WO2020115750A1

WO2020115750A1 - Cannabis-based compositions for the treatment of migraine and headache

Info

Publication number: WO2020115750A1
Application number: PCT/IL2019/051332
Authority: WO
Inventors: Lihi BAR-LEV SCHLEIDER; Sid TAUBENFELD
Original assignee: To Pharmaceuticals Llc
Priority date: 2018-12-06
Filing date: 2019-12-05
Publication date: 2020-06-11

Abstract

The invention relates to therapeutic products and methods applicable to the treatment of headache and migraine in particular. To that end, the products and methods of the invention apply certain type of cannabis-based compositions with a high content THC and a low content of all other cannabinoids, provided under specific dose regimens and modes of administration.

Description

CANNABIS-BASED COMPOSITIONS FOR THE TREATMENT OF

MIGRAINE AND HEADACHE

TECHNOLOGICAL FIELD

The present invention generally relates to therapeutic products and methods applicable to the treatment of headache and migraine, and specifically those using certain cannabis-based preparations.

BACKGROUND

Clinical value of cannabis is well documented in the medical literature. Cannabinoids, the active ingredients of cannabis, are present in significantly higher concentrations in resin- producing pistillate inflorescences of cannabis plants. Various types of cannabis, such as C. Sativa, C. Indica and C. Ruder alis, may contain more than 100 different types of cannabinoids in distinct concentrations and proportions. The two predominant types, the tetrahydrocannabinol (THC) and cannabidiol (CBD), have been related to a number of clinically beneficial effects attributed to their analgesic, antiemetic, antioxidative, neuroprotective and anti-inflammatory activities in mammals and humans.

The mammalian endocannabinoid system is a signal transduction system acting predominantly in the brain, and also in the peripheral tissues. Several cannabinoid receptors have been identified so far, the most prominent being the cannabinoid receptors types 1 and 2 (CB₁ and CB₂). The endocannabinoid system has been implicated in maintenance of pain, appetite, memory, immunity and inflammation, among others. This underlies the notion of high therapeutic potential of exogenous cannabinoids and cannabis-based medicines, and the likelihood of their broad clinical applications. However, a rationalized use of cannabinoids still imposes significant challenges due to lack of significant controlled clinical trials.

A number of oral formulations of cannabinoids are commercially available today by prescription for specific indications. Marinol capsules containing dronabinol, a synthetic D⁹- THC isoform, in oil - were approved in a number of countries as an antiemetic in cancer patients under chemotherapy and in patients with AIDS. Cesamet capsules with a synthetic THC analog were approved as a Marinol substitute. Additional formulations such as Namisol and Arvisol tablets with pure THC and pure CBD, respectively, are now under clinical trial for various indications. More recently, orphan cannabis-derived compositions such as Sativex have been approved for spasticity in multiple sclerosis and Epidolex - for rare forms of epilepsy. The invention is relevant to a group of conditions collectively named headache, Headache is an almost universal human experience, being one of the most common complaints encountered in medicine and neurology. References to headache, migraine, and neuralgia have been traced to most ancient texts and relics.

Lifelong prevalence of headache is 96%, with a female predominance. The global active prevalence of tension-type headache (TTH) is approximately 40% and migraine 10%. Migraine occurs most commonly between the ages of 25 and 55 years and is 3 times more common in women.Despite the fact that it causes significant disability, migraine remains underdiagnosed and undertreated. Chronic daily headaches of long duration include chronic migraine, chronic TTH, hemicrania continua and new daily persistent headache. Worldwide prevalence of chronic daily headache has been consistent at 3%-5%, most of which likely represents chronic migraine.

The etiology of headache is heterogeneous and complex. By the most general classification, headache is classified into primary and secondary headaches, the latter being the result of another condition causing traction or inflammation of pain-sensitive structures. Therefore, the approach to treatment of many of the secondary headaches is focused on treatment of the suspected cause (e.g., sinus infection, psychiatric condition). For the primary headache, however, the underlying cause of the majority of these conditions remains unknown. The most common primary headaches include migraine, TTH and cluster headache.

The treatment of migraine and other primary headaches is not uniform but is proportioned to the severity of symptoms and disability. Mild and infrequent symptoms may be initially treated with lifestyle modifications, stress management techniques, and over-the- counter (OTC) abortive medications. Prescription medications are added as warranted to impede disability and maintain function. A distinction is made between prescription of abortive and preventive medications in the management of headaches. Abortive medications are prescribed to treat an individual attack, and preventative medications - to reduce the frequency and severity of chronic attacks.

In migraine for example, during attacks acute treatment is managed with abortive medications, including: triptans (serotonin receptor agonists), nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, ergotamine tartrate, dihydroergotamine or OTC medications (e.g., aspirin, paracetamol). Tripans, however, despite their specificity, efficacy, and safety, have certain limitations. Many migraineurs do not respond optimally or at all to these drugs, or have contraindications to their use. Among the responders, some do not experience complete and sustained pain relief or experience intolerability to adverse effects. Therefore despite recent advances, millions of migraine and cluster headache sufferers still cannot be afforded an adequate relief of headache and its ensuing functional disability, and associated symptoms. Successful treatment headaches, chronic or acute, would not only benefit patients by reducing their disability and improving health-related quality of life, but would also reduce the need for healthcare resources and increases economic productivity.

