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.” — Dr. Sanjay Gupta [4]

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.