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The Use of Cannabis for Headache Disorders

Headache disorders are common, debilitating, and, in many cases, inadequately managed by existing treatments. Although clinical trials of cannabis for neuropathic pain have shown promising results, there has been limited research on its use, specifically for headache disorders. This review considers historical prescription practices, summarizes the existing reports on the use of cannabis for headache, and examines the preclinical literature exploring the role of exogenous and endogenous cannabinoids to alter headache pathophysiology. Currently, there is not enough evidence from well-designed clinical trials to support the use of cannabis for headache, but there are sufficient anecdotal and preliminary results, as well as plausible neurobiological mechanisms, to warrant properly designed clinical trials. Such trials are needed to determine short- and long-term efficacy for specific headache types, compatibility with existing treatments, optimal administration practices, as well as potential risks.

Introduction

Headache is a major public health concern, with enormous individual and societal costs (estimated at $14.4 billion annually) due to decreased quality of life and disability. 1 Each year, ∼47% of the population experience headache, including migraine (10%), tension-type headache (38%), and chronic daily headache (3%). 2 A sexual dimorphism exists for headache disorders, with women 2–3 times more likely to experience migraine 3 and 1.25 times more likely to experience tension-type headache than men. 4

The present review will focus largely on migraine, tension-type headache, trigeminal autonomic cephalalgias (specifically cluster headache), and medication-overuse headache (MOH). Migraine is classified as a 4–72 h headache that is typically unilateral, pulsating, of moderate-to-severe intensity, and associated with photophobia and phonophobia. 5,6 Tension-type headache is classified as frequent, infrequent, or chronic, typically presenting with bilateral tightening pain of mild-to-moderate intensity and lasting minutes to days. 6,7 Cluster headache is defined as severe unilateral pain in orbital, temporal, and/or supraorbital locations, lasting 15–180 min and typically occurring frequently and at regular intervals. 6,8 MOH is a chronic condition (occurs more than 15 days per month) that develops from frequent use of anti-headache medications. 6,9

The pathophysiology of headache disorders is still under investigation. However, it is believed that migraine and cluster headaches are initiated in the brain in areas such as the hypothalamus, brainstem, or possibly cortex. 6 Tension-type headaches can not only originate in the central nervous system but may also be triggered by myofascial tissue, often developing in response to stress. 10 Regardless of origin, headaches usually involve overactivation of the trigeminovascular pathway, resulting in the release of vasoactive peptides, such as calcitonin gene-related peptide (CGRP) and substance P, as well as vasoactive mediators such as nitrous oxide (NO), which can lead to further sensitization of nociceptive receptors in the head and neck. 11 Serotoninergic signaling, parasympathetic efferents, inflammation, and increased intracranial pressure also play important roles in headache disorders. 12,13

Treatment depends on the underlying headache condition; however, some popular options include NSAIDs for mild headaches and triptans, anti-depressants, verapamil, or ergotamine for more severe or chronic headaches. 14 These may be complemented by nonpharmacological interventions such as cognitive-behavioral therapy or relaxation training. 15 Despite many treatment options, less than half of headache sufferers experience remission, and many continue to develop more severe or chronic headaches throughout their lifetime. 16 Moreover, headache disorders are often underrecognized and undertreated. 17 This current situation warrants an exploration of additional treatment options for headache disorders, with favorable side-effect profiles and efficacy in refractory patients.

One such option, cannabis, has been ignored in the United States for the past several decades but has an established history in the treatment of headaches. Assyrian manuscripts from the second millennium BCE recommended cannabis to “bind the temples,” 18 and Ayurvedic preparations in the third and fourth centuries BCE were indicated for “diseases of the head” such as migraines. 19 The prescription of cannabis was even recommended in ancient Greece, with Pedanius Dioscorides describing its use in his De Maternia Medica as a treatment for “pain of the ears.” 20 Other citations documenting the use of cannabis for headache disorders arise from the ninth century in the Al-Aq-rabadhin Al-Saghir, the earliest known document of Arabic pharmacology. 19 Further recommendations are found in Persian texts from the 10th 21 and 17th centuries. 22 Prominent physicians of the Middle Ages, including John Parkinson 23 and Nicholas Culpeper, 24 also recommended the use of cannabis for headache.

The reintroduction of cannabis to the West in 1839 25 began a century of its use as an effective treatment for headache disorders 26 until its illegalization in 1937. 27 Notable physicians who espoused the benefits of cannabis for headache disorders included John Russell Reynolds, the personal physician of Queen Victoria, 28 American neurologist Silas Weir Mitchell, 29 the president of the New York Neurological Society Edouard C. Seguin, 19 William Gowers, a founding father of modern neurology, 30 and Sir William Osler, often considered the father of modern medicine. 31

When cannabis was deemed illegal by the U.S. government, its therapeutic use and research into its medical potential was largely discontinued. To this day, there are few clinical investigations of the use of cannabis for headache; however, the studies that have emerged demonstrate potential efficacy. In addition, numerous pre-clinical investigations 18 have validated the role of endocannabinoids in preventing headache pathophysiology, which suggests a mechanistic role of cannabis in the treatment of these disorders. Although the cannabis plant comprises more than 100 cannabinoids, there has been little study of the individual effects of these cannabinoids on headache disorders; therefore, the present review will focus largely on the clinical potential of the cannabis plant as a whole.

The present review has four unique aims: (1) Highlight common historical trends in the use of cannabis in the treatment of headache to inform future clinical guidelines. (2) Briefly present the current clinical literature on this topic, with a focus on more recent publications that have not been discussed in past reviews. (3) Compile various preclinical studies into a prospective integrated model outlining the role of cannabinoids in the modulation of headache pathogenesis. (4) Outline several 19,32–35 future directions that warrant exploration based on the limited, but promising findings on this topic.

Materials and Methods

The material presented was drawn from standard searches of the PubMed/National Library of Medicine database, influential sources of current medical literature, and past review articles. Search keywords included cannabis; cannabinoids; headache; migraine; cluster headache; medication-overuse headache; tetrahydrocannabinol; cannabidiol; clinical trial; placebo; and double blind. CliniacalTrials.gov was also queried for studies that have not yet been published. Individual articles were selected based on historical, clinical, or preclinical relevance to cannabinoids or cannabis as a treatment for headaches.

Historical Use of Cannabis for Headache

Historical reports, though not ideal forms of evidence, are important resources for understanding the potential use of cannabis in the treatment of headache disorders. Clinical publications between 1839 and 1937 provide valuable insights into the most effective practices, challenges, and benefits during an era when cannabis was commonly used to treat headache. A summary of historical treatment practices using cannabis for migraines can be seen in Table 1 . Historical sources indicate that cannabis was used as an effective prophylactic and abortive treatment for headache disorders. Although dosing varied among physicians, most prescribed alcohol extractions of the drug in the range of ¼ to ½ grain (16–32 mg). 28,32,36–40 This dose was likely chosen to minimize the effects of intoxication while also providing effective therapeutic relief. Other providers suggested that doses should be progressively increased until modest effects of intoxication were felt. 19 For prophylactic treatment, these doses were usually administered two to three times daily for weeks or even months. 28,32,36–38 Acute treatment often involved higher doses taken as needed and, in some cases, smoked cannabis was recommended. 19,41–42

Table 1.

Historical Reports of the Use of Cannabis as a Treatment for Headache (19th and Early 20th Century)

Usage Administration Sample Result Source
Migraine A: 0.03 fluid ounce of alcohol extract 1 h before pain onset 4 Case studies Distinct termination of migraine. All patients experienced improvement, some were cured. Donovan 41
Migraine A: 21.6 mg 2 Case studies Immediate relief and elimination of headache for 14 months after treatment. No lasting harm. Reynolds 27
  P: 21.6 mg—three times daily      
Migraine/headache P: 21.6 mg, 1–2 times per day (can increase to 43.2 mg) 9 Case studies and clinical experience Responses in majority of cases. Usually lasting relief, sometimes curative. Palliative during headache. Greene 35 ; Russo 18
Clavus hystericus and migraine P: 21.6 mg to 43.2 mg every night Textbook Palliation even in severe cases. Waring 36
Migraine or sick headache P: Taken before each meal (Women: 21.6 mg increased to 32.4 after 2–3 weeks; Men: 32.4 increased to 48.6) Clinical experience Majority of patients reported migraine relief for months. Seguin (1878) cited in Russo 18
Migraine or sick headache A: 21.6–32.4 mg at beginning of attack. Clinical experience Found to be the most effective drug for migraine. Can abort attacks in some cases. Ringer 37
  P: 21.6–32.4 mg, 2–3 times daily, for weeks or months continuously.      
Migraine P: 8.1–16.2 mg of solid extract twice a day. Clinical experience Helpful prophylactically and abortively, even in cases of migraine refractory to other treatments. Hare 40
  A: Take as needed      
Chronic daily headache P: 21.6–32.4 mg (increasing if necessary), 2–3 times per day for weeks to months. 4 Case studies Cured complaints in a majority of cases. Mackenzie 38
Migraine P: 16.2 mg twice a day continuously Short report Given immediately will stop attack, given periodically will reduce severity and frequency. Suckling 39
  A: Take 16.2 mg during onset of attack      

A, abortive; P, prophylactic.