A relief from chronic pain is the most common indication for use medical cannabis. The Committee on the Health Effects of Marijuana in a recent review on therapeutic effects of cannabis has identified applicability to the following conditions: pain, nausea and vomiting, and spasticity in patients with multiple sclerosis [1]. In the context of headache, cannabis was previously suggested for treating menstrual (catamenial) migraine [2-3] More recently, certain cannabis-based compositions have been suggested as potential new medicines for a wide-range of seemingly unrelated conditions, including among others the alleviation of migraine [4-6]

REFERENCES

1. Committee on the Health Effects of Marijuana. 2016. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.

2. Fishbein M. Migraine associated with menstruation. JAm Med Assoc, 1942, 237: 326.

3. Sarchielli P et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology 2007, 32: 1384-1390.

4. US6946150

5. US7025992

6. WO16092539

GENERAL DESCRIPTION

The presently disclosed invention seeks to provide a comprehensive therapeutic solution for headache, including acute and chronic headache attacks, and thereby also to functional disability and secondary symptoms of this condition. In other words, the invention provides a complete framework of compositions and methods serving at the same time as abortive and/or preventive medications for alleviation of acute and chronic headaches. In this sense, the invention is equally relevant to the primary as well as secondary headaches, when in the latter it serves for immediate alleviation of pain.

One example of particular population that can benefit from the invention includes patients suffering from migraine or TTH (primary headache) who do not respond to tripans or have a contraindication for using tripans, constituting a substantial proportion of patients. At the core of the invention is certain type of cannabis-based compositions generally characterized as being enriched in THC. The compositions of the invention have been found effective for treating acute migraine attacks, in terms of alleviation of pain (headache) and secondary migraine specific symptoms (e.g., photophobia, phonophobia, nausea, vomiting), and also in terms of recurrence and/or frequency of attacks, their overall severity and duration. These findings were highly unexpected and reassuring in view the significant burden imposed by migraine, and headache in general, on individual quality of life and society at large in terms of healthcare resources and economic productivity.

Cannabinoids, and particularly THC, act on the CB₁ and CB₂ receptors in the endocannabinoid system. The CB₁ receptor is thought to be one of the most widely expressed G protein-coupled receptors in the brain, most notably in the brainstem and the trigeminal ganglia responsible for sensation and motor function in the head and face (biting and chewing). In humans, the CB₁ receptors are also expressed in the peripheral nervous system. The CB₂ receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues and organs, such as lymph nodes, the spleen, tonsils and other specialized tissues in the mucous membranes of the bowel, for example. That said, the involvement of the endocannabinoid system in the pathophysiology of migraine, and headache in general, remains unknown.

Therapeutic value of the compositions of the invention for alleviation of headache and for acute migraine in particular is now exemplified with oil extracts of certain type of THC enriched cannabis strains. An exemplary member of this group is the strain referred to herein as 'Erez' generally described in US Plant Patent Application No. 2014/0245494.

More precisely, Erez herein encompasses a group of strains or cultivars produced from the original Avidekel strain selected due to its particularly THC content, starting from THC as high as 18% and more. A typical Erez strain can comprise THC in the range of 18-25% (w/w), and CBD and CBN in the range of 1% (w/w), and other cannabinoids in a lesser concertations.

More specifically, Erez can be further defined as a cannabis strain comprising THC up to at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% or more (w/w).

Erez strain is about 70% Indica breed.

According to the invention, crude plant material of Erez (female flowers) can be extracted in oil, e.g., olive oil or other vegetable or natural oil, using known in the art methods. The advantage of this procedure is that it preserves other plant components, such as terpenes, contributing to beneficial medicinal effects and other properties of this product (flavor and smell). After the extraction step, the THC concentration is carefully titrated with olive oil to achieve with final concentrations of 3% THC (w/w) (see Example 1). More precisely, such oil preparations of Erez can be defined as comprising THC up to at least 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).

In terms THC amount, typically a single drop of Erez oil comprises about 1.2 mg THC, 2 drops - about 2.4 mg THC, 3 drops - about 3.6 mg THC, and 4 drops, being the maximal dose used in this study - about 4.8 mg THC (see Example 3 and Table 3).

As has been noted, Erez oil can include additional types of cannabinoids, at much lesser concentrations and proportions, and also teipenes, all of which can potentially contribute to the presently demonstrated therapeutic effects.

Safety and efficacy of the compositions of the invention have been evaluated in a double-blind, placebo controlled randomized clinical trial (Example 3). In this trial, the compositions of the invention have been tested as a monotherapy for acute migraine. Specifically, the effective dose of the cannabis oil has been titrated in each patient starting from 2 drops and increasing the dose to 3 and 4 drops in 40 min intervals, if the treatment has been ineffective and in absence of adverse events. Rescue medicines (conventional drugs) could be applied in cases wherein cannabis oil has been found ineffective 2 hours after administration.

Therapeutic validity of the compositions of the invention have been demonstrated using the ICHD-III criteria (International Classification Headache Society disorders 3^rd edition), and further questionnaires for the assessment of a series of clinically relevant parameters:

i. Patient overall assessment of disease activity, also referred to as Patient-Reported Outcomes (PRO) or Patient Global Assessment (PGA) determined at a number of time points;

ii. Pain relief manifested in a reduction of headache severity assessed on a 4 Point Assessment Severity Scale (4-PASS) as a result of administration of the cannabis oil; iii. Pain free manifested in a reduction of headache severity up to complete abolition of headache according to 4-PASS as a result of the administration;

iv. Sustained pain free manifested in lack of recurrent attacks up to 24h post administration;

v. Elimination of migraine associated symptoms as nausea, photophobia or phonophobia; vi. Elimination of functional disability assessed in a 4-grade scale;

vii. Rescue medication use within 24h after the attack;

viii. Patient overall satisfaction level determined at a number of time points;

Safety of the tested compositions has been assessed by evaluation of adverse events (AE) and serious adverse events (SAE), and blood and urine analyses. The success rate has been established using a number of high-fidelity statistical methods comparing the above outcomes in the treatment and control groups, and moreover, by comparing the results of this trial to other clinical trials using conventional medicines. A detailed description of this trial is provided further below (Example 3).

