Virginia Thornley, M.D., Board-Certified Neurologist, Epileptologist
April 6, 2018
Medical marijuana seems like the shining breakthrough drug the shining pill in armor, the magic pill that seems to cure everything. However, there are always two sides to every coin. One must still proceed with caution. The phytocannabinoids, cannabidiol, and tetrahydrocannabinol exert their effects through the endocannabinoid pathway, the CB1 receptor is most abundantly found in the nervous system. Cannabidiol which has no euphoria acts weakly with the CB1 receptor almost as a reverse agonist blocking the THC from exerting its effect offsetting potent side effects of tetrahydrocannabinol.
The medical benefits are overwhelmingly numerous including ameliorating seizures, spasms from multiple sclerosis, peripheral neuropathy in HIV patients, chronic debilitating pain, post-traumatic stress disorder symptoms and other associated diseases. Despite the stigma of using it, the delay in clinical trials and marked hesitation of the medical community, medical marijuana has landed and there is no going back. Yet even with its numerous health benefits, it is always prudent to take a step back and examine any flaws as with any other new kid on the block or any new agent that comes along even though it’s been around for thousands of years.
Is marijuana safe for medical use? The take on medical marijuana by the FDA
So far from the FDA official website, the FDA does not recognize medical marijuana coming from the botanical plant with any medical indication. The FDA does not recognize it to be safe or beneficial for any type of disease or condition. The FDA will facilitate any companies interested in bringing quality products including science-based research. The full take of the FDA on marijuana can be found here https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm#use
Long-term effects on the brain
Perusing the scientific literature, it is difficult to find any long-term damage to the brain. There was a report in a heavy marijuana user where there was damage to the corpus callosum, possibly worse with young users (1). This is a small study of 11 heavy marijuana users with 11 age-matched cohorts. Diffusion tensor imaging was used. Previous reports alluded towards poor cognition with heavy marijuana use. This study is aligned with that. It was suggested that there may be increased diffusibility within the white matter tracts of the corpus callosum. Young age is thought to make the corpus more susceptible to white matter damage. The only caveat is this is with heavy use and the substance found in recreational marijuana is going to be a different form compared to medical marijuana extracted from the marijuana plant used for medicinal purposes. It is not clear if this report would carry over to medical marijuana users where the preparation of the product is much different(1).
Effect on schizophrenia spectrum diseases
In a large study of 171 patients, it was found that with heavy use of cannabis, the age of onset of schizophrenia spectrum disorders seems to occur earlier (6). This is one of the reasons why in some dispensaries, it is not sold to patients with a history of schizophrenia. There are some anecdotal reports of some patients having a paranoia with medical marijuana that is reversible once taken off.
Effect on the heart, reports of myocardial infarcts and ST elevations
While the literature suggests low toxicity and most side effects are related to cognition and gastrointestinal problems, there are several cannabis-associated myocardial infarcts in the literature. The dispensaries in the state of Florida use a previous history of a previous myocardial infarct as a contraindication in using medical marijuana. These were synthetic drugs used recreationally. There was one case report where a heavy user suffered from an ST elevation and subsequent myocardial infarct after becoming toxic to marijuana used recreationally. In one study, synthetic cannabis was used, the myocardial happened to a young patient where an atheromatous plaque was excluded as the source. Etiology and mechanism are unclear why infarcts should occur. It is quite possible that because it works on the 5HT receptor for anxiety which can cause vasoconstriction, this may be one mechanism. Other studies are needed to elucidate the mechanism of action.
Because medical marijuana is used as an adjunctive agent for epilepsy, perhaps off-label since it has not been approved through FDA as an anti-epileptic agent yet, it was found that medical marijuana used in conjunction with Clobazam (Onfi) tended to elevate Onfi at higher levels.
In one small clinical study, in 13 patients, 9 had an increase of about 60 in the Clobazam level and by 300 in Norclobazam level. There was, however, a tremendous reduction of seizures by >50% but Onfi (Clobazam and Norclobazam levels) should be monitored (3) on a routine basis to avoid any untoward toxicity.