Early reports of cannabis for the treatment of headache appear to be largely positive, with many patients experiencing a decrease in the frequency and intensity of their headache episodes. In some cases, headache was cured entirely even after cannabis discontinuation. 28,32,36–42 Furthermore, these early clinical reports praise the apparent safety of long-term cannabis use, as well as its added benefits of mollifying the nausea and anxiety that often accompany headaches. A common emphasis was placed on the importance of specific purity, preservation, and administration of the cannabis as well as patient adherence in the efficacy of treatment.

Clinical Studies on Cannabis Use for Headache

The schedule 1 classification of marijuana in 1970 has made rigorous clinical studies on the treatment efficacy of this substance difficult. Currently, there are no placebo-controlled clinical studies examining the use of cannabis for headache; nevertheless, there have been a number of other studies published that give insight into its therapeutic efficacy ( Table 2 ). 19,43–58 However, care should be taken when interpreting the findings from these studies. With one exception, 53 these studies did not include a control group, and given that the placebo effect can be altered by the context of treatment, 59 it is reasonable to expect a significant placebo response given the pre-existing public popularity and notoriety of cannabis. Moreover, self-reports and case studies may have a bias toward immediate improvement without awareness of possible dependence, rebound, or withdrawal responses, which are important concerns in headache treatment. 60 In fact, studies show that headache can be induced in 23.2% patients undergoing cannabis withdrawal. 61

Table 2.

Clinical Reports of the Use of Cannabis or Exogenous Cannabinoids as a Treatment for Headache

Subject population Type of study Significant findings Source
3 Chronic smokers Case series Migraines after cannabis cessation. Remission of headache with return to use in one patient. El-Mallakh 42
Patient with migraine Case report Women found superior relief of migraine with cannabis compared with beta-blockers, opiates, and ergots. Petro (1997) cited in Russo 18
Patient with migraine Case report 18 years of treatment failure with standard pharmaceuticals, found success with smoked cannabis. Grinspoon and Bakalar 45
Patient with migraine Case report Successful treatment with cannabis that did not produce inebriation. Terwur (1997) cited in Russo 18
121 Patients prescribed cannabis for migraine Retrospective study Migraine occurrences decreased from 10.4 to 4.6 per month; 39.7% had a positive effect, 19.8% had decreased frequency, and 11.6% had aborted pain. Rhyne et al. 46
5 Cases of chronic migraine headache Case series All cases successfully treated with dronabinol or cannabis. In one case, cannabis improved response more than dronabinol. In three cases, cannabis was used to abort headache in the prodromal phase. Mikuriya 48
1655 Patients seeking physician recommendation for medical cannabis Survey 40.8% of applicants reported improvement of headache symptoms with cannabis. Nunberg et al. 49
3 Subjects with chronic headaches Case series Smoking cannabis caused relief similar or greater than ergotamine and aspirin. Noyes Jr. and Baram 50
30 Outpatients with medication-overuse headache Clinical Trial (RDAC—Crossover) Nabilone was superior to ibuprofen in reducing pain intensity, analgesic intake, and medication dependence while improving quality of life. Pini et al. 52
Patient with refractory cluster headache Case report Smoked cannabis or dronabinol at the beginning of cluster headache provided complete immediate headache relief. Robbins et al. 53
113 Patients with chronic cluster headache Survey 26% regularly used cannabis. Use as treatment unknown. Donnet et al. 54
139 Patients with chronic cluster headache Survey Overall, 45.3% had used cannabis, and 19.4% had used it to treat cluster headache; 25.9% found efficacy, and the remainder found variable or negative effects. Leroux et al. 55
Patient with pseudotumor cerebri Case report Complete resolution of headache with smoking cannabis in <5 min without reoccurrence. Evans and Ramadan 56
112 Patients with MS-associated trigeminal neuralgia Survey Overall, 70% found relief from trigeminal neuralgia, and 90% found chronic pain relief. Consroe et al. 57

MS, multiple sclerosis.

Nabilone, a synthetic cannabinoid mimicking tetrahydrocannabinol (THC), has been shown to decrease analgesic intake while reducing MOH pain in a double-blind, placebo-controlled trial. 53 In this study, 26 patients with treatment refractory MOH completed a course of either nabilone (0.5 mg) or ibuprofen (400 mg) for 8 weeks, then after a week-long washout period, completed a second 8-week course of the previously excluded medication. Oral cannabinoid administration was chosen over an oromusocal THC spray, both because oral administration avoids the concentration peaks that can lead to euphoric effects and because chronic administration better overcomes individual differences in bioavailability. Although both substances showed improvement from baseline, nabilone was significantly more effective than ibuprofen in reducing pain intensity, analgesic intake, and medication dependence, as well as in improving quality of life. This study also examined the safety of nabilone as a treatment for headache and found that patients only experienced mild adverse effects that disappeared after discontinuation of the medication. The results of this study are significant, especially given that MOH is exacerbated by many pharmacological treatments. This study also highlights the potential value of cannabis in combination therapies, as a supplement to traditional treatments, or as a secondary treatment in refractory cases. Currently, a multicenter, double-blind, placebo-controlled study is being performed to examine the safety and efficacy of a dronabinol, or synthetic THC, metered dose inhaler for the treatment of migraine (clincaltrials.gov, NCT Identifier: <"type":"clinical-trial","attrs":<"text":"NCT00123201","term_id":"NCT00123201">> NCT00123201). When published, this study could give valuable insights into the efficacy and risks of cannabinoids for the treatment of migraines.

Cannabis and cannabinoids have been studied clinically for other conditions, showing efficacy in the treatment of neuropathic/chronic pain, spasticity, and nausea. 62–66 These three conditions are associated mechanistically and qualitatively with the experience of headache and, although the clinical literature for each of these conditions exceeds the scope of this review, it is plausible that their efficacy will carry over in the treatment of headache disorders as well. For example, the analgesic properties of cannabis seen in the treatment of neuropathic pain will likely apply to chronic headache, the antispasmodic properties seen in the treatment of multiple sclerosis could apply to muscle strain known to induce tension headaches, and the antiemetic properties seen in the treatment of chemotherapy-associated nausea might also palliate migraine-induced nausea.

Many individuals are currently using cannabis for the treatment of migraine and headache with positive results. In a survey of nine California clinics (N=1746), physicians recorded headaches and migraines as a reason for approving a medical marijuana ID card in 2.7% of cases, and 40.7% patients self-reported that cannabis had therapeutic benefits for headaches and migraines. In another California survey of 7525 patients, 8.43% of patients reported that they were using medical cannabis to treat migraines. Another survey of 1430 patients found that 9% of patients were using medical cannabis to treat migraines (subdivided into 7.5% for classical migraines, 1% for cluster headaches, and 0.5% for others). Other studies have reported the use of cannabis for migraine or headache relief, with specific estimates including 5% (N=24,800) and 6.6% (N=128) for migraines and 3.6% (N=128) and 7.4% (N=217) for headache.

Other studies have looked specifically at the change in the occurrence of headache disorders with use of cannabis. 52 One retrospective study described 121 patients who received cannabis for migraine treatment, among whom 85.1% of these patients reported a reduction in migraine frequency. 47 The mean number of migraines at the initial visit was 10.4, falling to 4.6 at follow-up visits after cannabis treatment. Moreover, 11.6% of the patients found that, when smoked, cannabis could effectively arrest the generation of a migraine. These results indicate that cannabis may be an effective treatment option for certain migraine sufferers.

Reports from 139 cluster headache patients 56 indicate that cannabis could have value in treating a portion (25.9%) of these patients as well. However, cannabis was reported to provoke cluster headache attacks in some patients (22.4%) as well. One possible explanation for this provoking effect is that cannabis is known to increase heart rate, increase blood pressure, and cause systemic vasodilation. 67 Cluster headache sufferers seem to be highly sensitive to vasodilation of the carotid tree and increased oxygen demands, findings that are supported by evidence that alcohol is a reliable trigger and supplemental oxygen is an effective abortive therapy. 68 The increased oxygen demand and/or the vasodilation effects of cannabis could theoretically be responsible for this exacerbation in some cluster headache sufferers. Interestingly, cluster headaches appear to show improvement with treatment using hallucinogens such as d-lysergic acid amide (ergine or LSA), psilocybin, and lysergic acid diethylamide (LSD). 33 As such, it is possible that the psychoactive properties of THC could play a role in the treatment of cluster headaches.