This clinical trial has further provided tools for establishing therapeutically effective doses and regimens for maximization of beneficial clinical outcomes and avoidance of side effects and cross-drug interaction. In other words, this study provided an exemplary framework for applying the compositions of the invention in a rationalized manner to achieve more effective and safe treatment of acute headache.

In terms of methods, the compositions of the invention have been presently administered via an oral route, specifically by sublingual administration. Another advantageous route of administration could be topical administration on a head surface, as temples or forehead. In this connection, a particularly advantageous form could be as atransdermal patch.

Ultimately, the compositions and methods of the invention, being proven as efficacious safe, can replace other abortive and preventive medications for headache, and provide a constructive solution for patients with intolerability to the existing drags.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Tetrahydrocannabinol (THC) refers herein to a class of psychoactive cannabinoids characterized by high affinity to CB 1 and CB2 receptors, having a molecular formula C₂₁H₃₀O₂, an average mass of approximately 314.46 Da, and a general structure of Formula I.

THC is responsible for the psychoactive ('high') effect of cannabis. The term THC herein further refers to isomers, derivatives, or precursors of this molecule, such as (-)-trans-D9-tetrahydrocannabinol (D9-THC), D8-THC, and further to THC derived from the 2-carboxylic acid (2-COOH), THC- A.

In the broadest sense, the term THC refers to a synthetic or semi-synthetic or a natural cannabinoid (i.e. purified or extracted from a cannabis plant).

Cannabis-based and cannabis-derived, these terms herein are interchangeable and denote a composition or a constituent thereof purified or extracted from a cannabis plant using known in the art technologies. These terms can further relate to a crude dry plant material. Regarding extracts, there are number of methods for producing a concentrated cannabis-derived material, e.g., filtration, maceration, infusion, percolation, decoction in various solvents, Soxhlet extraction, microwave- and ultrasound- assisted extractions and other methods. Certain oil extracts from the cannabis strain Erez are presently exemplified.

The terms therapeutic dose or therapeutically effective dose, w'hich herein are interchangeable, relate to doses of the compositions of the invention, in any dosage form, capable of producing an improvement/ reduction of at least one symptom of headache, chronic or acute, according to clinically accepted criteria (e.g., Example 3). Such improvement can be further evaluated according to severity scales. Thus an improvement in this context relates to a type and/or a number of symptoms, a severity, a frequency of symptom(s), specific groups of symptoms (partial symptoms), and/or overall manifestation of symptoms in a subject or a group evaluated by a physician or self-reporting and estimated as at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 100% reduction or total abolition thereof.

Therapeutically effective amount (also pharmacologically, pharmaceutically or physiologically effective amount) herein denotes an amount of active agent needed to provide a desired level physiological response or improvement as above. The precise amount depends on numerous factors, e.g. type of an agent, activity of a composition, intended patient use (e.g. number of doses per day), patient's considerations, and others. An effective amount of an agent can be administered in one administration, or multiple administrations. The exact amount can be the result of empirical and/or individualized (case-by-case) determination.

Approximately or about, these terms herein are interchangeable, denote up to ± 10% deviation from a respective measurement, or 9%, 8%, 7%, 6%, 5% or less a deviation thereof.

Thus in one of its main aspect the invention provides certain type of cannabis-based compositions for treating, alleviating or reducing headache, characterized in that they comprise THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w). As has been noted, the term headache encompasses herein a range of disorders with the manifestation of a headache as a primary or a secondary symptom, or the only symptom, and also those including other symptoms related or unrelated to the headache. This term further encompasses acute and chronic headache attacks, and also functional disabilities and secondary symptoms of this condition, such as photophobia and nausea, for example in the case of migraine, or more long-term manifestations as depression and anxiety.

In this sense the compositions of the invention can be regarded, at the same time, as abortive and preventive medicines for the treatment of a wide range of conditions including headache as the only or additional clinical feature.

Thus in numerous embodiments the compositions of the invention are meant to provide an immediate relief to an acute headache attack and at the same time to prevent a recurrence of such attacks or reduce duration or frequency thereof.

The term immediate relief is meant to convey the efficacy of the presently disclosed compositions, and mote specifically can be defined by a timeframe up to 0.5h, lh, 1.5h or 2h or more after administration of the compositions of the invention.

Thus in numerous embodiments the compositions of the invention are applicable to a chronic headache or an acute headache attack. Or in other words, the compositions of the invention can be applied at the time of an attack for an immediate relief, and also between attacks for preventing thereof.

With respect to the target population that could benefit from the presently disclosed compositions, according to the International Classification of Headache Disorders, 3^rd Edition (ICHD IP, also used in the presently described trial), a diagnosis of headache is associated with one of the following disorders:

Part I: The Primary Headaches

1. Migraine

2. Tension-type headache

3. Trigeminal autonomic cephalgia

4. Other primary headaches

Part P: The Secondary Headaches (including Facial Pain)

5. Trauma or injury to the head and/or neck

6. Cranial or cervical vascular disease

7. Nonvascular intracranial disorder

8. A substance or its withdrawal

9. Infection 10. Disorder of homeostasis

11. Disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other fecial or cervical structure

12. Psychiatric disorder

Part. III: Painful Cranial Neuropathies. Other Facial Pains, and Other Headaches

13. Painful cranial neuropathies and other fecial pain

14. Other headache disorders

Thus the compositions of the invention are applicable to an individual affected by each one of the above conditions.

