EVERYTHING YOU NEED TO KNOW ABOUT CBD (CANNABIDIOL) USE FOR MIGRAINE, HEADACHE, PAIN, AND OTHER CONDITIONS.
CBD is everywhere! You can buy it at the local grocery store, supplement store, gas station, video rental store, and almost anywhere else nowadays. There are hundreds of brands. Is it right for you? Will it work? How do you take it? How do you know which products are of good quality and are safe? Are there downsides? Are there side effects? Will you test positive on a drug screen? These are a few of the many questions you likely have. Our patients ask about CBD use all the time in regard to migraine and pain. So, I decided to write this blog to provide an overview and answer these burning questions you may have!
There have been a multitude of studies documenting the analgesic and anti-inflammatory benefits of medicinal cannabis across many chronic pain syndromes1–4, and it has been a historical treatment for headache and migraine for centuries.2,3,5–7 The vast majority of supporting evidence of cannabis and cannabinoids involves various chronic pain syndromes. These benefits are hypothesized to extend to headache disorders such as migraine given overlapping neurobiological pathways of pain. Some data suggests that cannabinoids appear to work uniquely within the inherent anatomical pathways of migraine (including serotonergic triptan pathways) and pain.1,2,5–37 Unfortunately, the majority of data supporting the use of cannabis and cannabinoids in migraine and headache disorders is based on case series, case reports, surveys and anecdotal evidence.5,6,32,33,38–57 There has been one retrospective study of cannabis use in the treatment of migraine which reported strong statistically significant findings of benefit.58 There have been only two limited prospective trials of cannabinoids containing a control group in headache disorders. One reported significant benefit in chronic daily headache associated with medication overuse headache,59 and the other reported significant benefit in both the acute and preventive treatment of chronic migraine.60
The endocannabinoid system is a normal and important biological system within everyone. It plays a role in many regulatory physiological processes across all organ systems, and is widely distributed throughout the central nervous system (brain and spinal cord) and peripheral nervous system (nerves outside of the spinal canal). Notably, it plays a strong role in pain pathways. This system works by the interaction of our own natural endocannabinoids turning on or turning off various endocannabinoid receptors throughout our body.
Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are the two predominant cannabinoids found in cannabis (marijuana). Cannabinoids are unique to the cannabis plant, and can be thought of as the “plant equivalents” of our own endocannabinoids. So, they interact with the same endocannabinoid receptors in our body as our own endocannabinoids do. Given the growing evidence of cannabis and cannabinoids in the treatment of chronic pain and other medical conditions, in February 2019 The World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category. In January 2017, the National Academies of Sciences, Engineering, and Medicine concluded that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults. In 2014, the Canadian Pain Society revised their consensus statement to recommend cannabinoids as a third-level therapy for chronic neuropathic pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3 (the number of patients needed to treat for 1 of them to receive benefit). So naturally, there has been a quickly growing public interest in these potential therapies for a variety of reasons, especially in pain disorders.
THC causes the psychoactive qualities (“high”) of cannabis. THC has been shown to be 20 times more anti-inflammatory than aspirin and 2 times as anti-inflammatory as hydrocortisone. It is also a potent anti-emetic (anti-nausea), which is why there are two FDA-approved synthetic THC medications for chemotherapy related nausea and vomiting (Dronabinol, Nabilone). The existing literature and research on the treatment of pain have primarily studied cannabis itself with its variable and often undefined combinations of THC, CBD, other cannabinoids, terpenes, and other constituents. The medicinal benefits of cannabis are suspected to be from the “entourage effects” from synergistic action (working together) between various cannabinoids such as THC and CBD, and terpenes.1,61
In contrast to THC, CBD is non-intoxicating (no “high”). CBD has been shown to be several hundred more times anti-inflammatory than aspirin. Greater than 65 molecular receptor targets and greater than 80 mechanisms of action have been identified. There have been scientific, animal models, and very limited human clinical trials documenting its anti-inflammatory and analgesic (pain-relieving) properties. However, there are no high-quality research studies to date evaluating isolated pure CBD in any pain, migraine, or other headache disorders. So, it is unclear how much benefit CBD in isolation provides outside of the presumed entourage effects that it contributes to.