Case reports also give insights into the mechanisms behind the anti-headache action of cannabis. Smoking cannabis has been reported to relieve pain associated with pseudotumor cerebri, 57 a condition that is characterized by an increase in the intracranial pressure of an uncertain etiology. This suggests that the therapeutic effect of cannabis in some headache conditions could be a result of reducing intracranial pressure. In fact, dexanabinol, a synthetic cannabinoid, has been found to relieve intracranial pressure and improve outcomes after traumatic brain injury. 69

Cannabinoids and Headache Pathophysiology

The pathophysiological mechanisms of many headache disorders are not entirely understood. Nevertheless, preclinical data examining the effects of endocannabinoids on the neurological and vascular systems demonstrate the influence of endocannabinoids in modulating several major components of migraine pathogenesis ( Table 3 and Fig. 1 ). 35,70–85

Use of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial

Dementia is a neurological condition that affects the cognitive and functional ability of the brain and is the leading cause of disability among those aged 65 years and above. More effective ways to manage dementia symptoms are needed because current treatment options (antidepressants and antipsychotics) can be ineffective and are associated with substantial side effects, including increased rate of mortality. Cannabinoid-based medicine (CBM) has shown an ability to inhibit some symptoms associated with dementia, and the adverse effects are often minimal; yet, little research has explored the use of CBM among this population.

To monitor the safety of a purified dose of CBM oil (3:2 delta-9-tetrahydrocannabinol:cannabidiol) on behaviour symptoms, quality of life and discomfort caused by pain.

Methods/design

We will carry out an 18-week, randomised, double-blind crossover trial that consists of a 2-week eligibility period, two 6-week treatment cycles, and two 2-week washout periods (between both cycles and after the second treatment cycle). We aim to recruit 50 participants with dementia who are living in residential aged-care facilities. The participants will be randomised into two groups and will receive a dose of either CBM oil or placebo for the first treatment cycle and the opposite medication for the second. Data will be collected using the Neuropsychiatric Inventory Questionnaire, the Cohen-Mansfield Agitation Inventory, the Quality of Life in Alzheimer’s Disease questionnaire, and the Abbey Pain Scale on seven occasions. These will be completed by the participants, aged-care staff, and nominated next of kin or family members. The participants’ heart rate and blood pressure will be monitored weekly, and their body composition and weight will be monitored fortnightly by a research nurse, to assess individual dose response and frailty. In addition, pre- and post-surveys will be administered to aged-care staff and family members to understand their perceptions of CBM and to inform proposed focus groups consisting of the aged-care staff and next of kin.

Discussion

The study design has been informed by medical professionals and key stakeholders, including those working in the residential aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility.

Trial registration

Australian New Zealand Clinical Trials Registry, ACTRN12619000474156. Registered on 21 March 2019

Background

Dementia is a collection of symptoms that progressively reduces the cognitive and functional ability of the brain [1] and affects memory, intellect, rationality, social skills and physical functioning [2]. The symptoms associated with dementia present themselves in a variety of ways and can include depression, frustration, clinginess, forgetfulness, wandering, sexual aggression, hoarding, sleep disturbances and ‘the sundowner effect’ (increased manifestations of challenging behaviours at the end of the day [3]). Severe cognitive fluctuations in patients with dementia have been associated with an individual’s impaired ability to engage in activities of daily living, including social interactions and poorer quality of life (QOL) [4]. The slow progression and degeneration of dementia require that the affected individual receive additional support and assistance to remain at home or ultimately admission into residential aged-care facilities with 24-h care.

Dementia is the second leading burden of disability among Australians aged 65 years and older, and the burden of disease is expected to increase exponentially over the next 30 years [5]. Alzheimer’s disease is the most common cause of dementia and affects approximately 50–70% of the elderly with dementia. Pharmacological management of behavioural and physical symptoms of dementia is currently the most common treatment option, and many are prescribed medications such as off-label antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, and antidepressants to mask and alleviate the array of dementia symptoms [6, 7]. Medications such as aripiprazole, olanzapine, risperidone and memantine have been shown to reduce troublesome behaviours [8], although unclear guidelines are often provided for administration [2, 7]. This results in polypharmacy and its inherent risks, with numerous medications being prescribed for a longer duration than recommended [9]. Many of these medications lead to a number of substantial side effects [10], including increased rate of stroke and mortality [11].

Cannabinoid-based medicines (CBMs) have been shown to improve dementia symptoms such as aggression and agitation [12, 13], and they appear to be safer to prescribe than other pharmacotherapies [3] because the adverse effects are often minimal [14]. For example, Weier and Hall [15] found sedation to be the only adverse effect among patients with dementia prescribed either cannabinoids or pharmacotherapies. While periods of euphoria, somnolence and tiredness were observed among those prescribed dronabinol, a synthetically derived delta-9-tetrahydrocannabinol (THC) [16], there were only a small number of adverse events (6 of 98) related to the administration of the synthetic THC similar to those manifested by the placebo [14, 17]. However, well-designed, randomised, double-blind, placebo-controlled trials need to be completed to understand the most efficacious formulation, safety profile, drug–drug interactions and true effect to determine the place of CBM in dementia [18, 19], allowing greater generalisability of these outcomes [20].

A range of CBMs (synthetic compounds such as dronabinol or nabilone or pure cannabinols) are available; however, the combination of cannabidiol (CBD; the non-psychoactive compound) and THC (the psychoactive compound) [21] appear to be most effective, because both compounds improve psychomotor activity, mood, sleep–wake cycles and eating behaviours [14, 22, 23]. THC and CBD interact with the endogenous cannabinoid systems CB1 and CB2 receptors [19, 23, 24], producing symbiotic neuroprotective effects. For example, in pre-clinical trials, THC is found to be a partial CB1 antagonist and improves immune function [25], encourages amyloidogenesis [14, 22, 23, 26, 27], reduces neuropsychiatric symptoms, reduces pain sensation [28], stimulates appetite [21,22,23, 29], and inhibits acetylcholinesterase, similarly to cholinesterase inhibitors such as donepezil [30]. CBD is an inverse CB1 agonist [31] that promotes neurogenesis and vasodilation within the brain; increases neuronal plasticity and cerebral blood flow [32]; prevents cell destruction; and has anti-inflammatory (neuroinflammation and peripheral inflammation), analgesic, anticonvulsant and anxiolytic properties [25]. CBD is an important compound because it reverses the negative cognitive consequences and ameliorates the psychoactive properties of THC [21,22,23, 29].

Studies assessing the safety and efficiency of CBMs have shown many benefits among other neurodegenerative diseases, such as Parkinson’s disease [33, 34], epilepsy, post-traumatic stress disorder [18, 35], anxiety [12], and spasticity due to multiple sclerosis [36], with the use of CBM reducing benzodiazepine prescriptions by 45% [37]. However, only a handful of studies have investigated the use of CBM in patients with dementia [13, 14, 23]. Recently, an observational study monitored the use of a CBM medication over a 2-month period among ten females with severe dementia and found a 40% reduction in behavioural problems and 50% reduction in rigidity [38].

The pharmacodynamics and pharmacokinetics of THC (weeks 1–6, 0.75 mg; weeks 7–12, 1.5 mg) administered to ten participants with dementia was safe and well tolerated [14]. Administration of THC 2.5 mg in 11 patients with dementia demonstrated positive effects on mental state; dementia severity; and behavioural symptoms such as delusions, irritability, sleep and caregiver distress [23]. Studies reporting the use of dronabinol (2.5 mg daily) found improvements in anorexia and body weight, as well as less disturbed behaviours [16] such as agitation and motor behaviours, with no adverse effects observed [39]. Retrospective observations of dronabinol administration among 40 hospitalised patients indicated improvements in agitation and aggression, sleep duration, and meal consumption [13]. Two independent case studies monitoring the effects of nabilone (maximum dose 0.5 mg twice daily for 6 weeks) among elders with dementia found improvements in severe agitation and aggression [40], psychomotor activity, and smiling, as well as positive experiences among family members [41]. No changes in the number of falls or in balance (with eyes open) were reported among 18 participants administered 1.5 mg of oral THC twice daily [42], with recommendations suggesting higher doses (THC 1.5 mg three times daily), and longer study durations (great than 3 weeks) are needed to understand the true effects on behavioural symptoms, including QOL and activities of daily living [43]. Therefore, further research in this area is needed because many beneficial outcomes have been reported, although dosing, samples size, patient cohort (2–50 participants) and outcomes have varied in what are generally small studies with poor experimental designs.

The primary aim of the present study will be to see if a purified CBM oil is safe and improves behavioural and neuropsychiatric symptoms of dementia (BPSD). In addition, two secondary aims of this study will include examining QOL and discomfort caused by pain among patients with dementia receiving CBM oil.

Methods and general study design

This study has received approval from the Human Ethics Research Committee at the University of Notre Dame Australia. The study will use a parallel mixed methods design. The research methodology for this study is a phase II, randomised, placebo-controlled crossover trial. The design will include a 2-week eligibility (assessment) period, two 6-week-treatment cycles to allow each participant to take part in both the control and treatment cycles, and two 2-week washout periods (one between both treatment cycles and the other after the second treatment cycle). The 6-week treatment cycles have been selected on the basis of safety, pharmacodynamics, and pharmacokinetics as reported by Ahmed et al. [14], and a 2-week washout period has been shown to be safe and an appropriate length of time for cannabis to metabolise in older individuals [44].

In addition, residential aged-care staff and next of kin perceptions towards the use of CBM oil will be evaluated via surveys administered prior to and upon completion of the study. At the end of the second treatment cycle, the residential aged-care staff and family members will be asked to participate in a follow-up focus group to gather more in-depth information regarding individuals’ perceptions before and after the administration of CBM. Each participant will be in the trial for approximately 4 months (18 weeks), but the duration of the study will last over 12 months in order to recruit participants from a number of aged-care facilities.