In certain embodiments the compositions of the invention are applicable to a type of headache manifested as migraine. Thus migraneurs, female or male, is one of the particular populations that could benefit from the invention.

The term migraine herein encompasses the main subtypes of migraine, as migraine with and without aura. Aura denotes a reversible set of nervous system symptoms, most often visual or sensory symptoms, that typically develops gradually, recedes, and is then followed by headache accompanied by nausea, vomiting, photophobia, and phonophobia. Less common symptoms of aura include speech/language symptoms, motor or brainstem symptoms, or retinal symptoms.

In other words, aura is another term for a migraine related symptom or a 'secondary migraine related symptom', these terms herein are interchangeable.

According to the ICHD HI migraine is diagnosed with:

A. At least 5 headache attacks fulfilling the criteria B-D

B. Attacks last 4-72h

C. With at least 2 of the following characteristics:

1. Unilateral location

2. Pulsating quality

3. Moderate or reverse pain intensity

4. Aggravation by or causing avoidance of routine physical activity

D. At least 1 of the following during headache:

1. Nausea and/or vomiting

2. Photophobia and phonophobia

Thus the compositions of the invention are applicable to an individual affected by migraine in its various forms and manifestations. The compositions of the invention are applicable for treating, alleviating or reducing least one secondary migraine related symptom, or a symptom of aura.

In further embodiments the symptom of aura treatable by the compositions of the invention is selected from the group of nausea, vomiting, photophobia, phonophobia.

As has been noted, a specific population of patients that could benefits from the presently disclosed compositions includes non-responders or subjects with intolerability to the conventional headache medicines. Conventional headache medicines have been referred to above. In brief, in the context of headache they usually refer to nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen or OTC medications (e.g., aspirin, paracetamol). In the context of migraine, they can further refer to triptans (serotonin receptor agonists), ergotamine tartrate, dihydroergotamine, and in TTH - tricyclic antidepressant (TCAs), Selective Serotonin Receptor Inhibitors (SSRIs), muscle relaxants, and others.

With respect to the nature of the presently disclosed compositions, in numerous embodiments these compositions comprise THC at a concentration of at least about 2%.

Compositions comprising about 3% THC (w/w) have been presently found particularly applicable to the treatment of headache attacks.

Still in numerous embodiments the compositions of the invention can comprise THC up to at least 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).

And in terms of amounts of said active, the compositions of the invention can comprise a THC dose in the range of at least about 2 mg THC to at least about 6 mg THC or more, or more specifically between 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg THC or more.

In certain embodiments the compositions of the invention are provided in a form of an oil extract of a cannabis strain. Oil extracts are particularly advantageous as they retain a range of lipophilic components, i.e., cannabinoids, terpenes, carotenes and others, in specific proportions and combinations, being responsible as a whole for the presently demonstrated effects. In addition, the oil extracts are easily applicable via oral, sublingual and topical routes. Certain type of olive oil extracts of cannabis has been presently exemplified.

Notwithstanding, herein the term 'oil extract of a cannabis strain' denotes herein various types of oils and various types of plant material from the relevant cannabis strains. With respect to the latter, the most applicable plant material with the highest concentration of actives is the inflorescences female cannabis plants, more precisely the resin-producing part of these flowers. It is possible however that other parts of cannabis (seeds, stem, etc.) can be applicable for the purpose of specific embodiments. In the same way, other types of oils can be applicable for producing the cannabis extracts of the invention, vegetable oils in general (e.g., soybean, canola, com, cotton seed, sunflower, peanut, sesame, rice bran oils), and also essential oils (e.g., lemon, cinnamon, lemongrass, clary sage, lavender, tea tree, eucalyptus).

The transdermal patches (see below) can comprises higher concentrations of actives.

Thus in terms of formulations and dosage forms, the presently disclosed compositions can be adapted for oral, sublingual, topical or transdermal administration.

Still in other embodiments , the compositions of the invention can be provided in the form of a transdermal patch, or incorporated into various transdermal delivery systems by means of known in the art technologies, including first-, second- and more recent third- generation delivery systems.

The terms 'transdermal patch' or 'transdermal delivery system' in this context refer to a variety of systems, including first-generation transdermal delivery systems known to be applicable for lipophilic drags. First-generation transdermal delivery systems are systems where the drag is stored in a reservoir enclosed on one side with an impermeable backing and on the other side - with an adhesive contacting to the skin. This term encompasses systems wherein the drag is dissolved in a liquid or gel-based reservoir, and also systems where the drag is incorporated into a solid polymer matrix.

For example, the transdermal delivery system of the invention can be composed of four layers, including an impermeable backing membrane, a drag reservoir, a semi-permeable membrane that may serve as a rate-limiting barrier, and an adhesive layer. These particular systems can permit the use of liquid chemical enhancers, such as ethanol.

Further, transdermal delivery systems can have three layers, by eliminating the semi- permeable membrane, or just two layers, by incorporating the drag directly into the adhesive.

Another type of transdermal delivery systems employs second-generation delivery systems, i.e., those using chemical enhancers, non-cavitational ultrasound and iontophoresis.

The most recent type of transdermal delivery systems are third-generation delivery systems, i.e., target their effects to skin’s barrier layer of stratum comeum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound.