In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related problems associated with its use. In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes. In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD. The Farm Bill also removed hemp from the Controlled Substances Act, making it no longer an illegal substance under federal law. To review, up until the Farm Bill was passed, any form of cannabis or cannabis derivatives (including CBD) have been federally illegal since the Controlled Substance Act of 1970, which is when cannabis was changed to a Schedule 1 drug of which it has remained since. Therefore, it is important to remember that cannabis chemovars (strains) and CBD oils with greater than 0.3% THC are still considered marijuana, and thus are illegal federally, require a medical marijuana card for use, and are illegal to cross state lines with. In May 2019, TSA began to allow travel with CBD products containing 0.3% or less of THC.
Thus, the use of CBD products has been exponentially increasing for a wide variety of uses, including pain and headache, and anecdotal benefits are commonly reported. Although the various CBD companies provide guidance on dosing, there are no standardized dosing guidelines on optimal dosing, and strengths and frequencies used are widely variable. Some cannabinoid experts feel that most over the counter bought CBD products have too low of milligram content to have true physiological effects based on the high dose needed to enter the central nervous system through the blood-brain barrier. On the other hand, some suggest that “micro-dosing” with the lower CBD doses found in many products is enough to help replace endocannabinoid deficiencies. These dosing uncertainties have yet to be clarified and confirmed scientifically. Pure isolated CBD has never been evaluated prospectively in a randomized controlled trial in the treatment of migraine, headache, or pain to date. So, its use in the treatment of pain disorders including migraine remains primarily anecdotal at this time, but we anticipate future trials will provide more objective scientific data. The FDA is currently gathering and assessing available objective scientific data in anticipation of providing general dosing guidelines and recommendations of use.
SAFETY AND SIDE EFFECTS
CBD is generally very well tolerated, and pure CBD is not felt to be sedating. Actually, low to moderate doses are often more alerting.62 Early anecdotal literature involved CBD with sedating components (full spectrum products) including trace THC, other cannabinoids, and terpenes. For example, myrcene is a terpene often attributed to the “couch lock” phenomenon of some cannabis chemovars (strains). So, the sedation was not from the CBD, but actually from these other associated components. More recent studies (up to 600 mg pure CBD) have reported no sedative side effects.
There is one FDA approved form of CBD called Epidiolex, and these trials are what most of the known CBD safety data comes from. This is a purified cannabis derived form of CBD which was FDA approved in June of 2018 for some forms of refractory pediatric epilepsies.63 Dosing ranges from 5 to 20 milligrams per kilogram body weight total daily dose, which is divided between a morning and evening dose. These does are significantly higher than any form of over the counter non-prescription forms of CBD commonly sold. CBD is metabolized (broken down) in the liver. So, patients with liver disease many need to be more cautious with their dosing. In the Epidiolex studies, there was a slight elevation in liver enzymes in some patients. However, the vast majority of these liver enzyme elevations were in patients using the highest 20 milligram per kilogram daily dose and particularly when CBD was also being used with other anti-seizure medications, especially valproate and clobazam. This risk was much lower in patients outside of these categories. None the less, caution should be used when CBD is used with other medications that are metabolized by the same liver enzyme systems to avoid causing high or low levels of other medications. For example, high doses of CBD (such as those in the Epidiolex trials) may increase levels of certain medications such as warfarin, macrolide antibiotics, calcium channel blocker blood pressure medications, benzodiazepines, cyclosporine immunosuppressants, sildenafil, antihistamines, antidepressants, antipsychotics, antiretrovirals (such as HIV meds), and some antiseizure medications (such as clobazam), to name a few. With that said, the more commonly used doses bought over the counter are nowhere near the high doses of CBD in Epidiolex, so the clinical relevance of CBD use with these liver interactions is unclear at much lower doses. For example, Sativex studies (a whole plant CBD rich sublingual spray) found no interactions with liver enzyme systems with 40 mg CBD. The bottom line is that there are still many uncertainties so it is better to use caution until future studies can help clarify these questions.
