |
WO2020169850A1 (en) * | 2019-02-22 | 2020-08-27 | Gh Research Limited | 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) for treating depression |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11905535B2 (en) | 2019-10-01 | 2024-02-20 | Empyrean Nueroscience, Inc. | Genetic engineering of fungi to modulate tryptamine expression |
US12012381B2 (en) | 2021-12-30 | 2024-06-18 | Atai Therapeutics, Inc. | Dimethyltryptamine analogues as nitric oxide delivery drugs |
WO2023230303A1 (en) * | 2022-05-27 | 2023-11-30 | Lerer Leonard | Treatment of cognitive decline related to anesthesia and sedation |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022082058A1 (en) | Method of treatment by tryptamine alkaloids | |
US20230277568A1 (en) | Method of treatment for psilocybin or psilocin infusion | |
US10716950B2 (en) | Treatment of thalamocortical dysrhythmia | |
Mihaljević et al. | Therapeutic mechanisms of ketamine | |
US20060122127A1 (en) | Methods for reducing the side effects associated with mirtzapine treatment | |
US20060252761A1 (en) | Augmentation of extinction via administration of sub-antimicrobial doses of D-cycloserine | |
US9782404B2 (en) | Methods of treating disease-induced ataxia and non-ataxic imbalance | |
US20230347101A1 (en) | Method for treatment of depression using synaptic pathway training | |
KR20160128466A (en) | Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction | |
US20210008039A1 (en) | Promoting sleep using at1 receptor blockers | |
CN100386070C (en) | Pharmaceutical formulation comprising melatonin | |
WO2023137094A1 (en) | Psilocin benzoate formulation for intravenous infusion | |
CN111801096B (en) | Therapeutic agent for epilepsy | |
EP1534289B1 (en) | Adenosine a2a receptor antagonists for treating restless legs syndrome or nocturnal myoclonus | |
RU2665629C1 (en) | Method of treatment of alcoholism | |
Lavigne et al. | Mechanisms associated with unusual orofacial pain. | |
Mohamed et al. | Fentanyl versus midazolam as additive to local anesthetic mixture for peribulbar block during posterior segment surgery in adult patients a prospective randomized double-blind study | |
US20230096856A1 (en) | Combined treatment regimen of anesthesia/sedation with administration of psychedelic drugs associated with reduction in neuropsychiatric illness | |
Abdalla Mohamed et al. | Fentanyl versus midazolam as additive to local anesthetic mixture for peribulbar block during posterior segment surgery in adult patients a prospective randomized double-blind study | |
CN106963763A (en) | Compound and its medical usage | |
Enache et al. | Pain in otorhinolaryngology | |
WO2019182474A1 (en) | Buspirone combinations for treating dizziness | |
Creel et al. | Pharmacology of Antiemetics | |
AIDS | NERVOUS SYSTEM DISORDERS 1023 CMDT 2013 | |
Todtenkopf et al. | Buprenorphine in Combination with Samidorphan (ALKS 33) Results in Antidepressive-Like Effects in Two Distinct Rat Models |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21881234 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21881234 Country of ref document: EP Kind code of ref document: A1 |