In numerous embodiments of the compositions of the invention can incorporated into delivery systems permitting controlled or suspended release of actives. These types of systems have been subject to intensive R&D, yielding first-, second- and third-generation delivery systems, including so-called ' smart' polymers and hydrogels to make systems that are triggered by changes in environmental factors, such as pH, temperature, or glucose. Controlled drug delivery systems are applicable to oral and transdermal forms of the presently disclosed compositions.

Still, in numerous embodiments the compositions of the invention can be made of extracts of the cannabis strain designated herein as Erez. Such compositions using olive oil extracts of female flowers Erez strain have been presently exemplified.

It is another important aspect of the invention to provide methods for treating, alleviating or reducing headache in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of a cannabis-based composition comprising THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w).

In numerous embodiments the methods of the invention apply cannabis-based compositions comprising about 3% THC (w/w).

As has been noted above, the compositions and methods of the invention are at the same time abortive and/or preventive regarding treatment, alleviation or a reduction of headache.

Thus in numerous embodiments the methods of the invention are applicable to a chronic headache or an acute headache attack.

Therapeutic effect of the compositions and methods of the invention can be assessed using ICHD IP, the gold standard diagnostic criteria for headache, and further specific severity scales for the assessment of intensity of headache and other accompanying symptoms.

In the example of migraine, as in the presently described trial, the impact of the present compositions and methods on the severity of headache can be measured using a 4 Point Assessment Severity Scale (4- PASS). In the same way, the type and severity of the secondary- symptoms in migraine (the aura) can be measured using an analogous 4-point scale. Applicability of such methods have been presently exemplified (see Example 3).

Thus in certain embodiments the compositions and methods of the invention are applicable to the treatment and alleviation of migraine or specific secondary migraine related symptoms (i.e., at least one symptom of aura such as nausea, photophobia, phonophobia).

Thus it is meant that the compositions and methods of the invention can alleviate or reduce each one of these symptoms, or any combination thereof, in terms of intensity, frequency and/or duration. To that end, the compositions of the invention should be provided in therapeutically effective doses and under therapeutically effective regimens, and by permissible administration routes.

In numerous embodiments the methods of the invention apply the cannabis-based composition via oral, sublingual, topical or transdermal administration route. As has been noted such compositions can comprise THC up to at least 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).

And in terms of daily doses of said active or therapeutically effective doses, in numerous embodiments the methods of the invention apply a THC daily dose in the range of at least about 2 mg THC to at least about 6 mg THC or more, or more specifically between 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg THC or more. Applicability of such methods to the treatment of headache has been presently exemplified (Example 3).

In certain embodiments the methods of the invention apply such daily doses by means of a single daily dose.

This type of methods are particularly relevant to the treatment and alleviation of an acute headache attack.

In numerous embodiments, however, the methods of the invention can be also applied for the prevention of recurrence of chronic headache attacks.

Thus in certain embodiments the methods of the invention can apply said amounts as a single dose or as two or three doses per day, or more.

Importantly, according to the methods of the invention the therapeutically effective amount of the cannabis-based compositions can be personalized. In other words, the exact therapeutically effective amount is established for each patient by titration of the dose and monitoring of therapeutic effects.

Examples of such personalized methods have been presently demonstrated with administration of 2 drops of the disclosed compositions (2.4 mg THC), 3 drops (3.6 mg THC) and up to 4 drops (4.8 mg THC) in 40 min intervals, if the headache persisted and in absence of noticeable adverse events.

Further, in numerous embodiments the methods of the invention can be applied as a monotherapy therapy, potentially replacing other conventional headache medicines. Medicines belonging to this group have been referred to above.

In this connection, it should be noted that at least four drugs should be avoided in conjunction with cannabis: Astemizole, Cisapride, Pimozide and Terfenadine, due to potential cross-drag interaction and/or competition on metabolizing enzymes (CYP3A4 and CYP2C9).

Of particular interest are methods of the invention wherein the cannabis-based compositions are provided in a form of an oil extract of a cannabis strain.

This type of compositions are particularly applicable for personalization and careful titration to achieve a therapeutically effective dose. Thus in certain embodiments the methods of the invention apply the cannabis-based compositions comprising an oil extract of the strain Erez in the manner and therapeutic amounts as described above. Applicability of such methods has been presently exemplified.

It is another aspect of the invention to provide an oral dosage form of an oil extract of the cannabis strain Erez, the oil extract comprising about 3% THC and the THC amount is in the range of at least about 2 mg THC to at least about 6 mg THC.

In certain embodiments such oral dosage forms can comprise THC up to at least 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).

It further embodiments the oral dosage forms can comprise a THC amount in the range between 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg THC or more.

In numerous embodiments the oral dosage forms of the invention can be applied for treating, alleviating or reducing headache, the headache being a chronic headache or an acute headache attack.

Ultimately, it is another aspect of the invention to provide use of a cannabis-derived material for manufacture/ preparation of a medicament for treating, alleviating or reducing headache, the medicament comprising THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w).

According to the invention, such medicaments can be used an abortive or a preventive headache medicine for chronic headache or acute headache attacks.

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 to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

EXAMPLE 1

INVESTIGATIONAL PRODUCT (IP)

1.1 Characterization of Erez oil

In general, there are a number of methods for producing cannabis oils, and oil from other medicinal plants. Present preparations use olive oil as a solvent for preservation of cannabinoids and other beneficial components such as terpenes to be available in higher concentrations. Cannabis oil can be taken orally by ingesting a small number of drops under the tongue several times a day. An extract ofErez flowers (fiorn female plants) is dissolved in olive oil. In terms of the main active, Erez oil usually comprises THC (D9-THC) at a concentrations of about 3%. Fine tuning of THC concentration is achieved by a titration with pure THC and/or olive oil .