In the Epidiolex studies, the most common adverse effects in a minority of patients were somnolence, lethargy, drowsiness, fatigue, diarrhea, decreased appetite, and nausea/vomiting. However, these side effects were in patients who were also using other anti-seizure medications (virtually all of which have drowsiness as a universal side effect). In addition, Epidiolex is about 98% pure CBD, but still contains 0.15% or less of THC, traces other cannabinoids and terpenes at a dose of 10 milligrams per kilogram per day. Therefore, these side effects are most likely to be related to these other factors rather than from the CBD content itself.
DIFFERENCES IN CBD PRODUCT TYPE, QUALITY, AND SAFETY
CBD has a wide variety of formulations from oral (primarily oils), tinctures, vaporization, and topical creams. Full spectrum or “whole plant” oral CBD products are the most popular. They are most likely to provide the “entourage effects” of cannabis. They contain everything the cannabis plant contains including CBD, trace THC (should be ≤0.3% per Federal law), terpenes, and flavonoids. Broad spectrum CBD products can be thought of as full spectrum without the trace THC. CBD isolate products consist of CBD isolated from all plant contents, without trace THC. It is important to know that use of these products may have a risk of testing positive on a marijuana drug test (which tests for THC). Although this risk is very low and can also be influenced by differing metabolisms between people, it is still a risk to be aware of. The risk of this correlates with the presence of trace THC and this risk would be highest in full spectrum, followed by broad spectrum, followed by CBD isolate products. Lastly, there is a misconception that CBD converts into THC in the human body. This is not true, and there is no evidence of this happening in the human body, and actually more evidence that it does not happen.62 This notion was based on an old lab-based experiment which involved acids and conditions which are not reflective of normal human physiology.
CBD products chosen should include independent 3rd party laboratory testing for content and quality. The reason is because there are so many CBD companies and products, and many of them are of low quality. In 2017, there was a study published in the Journal of the American Medical Association (JAMA) which evaluated 84 CBD products analyzed from 31 different companies, including 40 oils, 24 vaporization liquids, and 20 tinctures.64 Only about 30% of the products were labeled accurately with what they claimed to contain, while about 70% of the products were inaccurately labeled based on actual CBD content (43% had higher than advertised CBD, 26% had lower than advertised CBD). In addition, 21.4% had high levels of THC, above legal limits.
Another study looked at 13 CBD products tested across Los Angeles and New Jersey.65 Five of them (almost half) had no traceable CBD, and only 1 had an accurately advertised amount of CBD! Two had high THC (3 mg), 1 CBD gel cap product was contaminated with a deadly strain of E. Coli (shiga toxin), and 2 had potentially dangerous levels of ethanol.
In 2017, 5 patients in Utah developed seizures, confusion, coma, and hallucinations with a labeled “CBD” product, and 52 patients were harmed through 2018 with this product. This “CBD” product actually contained a synthetic cannabinoid and no CBD at all. The International Cannabis and Cannabinoid Institute in the Czech Republic assessed 29 CBD products and found that 69% exceeded the recommended levels of polycyclic aromatic hydrocarbons. These are known carcinogens and genotoxic mutagens according to International Agency for Research on Cancer. Unregulated CBD products may contain pesticides or heavy metal contamination as well.
In summary, CBD shows analgesic and anti-inflammatory effects in scientific and animal models, but there is limited data involving human studies. However, this should be changing soon now that CBD is federally legal with easier access to research. None the less, there may be a wide variety of tremendous therapeutic potential to be harnessed. Non-FDA approved forms of CBD may have inconsistent levels of CBD, THC, and contamination. Therefore, non-FDA approved forms of CBD should be from companies using independent 3rd-party lab analysis to confirm quality and contents until FDA regulations are available. It is important to know that CBD involves drug interactions with some common liver enzyme metabolism systems, but dosing threshold to interfere with other medications being metabolized in these same pathways is unclear and needs to be further clarified.
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