Other milder symptoms
In one large study on Lennox-Gastaut syndrome where cannabidiol was titrated to a 20mg/kg over a course of 14 weeks, mild to moderate symptoms were noted including pyrexia, sedation, dizziness, and diarrhea. However, the titration rate was very rapid and the patents who were 50kg were quickly at 1000mg within 14 weeks which does not usually happen in the real world. Medications are usually increased over a longer period of time in slower increments.
While everybody is touting the horn of medical marijuana it is always prudent to stand back and ensure there are no possible risk factors for adverse side effects. The most serious and common seen in the literature appear to be related to schizophrenia spectrum disorders and cannabis associated myocardial infarct. The only caveat is that the literature is peppered with these reports, however, the quality of the recreational drugs are vastly different from medical marijuana which tends to be organic and all natural extracted from the plant in licensed medical dispensaries. The extraction of the medical components is vastly different from the smoked synthetic version of tetrahydrocannabinol. So, is difficult to know if these reports would actually corroborate with use in medical marijuana. The ones with side effects were heavy users of recreational smoked types of marijuana, it is unclear if it was synthetic or organic. As the popularity of medical marijuana progresses, more information will be available regarding the side effect profile.
- Arnone, et al, “Corpus callosum damage in heavy use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics,” Neuroimage, 2008, Jul., 1, 41 (3): 1067-74. “J Addict Med. 2017 Sep/Oct;11(5):405-407. doi: 10.1097/ADM.0000000000000326.
- Volpon, et al, “Multiple cerebral infarcts in a young patient associated with marijuana use, ” Journ. Addic. Med, 2017, Sep./Oct., 11(5):405-407.
- Geffrey, Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy,” Epilepsia, 2015, Aug., 58 (8):1246-1251.
- Stewart, et al, “Obstructive sleep apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones,” Epilepsia, 2017, Jun., 58(6): e87-90
Shahzade, et al, “Patterns in adolescent cannabis use predict the onset and symptom structure of schizophrenia-spectrum disorder,” Schizophrenia Research, 2018, Feb., 2 pii S090-9964 doi:10. 1016/j. schres. 2018.01.008 (Epub ahead of print)
Orsini, et al, “Prolonged cardiac arrest complicating massive ST-segment elevation myocardial infarct associated with myocardial consumption,” J. Community Hosp. Intern. Med. Perspect, 2016, Sep., 7. 6 (4):31695
Thiele, et al, “Cannabidiol in patients with seizures from Lennox-Gastaut Syndrome (GWPCARE4): a randomized, double-blind placebo-controlled phase 3 trial,” Lancet, 2018, Jan., 390 (10125):1085-1096
Virginia Thornley, M.D., Neurologist, Epileptologist
March 24, 2018
Any news outlet you peruse is bound to have mention of the current opioid crisis looming on the horizon. Opioids are commonly prescribed as the last resort for patients with chronic pain who have failed conventional medications, interventional measures such as epidural injections or surgery, non-pharmacologic measures such as physical therapy and even Eastern techniques such as acupuncture. With tolerance a common problem and patients needing higher and higher dosages for pain control because of the properties of opioids, it is little wonder that chronic pain control is difficult to maintain.
The hot topic of debate in many states is the recognition of medical marijuana as a legitimate medication for chronic ailments. However, because of the stigma it has incurred being well-known for its psychoactive properties and widely seen in pop culture in movies with kingpins smoking it for recreation, the medicinal values are often overshadowed and lack of side effects in low doses is easily overlooked.
Not your stereotypical patient and not your direct referral
Patients and even physicians likely have a preconceived notion of who seeks medical marijuana. While chronic pain is top of the list, often times, it is discovered by the hard-working carpenter who discovered it online and found a small scientific article on non-pharmacologic treatments trying to come off sedating pain-relieving medications. It will be the former business owner who lived an enjoyable life being active dancing or the woman afflicted with an autoimmune disorder and has failed every medication under the sun. Many times patients come in not because they want to feel good but because it is their last resort and they’ve exhausted every treatment option known to mankind. They dislike the side effects of the strong painkillers such as opioids and just want the pain to stop and live a normal life. It is amazing how indirectly patients hear about the wonders of medical marijuana, it will usually be a neighbor who swears by it, or somebody’s friend who mentions it out of the blue. Oftentimes, it is by word of mouth since the few physicians interested in recommending it are very reluctant to advertise with good reason.