In terms of an amount of active in the presently used dosage forms: one drop of Erez oil (about 0.04 ml) contains about 1.2 mg THC, two drops - 2.4 mg THC; three drops - 3.6 mg THC and four drops -4.8 mg THC.

In terms of other components, Erez oil usually comprises about 93% olive oil, 3% THC, 0.1% CBG, <0.1% CBD, <0.1% CBN, <0.1% CBC, <0.1% CBDV and other unidentified cannabinoids reaching up to 3.5%, and further certain percentages of terpenes, flavonoids, waxes and chlorophyll.

IP is stored at room temperature.

1.2 Administration mode

IP is indicated upon the occurrence of an acute migraine attack which is not spontaneously resolved. IP is administered in the form of drops under the tongue, starting with the dose of two drops (2.4 mg total THC), with optional third drop (3.6 mg total THC) if there is no improvement after 40 min, and optional fourth drop (4.8 mg total THC), in absence of adverse events. The maximal dose has been limited to four drops ofErez oil .

1.3 Concomitant medications

Patients receiving one of the following: Astemizole, Cisapride, Pimozide or Terfcnadine, are excluded fiorn the study. IP is given as a monotherapy under proper titration of effective dose, and monitoring of adverse events If found unsuccessful or upon adverse events, a patient can shift to a conventional headache medication.

EXAMPLE 2

RETROSPECTIVE ANALYISIS OF PATIENTS

In a preliminary study the inventors analyzed data collected on patients treated with cannabis. The population group included 82 patients with chronic headache (average age 47.2±15.0 years, 39% males, 45.1% employed, about 1/2 reported previous use of cannabis). The median pain intensity was 9/10 (IQR 8-10). Additional symptoms included: sleep problems (81.7%), vomiting (57.3%), weakness (37.8%) and anxiety (39%). The median number of different medications per day was four.

After six months treatment: 37 patients (45.1%) responded to the questionnaire, 94.6% of them reported an improvement and 5.4% reported no change. The median pain intensity was reduced to 5/10 (IQR3-6) (p<0.001). Fifteen patients (39.4%) reported on side effects, the most common being nausea and dry mouth. Four patients discontinued treatment.

According to this preliminary study cannabis appeared to be safe and potentially efficacious far treating chronic headaches.

EXAMPLE 3

A DOUBLE-BLIND, PLACEBO-CONTROLLED RANDOMIZED STUDY 3.1 Objective

To evaluate the safety and efficacy of Erez oil for the treatment of subjects experiencing acute migraine attack.

3.2 Working hypothesis

Administration of Erez oil to subjected under acute migraine attack will lead to a reduction of headache severity, an improvement of functional disability and an improvement of secondary symptoms (nausea, vomiting, photophobia, phonophobia), at least one of these parameters or a combination thereof, compared to the placebo.

3.3 Study endpoints

3.3.1 Primary efficacy endpoint

The proportion of subjects achieving a headache relief at 2h after administration measured as an improvement of at least 2 levels in migraine severity from baseline.

3.3.2 Secondary efficacy endpoints

- Patient Global Assessment (PGA) at 2h, 4h, 24h after IP/placebo administration.

- Overall satisfaction level (patient's report) at 2h, 4h and 24h after administration.

- Pain relief as the percentage of patients with a reduction of headache severity from moderate or severe at baseline to mild or none at 2h.

- Pain free as the percentage of patients with a reduction of headache severity from moderate or severe at baseline to none (i.e. complete abolition of headache) at 2h.

- Sustained pain free as the percentage of patients who were pain free at 2h, who did not have a recurrence within 2h-24h (retur of headache to moderate or severe), and who did not take any additional migraine medications within 24h.

- Elimination of associated symptoms as the percentage of patients with no nausea, no photophobia or no phonophobia at 2, 4 and 24h in the subgroup of patients who had each symptom at baseline. - Elimination of functional disability as the percentage of patients with no functional disability (grade 0 on the 4-grade scale) at 2h, 4h and 24h in the subgroup of patients who had some level of functional disability at baseline (grade 1, 2 or 3 on the 4-grade scale).

- Rescue medication use within 24h after the attack.

* Subgroup analyses consider gender, age and baseline migraine severity.

3.3.3 Safety endpoints

Incidence and severity of adverse events (AE) and serious adverse events (SAE) at 24h after administration.

3.4 Design

3.4.1 Duration

The study duration is 2 months, including: a) four weeks period for of applying for the cannabis license and coordinating the first trial visit; and b) four weeks of trial period.

3.4.2 Population

The trial includes approximately 90 subjects randomly assigned to receive Erez oil or placebo (1:1 ratio). The trial population includes patients diagnosed with migraine, i.e., suffering from at least two migraine attacks per month (followed up by a neurologist).

Inclusion criteria include:

- Males and females ages 18 - 65 years;

- Diagnosis of migraine with or without aura for at least 1 year prior to trial by

ICHD-in (International classification headache society disorders 3rd edition);

- Migraine attacks occur at least twice a month;

- Severity level above 1 on a 4 Point Assessment Severity Scale (4- PASS).

Measures severity of a symptoms using 0-3 score: 0=none, l=mild, 2=moderate 3=severe with respect to headache, and also for the secondary symptoms of nausea, photophobia and phonophobia.