Participants and setting

Participants will be recruited through residential aged-care facilities. Residential aged-care facilities within Australia are government-funded organisations that provide additional support for families who may have a family member with dementia, whereby many move from their residential homes into a residential aged-care facility so that they can be monitored and provided with additional care. PASS 2019 power analysis and sample size software (ncss.com/software/pass; NCSS, Kaysville, UT, USA) was used to derive the sample size. The Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH) is the primary outcome measure. Total sample size for a 2 × 2 crossover design assuming a two-sided t test to detect a mean difference of 6 on the NPI-NH scale with a standard deviation of 13 (for the difference) is 40 for a power of 80% and significance level of 5%. Fifty participants will be recruited to allow for a 20% attrition rate. Participants will be eligible to participate if they live in a residential aged-care facility, are aged 65 years or older, have a diagnosis of mild dementia (indicated by a score ≥ 20 on the Mini Mental State Examination [MMSE]), are able to speak English, are known as compliant with taking medication, are not bedridden, and are able to provide informed consent. Participants will be excluded if they have certain health conditions, such as frontotemporal or Lewy body dementia; have other comorbidities, such as epilepsy, anorexia nervosa, comorbid psychiatric conditions, Parkinson’s disease, or congestive heart failure; have a history of myocardial infarction or anginal pain, stroke, liver disease, or renal disease; or are taking medications such as primidone, phenobarbital, carbamazepine, rifampicin, rifabutin, troglitazone, Hypericum perforatum, and valproic acid that may interact with cannabis metabolism.

The pre-/post-surveys and focus group discussions are an exploratory, qualitative component of this study, and thus a definitive sample size calculation cannot be determined at this stage. We estimate that six focus groups comprising six to eight participants, including two groups of residential care staff, activity staff (care staff who monitor daily activities and social engagement), and family members, will ensure that data saturation has been reached. Written informed consent will be obtained from all participants, including the residential aged-care staff and the next of kin.

Rigor

Residential aged-care staff usually work within the aged-care setting for at least 3 months and therefore are likely to be working in the same facility for the duration of the 4-month trial. The same aged-care staff member will monitor the same participant(s) for the duration of the study and report any changes on the participants’ behalf. To be classified as a residential care staff member, the individual must spend at least two occasions per week with the participant. The same registered nurse will administer the medication for both treatment cycles.

Recruitment

The residential aged-care clinical and general managers who have established relationships with the participants and their next of kin will promote the study to those they feel would be eligible to participate. This will be performed through face-to-face conversations.

Randomisation

The randomisation process for this study will be done by creating a random number list using a 1:1 ratio allocation to ensure an equal number of cases in both the placebo group (n = 25) and the treatment group (n = 25) using Excel software (Microsoft Corp., Redmond, WA, USA). The determination of participant allocation will be completed by the laboratory manager in the drug manufacturing laboratory, with each case being provided a unique identification (ID) number (1–50). The primary researcher, who is responsible for recruitment, will provide the laboratory manager with the participant’s name to be sequentially matched against with the next available ID number. The laboratory will provide the pharmacy with both CBM and placebo in identical bottles labelled with the ID, but the medical practitioner and research team members will not know the order of treatment until the completion of the study. The pharmacist will place the participant’s name on the bottle before distributing the bottles to the aged-care facilities.

Blinding

This is a double-blind study. Therefore, the laboratory manager will be the only individual who will know the group allocation for the participants. This is to ensure that the pharmacist, aged-care staff, medical practitioners, research nurse, family members/next of kin, participants and researchers are all blinded to the participant’s group allocation. Once the study is complete, the laboratory manger will un-blind the information by providing the primary researcher with a list of participants and their group allocation in order to conduct the analysis.

Procedure

The study will run for 18 weeks, comprising a 2-week eligibility period for screening and clinical assessment and a 16-week experimental phase encompassing two 6-week cycles of treatment and placebo separated by a 2-week washout period between the treatment cycles and a 2-week washout period following the completion of the second arm (Fig. 1).

The key phases of the 18-week trial

Eligibility period

Individuals who express interest in participating in the study will initially be screened on the basis of inclusion criteria (described above). Following the initial screening process, potential participants will undergo a thorough clinical investigation by a geriatrician to ensure they have the cognitive capacity to provide informed consent using the MMSE. The MMSE [45] is the most widely used cognitive outcome measure to assess the severity of cognitive performance. It comprises 11 items, where a total score out of 30 can be calculated to assess the severity of dementia (25–30 = questionably significant, 20–25 = mild, 10–20 = moderate, 0–10 = severe). Those who seem suitable will be revisited by the geriatrician 1 week after the cognitive tests and will confirm that the participant has understood the purpose of the trial and has recalled the details of the study. Then the primary researcher will invite the eligible participants to enrol in the study and ask them to complete the consent form and provide some demographic and baseline information, including age, sex, education level, weight, medical history including comorbid illnesses, and prescribed medications. The participants will then be randomly allocated to treatment group A or B and receive either CBM oil or placebo for the first 6-week treatment cycle. No adjustments will be made to the participants’ currently prescribed medications.

Experimental phase

This phase of the study will take 16 weeks to complete. To minimise the risk of adverse events and variation in the maximum tolerated dose of CBM oil, each participant will receive one dose on the first and second days (2 pm) and two doses (9 am and 2 pm) for the reminder of both treatment cycles. A registered nurse will administer the dose along with a small meal (e.g., morning and afternoon tea), and the rate of titration will be monitored by the pharmacist to ensure it is appropriate for each individual. The participant will gradually receive an increased dose (titration) of the medication over several weeks, as shown in Table 1. During these weeks, the participant along with the care staff will record the presence of, and any change in, any potential adverse events that may be associated with the medication after the first dose, each afternoon when the dose is increased, and again on the final day of medication. If an adverse event is noted, the participant will revert to their previous best tolerated dose using the adverse events and safety protocol listed below.

An upper limit of 50 mg/day of THC will be permitted in those who do not experience any adverse events from the medication. Once a participant has reached their maximum tolerated dose (or a total of 50 mg/daily of THC), they will continue to receive that dose until the cessation of the 6-week period. The placebo group will follow a similar titration process using the indicated volumes shown in Table 1. They will continue to receive an increase in the volume of medication until they record an onset of an adverse event, at which time they will continue to take that volume of placebo until the end of the 6-week placebo cycle.

Management and administration of medication

The CBM oil (CogniCann; MGC Pharmaceuticals Ltd., Perth, Australia) will be provided in a sealed 10-ml glass spray bottle which contains a mix of THC and CBD in a 3:2 ratio (25 mg/ml THC; 17 mg/ml CBD) in a medium-chain triglycerides oil base. Each press of the vial will accurately dispense 100 μl of oil that contains 2.5 mg of THC. A total of 50 mg/day of THC and 34 mg/day of CBD can be administered for 4–5 days from one 10-ml glass spray bottle. CogniCann can be stored at room temperature (below 25 °C) for a total of 4 weeks. A certificate of analysis will be provided for each batch upon delivery.

The placebo will be administered in the same 10-ml glass spray bottle and collected following the procedures describe above. The placebo will comprise a terpene-based oil that contains esters that mimic the smell and taste of CBM.

The bottles of medication will be provided to the residential aged-care facilities by the affiliated pharmacist. The bottles will be delivered every week and collected again after 7 days of use (even if they are half-full) and returned to the pharmacy, where staff can determine how much was used (or left) and then dispose of the bottles to meet Therapeutic Goods Administration (TGA) requirements. At the start of the titration phase, one bottle will be administered for each participant (because the lower dose of 2.5 mg of THC allows for each bottle to hold 2–3 weeks of the medication). As participants begin to reach a higher dose (titration phase; see Table 1), two bottles will be provided on a weekly basis so that each participant will have sufficient medication to last for 7 days.

Data collection

The aged-care staff, resident participants with dementia, and nominated next of kin will complete a total of four outcome measures on seven occasions throughout the study. The questionnaires take approximately 20 min to complete and will be completed three times during the first treatment arm (baseline [day 0], after maximum tolerated dose has been reached [day 24], and the end of the treatment cycle [day 42]), three times during the second treatment arm (baseline [day 56], after maximum tolerated dose has been reached [day 80], and the end of the treatment cycle [day 97]) and once following the 2-week washout period after the second treatment arm (day 112). The questionnaires will be administered by the primary researcher.

Adverse events and safety protocol

An adverse events protocol will be put into place to minimise any potential harm or risks of receiving additional medication [14]. This will include participants reporting if they have experienced any adverse events 1 h after the increased dose has been administered (see Appendix). If moderate to severe adverse events are recorded (determined as ‘Somewhat worse’ (moderate) or ‘Much worse’ (severe) on the participant’s adverse event record) and these events have not ameliorated by the time for the next dose, the participant will receive the previous best tolerated dose. If the effects of the adverse event(s) have disappeared or become milder and do not interfere with the participant’s daily functioning or well-being, the registered nurse may increase the dose at the indicated rate. Recurrence of adverse events after two attempts to increase the dose will result in the participants remaining at their previous best tolerated dose for the remainder of the intervention period. A participant who experiences an adverse event will stay on the previous dose for another 2 days before the next dose is increased. At the beginning of the titration phase, a staff member at the aged-care facility will be vigilant in monitoring any acute adverse events such as dizziness, discoordination with a danger of falls and injury, and extreme fatigue. Any adverse events recorded will be reported to a facility line manager and will then be communicated to staff during shift changes.