Mechanisms of cannabidiol and tetrahydrocannabinol
Medical marijuana has been used since B.C. period for thousands of years as a medication. It was incorporated into the pharmacopeia of American medicine in the 1850’s until it was banned in the 1930’s. It regained popularity and notoriety as a recreational substance. However, more and more patients are turning towards this now alternative medication after years of frustration towards the ineffectiveness and adverse effects of conventional medications. The endocannabinoid pathway is found inherently in the system and is responsible for the runner’s high that people get after a vigorous run or after exercising and gives the sense of well-being. The CB1 receptor is found most abundantly in the central nervous system which is likely why many neurological conditions are found to benefit from its use. The CB2 receptor is most commonly found in the immune system. As more research is pursued, there are CB receptors found diffusely throughout many organ systems. Cannabidiol weakly interacts with the CB1 receptor. It takes at least 100 times cannabidiol to attain the same intoxication one gets with tetrahydrocannabinol, the substance which is more popular and found in the marijuana joints people smoke to obtain euphoria. THC at low concentrations is effective in treating many different medical conditions. It must be used in conjunction with CBD so that side effects are offset. Cannabidiol has no intoxication while low doses of THC does not give euphoria one associates with this drug. There is no tolerance.
Scientific evidence cannabidiol and tetrahydrocannabinol work in chronic pain and other medical diseases
In animal studies, it is well known to reduce seizures by inhibiting the excitation within the hippocampus of the brain where seizures are commonly propagated (http://www.pnas.org/content/early/2017/09/26/1711351114).There are many clinical trials in humans attesting its efficacy at controlling seizures effectively. CB1 receptors appear to be increased in many neurological disorders which implies it is a compensatory mechanism for diseases. In Parkinson’s disease, there are increased CB1 receptors which may help with the reduced dopamine commonly found in Parkinson’s disease. 9tetrahydrocannabinol was found to lower intraocular pressure in glaucoma in rabbits (https://www.ncbi.nlm.nih.gov/pubmed/6329602). Sativex is a combination of THC:CBD which reduces spasms in patients with multiple sclerosis and has been available in Europe for several years now with very little side effects http://jnnp.bmj.com/content/87/9/944. There is extensive evidence in both animal and human models that it works in chronic pain (https://www.ncbi.nlm.nih.gov/pubmed/26830780). Many diseases are being evaluated for mechanisms on which CBD and THC may exert its effects. It has been found to have anti-oxidant and anti-inflammatory properties which are important mechanisms by which many diseases cause pathology. In cancer cell cultures, it has been found to reduce proliferation of tumor cells in urologic cancer and reduce the pro-inflammatory states that are necessary for metastatic conditions (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434502/).CBD interacts with the 5HT1 receptor where many anti-depressants and anxiolytic medications exert their effects, making CBD an effective anxiolytic. It works to stimulate appetite and is commonly used by patients with cancer for anorexia and end-stage cancer pain.
In summary, cannabidiol and tetrahydrocannabinol are effective medications in treating pain from many chronic illnesses and is not reserved for patients with terminal illness. Despite the reticence of physicians, Congress and even patients, there is overwhelming evidence that cannabidiol and tetrahydrocannabinol are effective in many different diseases, although in some conditions there’s a long way to go from preclinical data to human trials. It is fairly clear in many disease states, medical marijuana is significantly effective. There is no tolerance and may be an effective treatment for patients with chronic pain. CBD by itself has no euphoric properties and low concentrations of THC do not give intoxicating psychoactive effects. These are 2 alternatives that may provide relief and solution to the growing epidemic of the opioid crisis.