Exclusion criteria include:

- Confusion state or Glasgow Coma Score <15;

- History of substance abuse except cigarette use;

- History of schizophrenia, affective disorder, history of psychiatric hospitalization and diagnosed psychiatric or anxiety disorder;

- Psychosis or psychiatric condition in a first-degree family member;

- Narrow angle glaucoma;

- Peptic disease; Pregnancy/breast feeding;

History of heart feilure, coronary heart disease, cerbro-vascular disease or renal insufficiency, or other related disorder, or recent surgery;

Patients receiving under Astemizole, Cisapride, Pimozide or Terfenadine;

Current participation in another drag or device clinical trial.

3.5 Procedures

Patients are instructed to take IP/placebo with the occurrence of a moderate or severe migraine attack that is not resolving spontaneously, with overall use of IP in no more than two migraine attacks during the four weeks of follow-up. IP/placebo is administered as drops applied under the tongue. IP is titrated in each patient to achieve reach target dose, with overall three dosing options as 2, 3, or maximum 4 drops. All patients start with 2 drops at the first administrations, followed by adding additional 1 or 2 drops, after 40 or 80 minutes, respectively, if the pain intensity is still moderate or severe, and in absence of adverse reaction.

During the entire period of the study (the total of 8 weeks including 4 weeks follow up) five visits are conducted for the recording of relevant data. Patients are asked to rate headache severity and functional disability, and note the presence of associated symptoms of nausea, photophobia, phonophobia and vomiting at the following time points: pre-dose, 2h, 4h and 24h. Headache severity and functional disability are rated using 4-grade anchored scales. For headache severity: 0 = no headache, 1=mild headache, 2=moderate headache, and 3=severe headache; and for functional disability: 0=normal, 1=daily activities mildly impaired, 2=daily activities severely impaired, and 3=unable to do activities, requires bed-rest).

A patient still suffering from a moderate or severe headache at 2 h after taking the initial dose of IP is allowed to take optional rescue medications, i.e.: standard analgesics (opiates, acetaminophen (paracetamol), NSAIDs) and antiemetic drags. Patients are prohibited from taking ergotamine or other 5-HT1B/1D agonists from 24 h before and after dosing.

3.5.1 Screening and enrollment

Patients who meet all of the inclusion criteria and none of the exclusion criteria are enrolled at a neurology clinic. Targeted physical examination is performed and vital signs, ECG and blood and urine samples are taken as standard of care.

3.5.2 Visit 1 -Baseline (Day 0)

Physical examination and vital signs are performed and urine samples collected. Patients are instructed on the treatments as: - In case the migraine attack is not resolved spontaneously, IP/placebo is taken as 2 drops, with an optional 3^rd drop after 40 minutes if there is no improvement and no AE, and an optional 4^th drop after another 40 minutes under the same conditions.

- Rescue treatment can be taken if needed 2h after IP/placebo administration.

3.5.3 Visit 2 - Telephone follow up (Day 7)

The following data is recorded by phone: how many attacks were experienced during the past week; how many times the investigational treatment was initiated; how many drops in each attack and whether a rescue treatment was used or not; and the kind and dosage of the rescue treatment.

3.5.4 Visit 3 - Follow up (Day 14)

The following data is recorded at the neurology clinic: physical examination and vital signs; safety and efficacy outcomes are assessed from patients' diaries; Patient Global Assessment (PGA) on the overall satisfaction with the treatment and AE and SAE are obtained by questionnaires.

3.5.5 Visit 4— Telephone follow up (Day 21)

The data is obtained in the same manner and parameters as in 3.5.3 above.

3.5.6 Visit 5 -End of study, EOS (Day 28)

The data is obtained in the same manner and parameters as in 3.5.4 above.

3.5.7 Vital signs

Vital signs are obtained at screening, baseline and EOS, including blood pressure, heart rate measurements, saturation and temperature.

3.5.8 Laboratory testing

Blood samples include routine biochemistry, haematology analyses.

Urine samples are detecting previous D⁹-THC use. Women of child bearing potential also perform pregnancy test (bHCG).

Error! Reference source not found.Table 1 (Schedule of events) summarized the main procedures.

3.6 Statistical analysis

The further included a systematic search of the existing literature to establish the success rate of the treatment of acute migraine at 2h after administration of a treatment.

Table 2 summarized the relevant studies with references to the PubMed/MEDLINE database.

Parametric procedures are applied for continuous variables, including paired and unpaired t-test and ANOVA. Non-parametric procedures (if parametric assumptions could not be satisfied, after data transformation attempts) include Mann-Whitney, Wilcoxon and Spearman Correlation tests. Parametric model assumptions are assessed using Normal-plot or Shapiro-Wilks statistic for verification of normality and Levene’s test for verification of homogeneity of variances. Categorical variables are tested using Pearson’s c² test for contingency tables or Fisher Exact test, as appropriate. Correlations between variables are tested using Pearson or Spearman tests, depending on the variables distribution. All statistical tests and/or confidence intervals, as appropriate, will be performed at a=0.05 (2-sided). Multivariable analysis is applied when the two trial groups are different by a baseline or procedural parameters to account for these discrepancies, with treatment success as a dependent variable in a logistic regression model.

3.7 Criteria for endpoint evaluation

For the for the following dichotomous endpoints the number and percentage of patients experiencing the outcome and the exact two-sided 95% confidence interval of the percentage are determined:

i. Safety endpoint - a composite endpoint of all serious adverse events (SAE) at 24 hours after each consumption;

ii. Freedom form pain two hours from IP administration, prior to any rescue medication was given;

iii. Decrease in headache severity from severe or moderate to mild or none within two hours before any rescue medication was given;

iv. Rescue medication use within 24h after the attack ignition.