Additional safety monitoring will be completed by a research nurse who will meet with each participant to discuss their adverse event records and measure their heart rate and blood pressure twice per week. In addition, the participant’s weight and non-invasive body composition measures such as lean body mass, bone mass, body fat percentage, and fat mass will be measured once per week using a portable scale. In addition, a nurse-led review will be completed 2 days into the washout periods to monitor the participant’s withdrawal symptoms once no more medication is being administered.

Measures

The Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH) [46] is a questionnaire that measures 12 neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability, aberrant motor behaviour, night-time disturbances and appetite changes). The frequency and severity of each symptom is rated (4-point and 3-point Likert scales). A total score can be calculated by adding the first 10 domains together, and all 12 domain scores can be summed in special circumstances where neurovegetative symptoms are of interest, and a carer disruptiveness score (summing the disruptiveness score of the 10 [or 12] behavioural domains) can be calculated. The NPI-NH can be completed in approximately 10 min.

The Cohen-Mansfield Agitation Inventory (CMAI) is designed to assess agitation cross three domains, namely physically aggressive behaviour, physically non-aggressive behaviour and verbally agitated behaviour [47]. The CMAI comprises 29 items, uses a 7-point Likert scale (never = (1), less than once per week = (2), once or twice per week = (3), several times per week = (4), once or twice per day = (5), several times per day = (6), several times per hour = (7)), and measures four subscales: aggressive behaviour, physically non-aggressive behaviour, verbally agitated behaviour, and hiding and hoarding. A total score of 203 is calculated, with a higher score indicating a higher frequency in behavioural occurrence, and the measure takes approximately 5 min to complete.

The Quality of Life in Alzheimer’s Disease (QOL-AD) instrument is designed to measure aspects important for an individual’s QOL. The QOL-AD consists of 13 items using a 4-point Likert scale (poor = (1), fair = (2), good = (3), and excellent = (4)) and is designed for both self-report and proxy report [48]. The QOL-AD measures four domains (physical health, mental health, social, and function) and can be completed with people with a wide range of dementia severity [49]. A total score out of 52 is calculated, with a higher score indicating a higher QOL. The self-report version can be completed in about 10–15 min and the proxy report in about 5 min. A composite score can also be calculated (participant QOL-AD × 2 + carer QOL-AD × 3).

The Abbey Pain Scale comprises six items assessing vocalisation; facial expression; change in body language; and behavioural, physiological and physical changes [50]. This questionnaire uses a 4-point Likert scale (absent = 0, mild = (1), moderate = (2), severe = (3)), and a total score out of 18 is calculated. The severity of pain is indicated as mild (score of 3–7), moderate (8–13) and severe (14+) and can be completed in less than 5 min.

Process evaluation outcomes

The one-page pre- and post-surveys will be administered to aged-care staff and next of kin at the beginning of the first treatment cycle and at the end of the second treatment cycle. These surveys comprise seven to nine questions regarding individuals’ perceptions towards CBM oil use and the symptoms of dementia they find most challenging. A total of six questions will be asked during the focus group discussions. These questions relate to positive and negative observations among those taking CBM oil, as well as changes in perceptions, knowledge and benefits regarding the use of CBM use.

Data analysis

Quantitative

The results of questionnaires completed on behalf of the aged-care staff, participants and family members will be analysed using IBM SPSS Statistics version 25 software (IBM, Armonk, NY, USA). The responses from the aged-care staff will be the main responses considered for analysis. Where available, participants and family responses will be included for secondary analysis. To examine group differences, the participants will be categorised according to their treatment cycle group allocation (group A or group B). Descriptive statistics will be derived. Each variable will be tested for normality. For those variables that meet the normality assumption, two-sided paired and/or independent t tests will be used to examine group differences within and between groups. If the normality assumption is violated, then non-parametric tests such as the Wilcoxon signed-rank test will be used. Within-subject differences of the four measurements between the first and second washout periods will be tested using paired t tests to ensure that the washout phase is long enough to rule out any carryover effects [51, 52]. All data collection points will be examined using general linear mixed modelling techniques to see if any changes in behaviour, QOL or pain have occurred over the duration of both treatment cycles. The covariates of weight, average dose of medication, and baseline measures will be controlled for in each model, and any interactions will be tested and reported. The proportion of adverse events during the CBM and placebo phases will be tested and reported for each individual. NPI-NH is the primary outcome measure for this study. All other measures (CMAI, QOL-AD, and Abbey Pain Scale) have been included for secondary analysis. The CMAI will be analysed using the reliability change methodology compared with the NPI-NH to allow small changes to be reported [53]. The α-value will be set at 0.05. In the instance where a participant withdraws halfway through a treatment cycle, the information collected prior to withdrawal will be retained in the study because their personal information will have been de-identified. The data management of the information collected will follow standard university procedures, be stored in a locked cabinet for a period of 15 years, be stored on a password-protected computer, and be backed up regularly in a secure format.

Qualitative

NVivo 12 software (QSR International, Doncaster, Australia) will be used for qualitative data management and assistance in the analysis of both the pre- and post-surveys and in the focus groups. Qualitative content analysis will be used to analyse the surveys to assess similarities and differences between responses. The focus group results will be transcribed verbatim, and the transcripts will be thematically analysed by repeated readings and a subsequent open coding process followed by line-by-line coding to identify key themes. To avoid bias, a triangulated approach including reflectivity by the primary researcher during the interview process, member checking to establish confirmability, and verbatim quotes to establish credibility will be used. The primary researcher and the research team at the University of Notre Dame Australia will have access only to the final data set. The data will be stored in university computers on a locked storage drive.

Discussion

To our knowledge, this is one of the first trials within Australia to evaluate the use of a purified CBM oil at the individual level among those with dementia to examine behavioural effects, QOL, and pain and discomfort. Only a handful of crossover trials have been conducted [14, 16, 41, 42, 54], although the majority have used fixed doses and have not incorporated an individually tailored dosing regimen. Soto et al. [28] reviewed 18 randomised clinical trials examining drugs prescribed for agitation and aggression and found large variations not only in the chosen questionnaires to measure these symptoms but also in the inclusion criteria. On the basis of their results, Soto et al. [28] suggested that trials lasting 9–12 weeks were adequate for assessing an acute response, whereas longer trials (6–12 months) were effective for assessing the stability of a response. The 18-week duration of this study is appropriate to assess the initial dose response [28], and the trial design is also reflective of other protocols of crossover studies and includes two 2-week washout periods to ensure patient safety and a chance for the medication to metabolise out of the body. For example, Babalonis et al. [31] designed a protocol to examine the use of a THC:CBD oromucosal spray among post-stroke spasticity patients and included two 4-week treatment cycles with a 2-week washout period between both cycles.

There are a number of strengths of our study. First, all participants will have a medical diagnosis of dementia. This ensures that the diagnosis is in line with the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [55]. Second, the residential aged-care staff spend a large amount of time with the participants, so they will be able to observe small changes, leading to accuracy in recording of the results. When possible, these results will also be compared with information from the participants and their next of kin to examine similarities and differences. Beattie et al. [56] published a protocol paper outlining a national project to collect multiple QOL perspectives from the care staff, family members and those living with dementia. Comparisons between care staff, family members and self-report QOL scores showed a linear relationship between reporters, with the residents often rating their QOL higher than the care staff [57, 58].

As an additional precautionary step, two separate questionnaires assessing behavioural symptoms have been included to ensure that the smallest effects of CBM oil are observed. A strict safety protocol monitoring of adverse events and nurse-led reviews during the washout periods will also be followed to ensure participant safety, which has been included due to the average age of the participants, additional medications currently prescribed, and the likelihood of having a comorbid condition. Weier and Hall [15] suggested that the therapeutic benefits of CBM are observed among patients with dementia when administered alongside adjacent therapy or medication. In addition, the dose of medication will be titrated to ensure that each participant receives their best tolerated dose and minimises the onset of any adverse events. This process of ‘start low and go slow’ is reflective of other studies as well as government documentation from Queensland Health [59, 60]. Educational training with the aged-care staff will be completed before the first participant is recruited to prevent unexpected issues arising during the trial and to ensure that they are familiar with the structure of the overall research protocol as well as the questionnaires.

This study has used a holistic approach to gain more in-depth information about BPSD and to capture staff and family members’ perceptions of CBM. The inclusion of the qualitative phase is important because little research has been completed to gain understanding of personal views of CBM use and the effects thereof in this setting. This approach allows the researchers to understand the perceived strengths and challenges in the use of cannabis within an institutional setting. Many symptoms associated with dementia, such as wandering, agitation, aggression, and psychotic behaviours, contribute to fatigue and burnout experienced by many caregivers [61]. Feast et al. [62] reviewed the relationship of BPSD and well-being of informal caregivers (child-adult or spousal caregivers) and found that the most distressing symptoms for caregivers were depressive behaviours, agitation and aggression, apathy (including irritability), aberrant motor behaviours, and delusions.

A number of challenges have been identified in the proposed study. It may be difficult to find those with a dementia diagnosis who have the cognitive capacity to give informed consent, because many experience a loss of short-term memory, intellectual reasoning, rationality, and social skills [1, 2]. This may lead to difficulty in recruiting participants into the trial and excluding those who do not have the capacity to give informed consent; yet, they are potentially the ones who exhibit a greater number of behavioural occurrences. Those who experience mild to moderate dementia still exhibit symptoms such as depression and anxiety and both verbal and physical agitation [2]. However, due to the limited legislation regarding including those who do not have the cognitive capacity to give informed consent in research projects, this limits who can be included in this study. The replication of this study design to include those with a moderate to severe diagnosis would warrant further generalisability of the results. Irreversible progression of cognitive impairment, the associated complications and comorbidities, and frailty of the participants may lead to participants dropping out of the study. To accommodate this, we have included a 20% increase in the sample size. It is also difficult to know if the questionnaires chosen for this study are suitable and sensitive enough to measure the changes attributed to the use of CBM oil, because no ‘gold standard’ exists to measure BPSD. Therefore, both the NPI-NH and the CMAI have been selected to account for the small effects. The pharmacodynamics of the medication will be monitored during the treatment cycles through the use of non-invasive body composition measures and monitoring of heart rate, blood pressure and weight. These measures will be collected by a research nurse external to the aged-care facilities to improve the feasibility of the study, to avoid additional workloads placed on the aged-care staff, and to ensure that each participant is receiving their best tolerated dose. In addition, only one residential staff member has been selected to complete the questionnaires, because they spend a great deal of time with the residents and can report symptoms easily. Independent reviews have not been selected for this study, because they are unfamiliar to the participants, which may lead to inaccuracy in recording of the results.

Trial status

The trial has been registered with the Australian New Zealand Clinical Trials Registry. The registration number is ACTRN12619000474156, and the trial was registered on 21 March 2019. Recruitment is set to begin in Feburary 2020. The approximate date that the recruitment will be completed is 20 July 2020.

Medicinal Cannabis For Migraine: A Patient Guide

Is marijuana for “pot smokers” or are there legitimate medicinal applications for cannabis? Why are governments and health regulators changing laws and legalizing cannabis? Australia, Canada, and most US and European states have now legalized medicinal cannabis.

It turns out that marijuana or cannabis has some complex properties that may provide important health benefits in a wide range of conditions.

This article looks at the evidence for medicinal cannabis to treat migraine. If you can withhold judgment until the end, you might be surprised by the controversy, political agendas, misinformation and the truth behind this hotly debated topic.

What is cannabis?

Cannabis is a plant with leaves and flowering tops that contain at least 489 distinct compounds across 18 different chemical classes. Two of the best known compounds are cannabidiol (CBD) and Delta-THC (THC).

THC and CBD

THC is responsible for the ‘high’ or intoxicating effect that can accompany cannabis use. THC still has some therapeutic value and is thought to act synergistically with CBD. Both CBD and THC have strong anti-oxidant properties.[1]

CBD delivers a significant proportion of the health benefits associated with cannabis. It is thought to have potential for analgesic, anti-epileptic, anti-nausea, anti-emetic, anti-inflammatory, anti-psychotic and anti-ischemic properties.[1] In animal studies its anti-inflammatory properties were found to be several hundred times more potent than aspirin.[1]

CBD is the compound which has a great deal of interest in epilepsy syndromes (see Charlotte’s Web below). The ratio of THC to CBD is often noted in cannabis-based treatments and useful to understand given their combined synergy and treatment applications.

Aside from THC and CBD there are many other compounds in cannabis that have also shown some benefit including terpenes and flavonoids.[1] These are referred to as cannabinoids. These vary significantly due to different strains, climate, soil, and techniques of cultivation. This also helps explain the variety of potential medical benefits and side effects.[1]

What is marijuana, hemp and hashish?

Marijuana refers to the dried flowers, leaves and stems of the cannabis plant.

The scientific name of the plant is cannabis. Generally speaking, marijuana is a variety of cannabis that has high levels of the THC and low levels of CBD.

Hemp is made up of the plant seed and fiber. It has high levels of CBD and very low, essentially insignificant levels of THC. Hemp is often used interchangeably as hemp or industrial hemp and was used in the production of industrial materials and fabrics before it was made illegal [see ‘The controversy, history and politics of medicinal cannabis’ below].

Kief is a powder derived from the leaves and flowers of cannabis plants. Hashish is pressed kief often in the form of a resin cake or ball.

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The endocannabinoid system

Receptors in the brain for cannabinoids (the chemical compounds found in cannabis) are 10 times more common than opioid receptors.[1] The brain makes its own cannabinoids called anandamide. The brain has receptors which interact with our own cannabinoids. Interestingly, cannabinoid receptors have been found to be the most common receptor in brain.[1]

This endocannabinoid system is something we all have. It helps maintain the balance of normal function within the body. It extends to every organ system including our neurological processes. Components of the endocannabinoid system are also found throughout the nervous system in spinal and peripheral pain pathways.[1]

If a neuron is over stimulated or excited, the body may use cannabinoids to help the neuron calm down. Research suggests that the platelets of those with migraine may have lower endocannabinoid levels than healthy patients.[5]

Strains of cannabis

the 3 types of cannabis plant

There are three primary species or strains of the cannabis plant:

  • Cannabis sativa
  • Cannabis indica
  • Cannabis ruderalis

Cannabis sativa

Cannabis sativa is a species of cannabis which has high levels of THC and low levels of CBD. The strain tends to have more uplifting, energetic, and euphoric properties. For this reason it is often used during the daytime.

Cannabis indica

Cannabis indicia contains a more balanced mix of THC and CBD. It has a moderate level of THC and very high levels of CBD. It has more calming, relaxing, and sedative properties. It tends to deliver a more full-bodied effect and may therefore be more appropriate for use at night as it can induce drowsiness.

Cannabis ruderalis

Cannabis ruderalis is essentially hemp with very low-to-zero levels of the psychoactive THC and high levels of CBD.

From these three cannabis species an almost infinite variety of combinations can be made up through crossbreeding strains and seeds. In the future, we may anticipate tailor-made strains that specialize in providing relief from certain symptoms specific to a disease or condition.

Forms of cannabis

Smoking is the classic form of consumption. It delivers the fastest onset and the shortest duration of effects. From a health perspective, smoking the plant gives off carcinogenic substances that are inhaled. It can also lead to pulmonary and lung issues. As a result experts will often recommend healthier alternatives to use medicinal cannabis.

Vaping is one of these alternatives. A vaping device is similar to an e-cigarette device. The vaping device heats the cannabis to a point where the cannabinoid vapors are inhaled but without overheating to the point of combustion which causes the smoke and respiratory toxins. It eliminates the dirty part of the smoke. Vaping has a very quick onset like smoking.

Oils or tinctures can deliver cannabis via an oil which is dropped under the tongue.

Sprays are also used in cannabis administration. Cannabis can be mixed into a liquid and used in nasal sprays or mouth sprays.

Topical formulations including creams, oils, and patches are also available.

Edibles are also common. This is where cannabis is mixed into foods. Common foods include candy, brownies, and other baked goods. Caution should be taken as the onset is typically delayed. It can take 1 – 2 hours before side effects are noticed. Secondly, it is also can be more potent when ingested and the effects can last longer.

Teas can also be made using cannabis as well as other drinks.

Pills can contain cannabis and help control the dose when made by an accredited manufacturer.

Suppositories can be used rectally and even vaginally for menstrual cramps.

What is medicinal cannabis?

Medicinal cannabis is a regulated and controlled formulation that may include pure or a crossbreed of hybrid strains to achieve a consistent and standardized ratio of CBD to THC and other chemical compounds.

The balance of these chemical compounds varies depending on the desired qualities of the treatment and the patient’s condition. The science of creating the optimal composition of cannabis-based chemical compounds to deliver the best therapeutic effect is in its infancy. There is tremendous potential for research to develop more effective treatments with fewer side effects.

Medical grade medicinal cannabis is different from what is considered “street” marijuana or cannabis. Street marijuana is not regulated. There are no guarantees of quality or composition. Those who obtain cannabis outside medical facilities or dispensaries have few assurances as to the type of cannabis they are receiving and any other potentially harmful substances or fillers that may be included. Street marijuana is often used for recreational use and is likely to contain significant levels of THC to deliver the psychoactive ‘high’ that recreational users seek.

Medicinal cannabis typically includes higher ratios of CBD to THC to maximize therapeutic benefit. THC levels are often insignificant which means patients may not experience any psychoactive effect or ‘high’ from use whilst still benefitting from its therapeutic properties. Current public perception paints all cannabis users, even those using medical formulations, as drug users seeking a ‘high’ which is simply untrue.