For the following continuous variables the number of observations (N), mean, 95% confidence interval of the mean, standard deviation, median, inter-quartile range, minimum, and maximum values are determined:

i. Patient global assessment at 2h, 4h and 24h.

ii. Overall satisfaction level at 2h, 4h and 24h.

iii. Pain level at 2h, 4h and 24h.

iv. Nausea level at 2h, 4h and 24h.

v. Photophobia level at 2h, 4h and 24h.

vi. Phonophobia level at 2h, 4h and 24h. The results of these analyses are further compared to the values obtained in analogous studies using the convention drags (Table 2).

3.8 Adverse events

In general, the tolerance to cannabis is considered to be relatively good, with only mild side effects. In rare cases, subjects on cannabis reported: dizziness, dry mouth, nausea, sleepiness, psychoactive effects, headaches, confusion and disorientation, increased appetite, weakness, red / irritated eyes, decreased memory, decreased concentration, heart palpitations, restlessness, vomiting and fear. Records include any undesirable experience occurring to a patient (sign, symptom, illness, abnormal laboratory value, or other medical event.

3.8.1 Treatment related adverse event

A treatment related adverse event relates to any adverse event, for which a causal relationship between the treatment and the event is at least a reasonable possibility, i.e., the relationship cannot be excluded, which is identified or worsens during a clinical trial

3.8.2 Serious adverse event

A serious adverse event relates to one of the following: death, life-threatening condition, hospitalization (initial or prolonged), disability - significant, persistent, or permanent change, impairment, damage or disruption in patient's body function/ structure, physical activities or quality of life.

3.8.3 Intensity of adverse event

The Sallowing categories of the intensity of an adverse event are used:

Mild: Awareness of a symptom that does not interfere with usual activity or is transient, resolved without treatment and with no sequelae;

Moderate: Interferes with usual activity, but a patient is still able to function;

Severe: Events that interrupt usual daily activity and generally require a systemic device therapy or other treatment.

3.8.4 Relatedness of adverse event

Relatedness of AE/SAE is to IP is defined according to the following scale:

1. Unrelated: the event is unrelated to the trial treatment;

2. Unlikely: the relationship is unlikely according to the current knowledge;

3. Possible: the event has a possible relationship to IP;

4. Probable: the event has a probable relationship to IP;

5. Definite: the event is related to the investigational treatment. Synopsis of the study protocol is provided in Table 3 below.

Table 3. Protocol synopsis

Claims

CLAIMS:

1. A cannabis-based composition for use in treating, alleviating or reducing headache, the composition comprising THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w), said use being abortive or preventive.

2. The composition of claim 1, the headache is a chronic headache or an acute headache attack.

3. The composition of claim 1 or 2 wherein the headache is manifested as migraine.

4. The composition of claim 3, wherein the migraine comprises at least one secondary migraine related symptom.

5. The composition of claim 4, wherein the at least one secondary migraine related symptom is selected from the group of nausea, vomiting , hotophobia, phonophobia.

6. The composition of claim 1 comprising about 3% THC (w/w).

7. The composition of any one of claims 1-6 adapted for oral, sublingual, topical or transdermal administration.

8. The composition of claim 7 in a form of an oil extract of a cannabis strain.

9. The composition of claim 7 in a form of a transdermal patch.

10. The composition of claim 8, wherein the cannabis strain is Erez.

11. The composition of any one of the preceding claims, the composition comprising at least about 2.0 mg THC up to at least about 10 mg THC.

12. A method for treating, alleviating or reducing headache in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of a cannabis-based composition comprising THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w) said treating being abortive or preventive .

13. The method of claim 12, wherein the headache is a chronic headache or an acute headache attack.

14. The method of claim 12 or 13, wherein the headache is manifested as migraine.

15. The method of claim 14, wherein the migraine comprises at least one secondary migraine related symptom.

16. The method of claim 15, wherein the at least one secondary migraine related symptom is selected from the group of nausea, vomiting, photophobia, phonophobia.

17. The method of any one of claims 14-16, wherein the treating, alleviating or reducing migraine further comprises treating, alleviating or reducing at least one secondary migraine related symptom.

18. The method of claim 12, wherein the cannabis-based composition comprises about 3% THC (w/w).

19. The method of any one of claims 12-18, wherein the cannabis-based composition is administered via oral, sublingual, topical or transdermal routes.

20. The method of any one of claims 12-19, wherein the cannabis-based composition is provided in a form of an oil extract of a cannabis strain.

21. The method of claim 20, wherein the cannabis strain is Erez.

22. The method of any one of claims 12-21, wherein the cannabis-based composition is administered in a daily dose in the range of at least about 2 mg THC to at least about 6 mg THC or more.

23. The method of claim 22, wherein the daily dose is administered as a single dose.

24. The method of claim 23, wherein the single dose is administered during an acute headache attack.

25. The method of any of claims 12-24 constituting a monotherapy for headache.

26. An oral dosage form of an oil extract of the cannabis strain Erez, the oil extract comprising about 3% THC and the THC amount is in the range of at least about 2 mg THC to at least about 6 mg THC.

27. The oral dosage form of claim 26 for use in treating, alleviating or reducing headache, the headache being a chronic headache or an acute headache attack.

28. Use of a cannabis-derived material for manufacture/ preparation of a medicament for treating, alleviating or reducing headache, the medicament comprising THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w), said medicament being abortive or preventive.

29. Use according to claim 28, wherein the headache is a chronic headache or an acute headache attack.