The controversy, history and politics of medicinal cannabis

The use of cannabis has evolved dramatically. In ancient times cannabis was used medically with roots in Western and Central Asia. It has been documented throughout Hindi literature, and 5,000 years ago Greek physicians used it for various aliments. In China, physicians used it for childbirth and joint pains.

Dr. William Brooke O’Shaughnessy introduced medicinal cannabis to the Western world in 1839. Based on his experiences in India as a professor and physician, he advocated for its use in pain relief and muscle relaxants. From around the mid 1800s to the early 1900s many prominent physicians prescribed cannabis. This included Sir William Osler, the father of modern medicine.[1]

These physicians used medicinal cannabis in both the prevention and acute treatment of headache. In 1845 cannabis preparations were listed on the US dispensary. It was produced by large pharmaceutical manufacturers many of whom still exist today including Bristol-Myers Squibb, Park Davis, and Eli Lilly.

In 1930 the Federal Bureau of Narcotics, which later became the DEA, began a campaign against cannabis led by Harry Anslinger. During the time of prohibition, cannabis was branded as a drug abused by minorities and low income communities. It was associated with psychosis, addiction, mental deterioration and violent crimes.[1] Some historians have argued that this was also to control the growing hemp industry. Hemp was widely used as a building material and provided strong fiber for clothing and fabric long before cotton.[2] The cotton industry had vested interests to see the use of hemp, its competitor, restricted.

Such claims and political agendas led to the Marijuana Tax Act of 1937 in the United States which delivered large fines and prison sentences to anyone with cannabis or hemp for medicinal or industrial use. This was despite the American Medical Association’s strong opposition to this legislation.[1] In 1941, cannabis preparations were removed from the United States Pharmacopoeia and National Formulary. Despite this, the editor of the Journal of the American Medical Association still recommended oral preparations of cannabis over ergotamine for menstrual migraine in 1942.[1]

Cannabis experienced a resurgence during the anti-establishment era of the 1960s and 70s in the US with its recreational use of marijuana. This counterculture image created a lasting impression that fuels much of today’s stigma associated with marijuana use. This is despite the overwhelmingly long and legitimate medical history of cannabis that existed for centuries prior.

The Controlled Substances Act of 1970 was the final nail in the coffin for marijuana. It labeled marijuana as a Schedule One drug alongside the most dangerous category of drug substances with no medicinal benefit. Marijuana was classified as dangerous as LSD and heroin. This new classification also prevented federal funding for research by making it illegal to conduct research in order to prove or disprove claims of medicinal benefit.

In 1976 a glaucoma patient sued the US government on the grounds that cannabis helped prevent glaucoma and vision loss. He won the case which led to a modest FDA investigation into cannabis use using a limited quantity. This closed in 1992. In 1996 California became the first state to pass the Compassionate Use Act which permitted medicinal marijuana. Since then lobbying has intensified from various medical associations and groups to reschedule marijuana from Schedule One to Two. This would enable research to be conducted and provide some access for patients who have failed standard treatments.

Medical groups and journals who have advocated for this transition include, amongst many others:

Image: dried cannabis flower buds

  • Epilepsy Foundation
  • American Medical Association
  • American Academy of Neurology
  • American Academy of Pediatrics
  • American Journal of Public Health
  • British Medical Journal

Today 29 states in the US have legalized medicinal marijuana use and 9 states have legalized recreational use. Federally, the DEA continues to refuse to change the “most dangerous” restriction. At the same time, the US government filed a patent for cannabinoids that was granted in 2003 for “cannabinoids as antioxidants and neuroprotectants”.[3]

Another contradiction to the Schedule One classification of marijuana is that the FDA approved synthetic versions in Dronabinol and Nabilone for medicinal use. Both treatments use key ingredients found in cannabis for medicinal treatment. The US government acknowledges the therapeutic benefit of cannabis with the approvals of these two treatments, yet the Schedule One status still remains.

What has reignited the cannabis debate?

In 2007 a young girl named Charlotte developed pediatric refractory epilepsy syndrome. She had literally hundreds of seizures per day and every medication she tried failed to help. Her parents had obtained all kinds of different and powerful medications which had significant side effects and were taking their toll. Charlotte remained unresponsive to treatment and within a few years her condition worsened until she was no longer able to walk, speak or eat. On several occasions she stopped breathing and came close to death.

As a last resort and in desperation her parents decided to try a cannabis oil. It was a blend that was high in the CBD and low in the psychoactive THC compounds. This meant Charlotte did not experience any intoxication or high associated with marijuana but still received the therapeutic benefits.

Astonishingly, her symptoms improved within hours and stayed that way. She improved dramatically and became a functional individual. Word began to spread within the epilepsy community and a flood of parents of children with epilepsy moved to Colorado where treatment access was available. Since then the treatment became known as ‘Charlotte’s Web’.

In 2013 the prominent CNN Chief Medical Correspondent, Dr. Sanjay Gupta retracted his anti-marijuana stance:

“Well, I am here to apologize. I apologize because I didn’t look hard enough, until now. I didn’t look far enough. I didn’t review papers from smaller labs in other countries doing some remarkable research, and I was too dismissive of the loud chorus of legitimate patients whose symptoms improved on cannabis. Instead, I lumped them with the high-visibility malingerers, just looking to get high.

I mistakenly believed the Drug Enforcement Agency listed marijuana as a Schedule 1 substance because of sound scientific proof. Surely, they must have quality reasoning as to why marijuana is in the category of the most dangerous drugs that have “no accepted medicinal use and a high potential for abuse.” They didn’t have the science to support that claim, and I now know that when it comes to marijuana neither of those things are true. It doesn’t have a high potential for abuse, and there are very legitimate medical applications.

In fact, sometimes marijuana is the only thing that works. We have been terribly and systematically misled for nearly 70 years in the United States, and I apologize for my own role in that.”

From here advocacy efforts have taken off to lobby for fair access to effective and safe treatment. Many of the public still have uninformed views that people only take marijuana to get high, but this is gradually changing.

The US government’s restriction on research

Research has been greatly restricted due to the Schedule One classification of cannabis in the most dangerous category of substances alongside heroin and LSD. To date there are no placebo-controlled clinical trials examining the use of cannabis for headache or migraine. [5]

Little is known about the therapeutic role of the various other compounds that cannabis contains including flavonoids, terpenes, phenols, amino acids, vitamins, proteins, steroids, nitrogenous compounds, enzymes, glycoproteins, simple alcohols, hydrocarbons, ketones, aldehydes, fatty acids, simple esters and lactones, and pigments.[1]

In 2017, the National Academies of Sciences, Engineering, and Medicine released this report ‘The Health Effects of Cannabis and Cannabinoids: The current state of evidence and recommendations for research.’

They found “substantial” evidence[6] to support the use of cannabis or cannabinoids in:

  • Chronic pain in adults
  • Chemotherapy-induced nausea and vomiting
  • Improving patient MS spasticity symptoms

They also found “moderate” evidence of efficacy in improving short term sleep outcomes in sleep apnea, fibromyalgia, chronic pain and multiple sclerosis.[6]

“Limited evidence” was found to support medicinal cannabis use in:

  • increasing appetite and decreasing weight loss associated with HIV/AIDS
  • MS spasticity symptoms
  • Tourette syndrome
  • Anxiety
  • PTSD

Evidence for cannabis treatment in migraine

The substance classification of cannabis has greatly restricted large scale research investigations. Large scale randomized and placebo-controlled studies are needed to prove clinical observations and initial findings. The current Schedule One classification of cannabis makes this extremely difficult. As a result, evidence for cannabis-based migraine treatment is limited to a number of smaller anecdotal reports, case studies and surveys.

One of the larger of these studies was from 2016 in Colorado where 121 migraine patients who were recommended and prescribed medicinal cannabis were reviewed. The study found that over 85% of patients reported some level of decrease in their monthly migraine frequency. Falling from 10 to around 5 attacks on average per month. [7]

There have been larger, high quality studies conducted looking at the efficacy of cannabis for chronic pain. Studies have shown that medicinal cannabis and cannabinoid extracts increase pain thresholds and provide pain relief. In a review of 38 published randomized controlled trials 71% found that cannabinoids demonstrated a significant pain relieving effect.[1]

In the same study 91% of patients were using medicinal cannabis as both an acute and preventative treatment for migraine.

Below is a summary of recent research summarized in a peer-reviewed published study. [13]

A recent 2018 study evaluating cannabis use for migraine and headache found that hybrid strains were the most preferred option for treatment. “OG Shark” which has high THC relative to CBD was the preferred strain within this group.[14]

Cannabis involvement in migraine biology

Cannabis and its cannabinoids appear to work through several neurological pathways and electrical channels in the brain, nervous system, nerves outside the brain and spinal cord.[1]

In some of these pathways, they activate the same circuits and brain receptors that many migraine medications target. Cannabinoids including THC have been shown to have a protective quality against pain stimulation in the brainstem.[1] The brainstem is believed to play a central role in the generation of a migraine attack. It is also suspected to be involved in the transmission of pain.[1]

There is also evidence to suggest that the endocannabinoid neurotransmitter system is a potential target for migraine treatment. Triptans may act on the brain’s endocannabinoid system to help treat migraine attacks. [8] Activation of cannabinoid receptors in the brainstems may also reduce or prevent migraine pain by inhibiting cortical spreading depression and the subsequent migraine attack.[9]

A deficiency in the endocannabinoid system has also been theorized as a potential cause of migraine and other chronic pain disorders such as chronic migraine and medication overuse headache.[1]

Widely recognized migraine triggers are known to degrade the endocannabinoid system. This results in an imbalance that increases the levels of CGRP and other chemicals known to be involved in migraine.[1]

One study has suggested that cannabinoid compounds may be an effective treatment for migraine due to the platelet stabilization and inhibition of serotonin.[10]

Is cannabis an alternative to opioids?

CBD is several hundred times more potent than Aspirin[1] and there is some evidence that suggests it may deliver pain relieving effects similar to some opiates.[1] This is an interesting alternative given the US opioid crisis. Around 45 people in the US die per day from prescription opiates which are being used for various pain disorders. 60% of these deaths are from a legitimate medical prescription. [6]

There has not been one recorded death from overdose or overuse with medical cannabis. In the Journal of American Medical Association (JAMA) a study showed states with medical cannabis have a 25% decrease in opioid related overdose or death compared to those states which do not have medical cannabis laws. This suggests medical cannabis may be a legitimate weapon in the war against the opioids.

Cannabis may also address migraine comorbidities

Medicinal cannabis has a wide range of potential medicinal applications in conditions that are often comorbid with migraine. It’s important to remember that these are not high quality placebo-controlled clinical trials. Many of the studies that support its potential are anecdotal, case based or laboratory based. That’s why it’s important to remember this is a list of potential areas where there are currently promising signs for therapeutic benefit. These include[1]:

  • chronic pain
  • neuropathic pain
  • fibromyalgia
  • rheumatoid arthritis
  • inflammatory bowel disease
  • irritable bowel syndrome
  • headache
  • facial pain
  • epilepsy
  • dystonia
  • depression, anxiety and mood disorders
  • post-traumatic stress disorder (PTSD)
  • autism
  • nausea and vomiting
  • asthma
  • autoimmune disease

Watchouts and side effects

Many of the most significant adverse events related to cannabis use come from smoking cannabis. Smoking cannabis (as opposed to vaping, oils or other formats) causes the release of harmful toxins and chemicals due to combustion. See ‘smoking’ above.

Research evaluating side effects suggest that medical cannabis is very well tolerated. Side effects that did arise they were mostly mild or moderate and temporary. Few side effects were sufficiently significant to cause a patient to withdraw from participation.[1]

Common side effects include:

  • Dizziness
  • Dry mouth
  • Disturbances in concentration
  • Drowsiness

Less common side effects:

  • Incoordination
  • Imbalance
  • Euphoria
  • Paranoia
  • Anxiety

Studies have suggested that tolerance to many of these minor side effects improves quickly with continued use.[11]

It is possible to have withdrawal symptoms from cannabis. One study showed that as many as 23% of patients may experience rebound headache after ceasing cannabis treatment. [12]

Cannabis edibles can be confused as foo. Children are particularly vulnerable. Candies, cookies, and brownies often look the same despite containing cannabis. Take care to keep these away from children who might confuse the edibles as candy.

Depression and anxiety is a common comorbidity with migraine. There is evidence that suggests cannabis can improve or worsen these two conditions depending on the type of strain being used. CBD to THC ratios can play an important role, for example, cannabis sativa strains are more energizing and uplifting which may be appropriate for depression.

On the other hand, cannabis indica strains are more relaxing and calming so these may be used for anxiety. Many patients with migraine also have some type of sleeping disorder. Cannabis indica may be utilized in this context to assist with sleep.

Long term use raises more questions and concerns. Cognitive impairment has been associated with long term use in adolescents who still have a developing brain. Some studies have demonstrated a drop in IQ and neural cognitive functioning in those who frequently used marijuana under the age of 21.[7]

In adults there are mixed results. Some studies have suggested that long term chronic use of cannabis in adults affected verbal memory recall (i.e. for every five years of frequent cannabis use, one in two people may recall 1 word less in a list of 15 words). Frequent long term cannabis use was also associated with cognitive processing speed. This decrease was slight but a noted concern.[7] More evidence supported by high quality clinical trials are needed to understand the full spectrum of risks and potential side effects.

In terms of serious risks, high risk individuals are those who may be psychotic or schizophrenic. These symptoms can worsen with cannabis use. Those with psychiatric disorders should not use cannabis.

In chronic cannabis use it is possible to develop a syndrome called hyperemesis where an individual experiences intractable nausea and vomiting.[1]

Lethal overdoses do not exist from cannabis. In terms of fatal risk, cannabis is 114 times less lethal than alcohol. There has not been evidence of a single death attributed to medicinal cannabis.[6] Note: illegal synthetic substances which may combine elements of cannabis with other chemicals. These substances can cause serious harm or potentially fatal overdoses (i.e. ‘K2’ or ‘Spice’).

Who should not use medicinal cannabis?

Due to the lack of definitive evidence, medicinal cannabis is still viewed as a last resort after standard therapies have failed.

Given the minimal side effects and safety profile of medicinal cannabis it may be a viable alternative to opioids which are also considered a last resort.

Caution is advised in the following patient groups:

  • young patients under 21 are not advised to use cannabis due to its potential effects on the developing brain
  • individuals with a history of substance abuse or addiction
  • those with a psychiatric disease, especially schizophrenia or family history schizophrenia
  • lung disease should avoid inhaling forms of cannabis
  • pregnant and breastfeeding women
  • those who are required to regularly drive, operate machinery and other hazardous tasks.

Where is medicinal cannabis legal?

There is a clear trend towards legalization. Current regulations and enforcement vary significantly between countries:

  • Australia – legal
  • Canada – legal
  • Mexico – legal
  • USA – legal in 29 states. Federally illegal.
  • United Kingdom – illegal
  • Many European nations have legalized medicinal cannabis which are not listed here.

If you would like to know about your country’s current status feel free to ask in the comments.

What should we expect in the future?

Expect more heated debates, controversial headlines and the progressive relaxation of strict marijuana regulations.

We still don’t know what combinations or ratio of cannabinoids and cannabis compounds are going to be effective for what disorder and symptoms.

New medicines may be developed based on cannabis plant-derived cannabinoids. These may be more effective in targeting specific diseases or symptoms, and with fewer side effects.

To discover these potential new treatments, much more research is desperately needed. Fortunately, research is on the increase. We are still only in our infancy of understanding all the functions within the cannabis plant and its potential.

This plant holds promise to deliver a whole new class of treatments across a wide range of disease, chronic disorders and symptoms. Medicinal cannabis presents an exciting new frontier for medical scientists and researchers which will ultimately benefit the patient.

What do you think? Is medicinal cannabis for migraine a new hope or a smokey haze with little real substance in it? Let me know in the comments.

MORE TREATMENT OPTIONS TO PREVENT MIGRAINE

Get a list of the top proven preventative migraine treatments according to guideline recommendations from the US and Europe.

Article References

[1] Baron, Eric P. “Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: What a long strange trip its been…” Headache: The Journal of Head and Face Pain 55.6 (2015): 885-916.

[2] Fattore, Liana, ed. Cannabinoids in Neurologic and Mental Disease. Academic Press, 2015.

[3] Hampson AJ, Axelrod J, Grimaldi M. Cannabinoids as antioxidants and neuroprotectants. 2003. U.S. Patent #6,630,507. Available at http://www.google.com/patents/US6630507 (Accessed March 20, 2015).

[4] Gupta S. Why I changed my mind on weed. 2013. Available at http://www.cnn.com/2013/08/08/health/gupta-changed-mind -marijuana/ (Accessed March 20, 2015).

[5] Lochte, Bryson C., et al. “The Use of Cannabis for Headache Disorders.” Cannabis and cannabinoid research 2.1 (2017): 61-71.

[6] National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. National Academies Press, 2017.

[7] Eric Baron, Migraine World Summit Interview 2016.

[8] Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: Implications in migraine. J Neurosci. 2013;33:14869-14877.

[9] Kazemi H, Rahgozar M, Speckmann EJ, Gorji A. Effect of ccannabinoidreceptor activation on spreading depression. Iran J Basic Med Sci. 2012;15:926-936.

[10] Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int J Clin Pharmacol Res. 1985;5:243-246.

[11] Grotenhermen, Franjo, and Kirsten Müller-Vahl. “Medicinal uses of marijuana and cannabinoids.” Critical Reviews in Plant Sciences 35.5-6 (2016): 378-405.

[12] Karschner EL, Darwin WD, McMahon RP, et al. Subjective and physiological effects after controlled sativex and oral THC administration. Clin Pharmacol Ther. 2011;89:400–407.

[13] Baron, Eric P. “Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science.” Headache: The Journal of Head and Face Pain 58.7 (2018): 1139-1186.

[14] Baron, Eric P., et al. “Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort.” The journal of headache and pain 19.1 (2018): 37.