Virginia Thornley, M.D., Neurologist, Epileptologist

March 11, 2018

Introduction

A patient comes to you asking “Doc, my seizures are getting worse, I really hate the side effects of my medications, I really want to go a different route. Have you heard about medical marijuana?” You start sweating profusely, fidgeting in your seat, thinking of every single reason why not to recommend it and come up with  the standard response, “uh, well, I’m not qualified to recommend it and it’s not FDA approved, plus we don’t really know much about it there could be so many side effects.” And then we have the oldie but goodie response, “there’s not enough large randomized control trials to recommend it.” This scene plays 100,000 times over if not a million times over in physician offices across the country. Patients who are disillusioned with adverse effects of medications are looking towards alternative therapy. As surprising as it sounds, patients with chronic pain do not want to get intoxicated by opioids. In fact, some want to be tapered off of them or refuse them all together. Patients with end-stage cancer at the terminal stage of their lives wish to live a comfortable and humane existence without the need for more chemotherapeutic medications or pain medications that consistently make them feel like a zombie. While other patients with epilepsy may be on 4 different anti-epileptic agents and can no longer function or have a good quality of life because of side effects. There are two sides to every coin.

Why you should be educated on cannabidiol and THC use in medical conditions

If patients do not get their answers from their trusted physicians who they trust with their well-being, their health, the temples of their souls, they will go to great lengths in procuring this knowledge. This is via various sites on the internet some of the dubious nature others are from high quality companies that have been in business even before this seeming treatment fad started. Or, the information may be obtained from their brother-in-law’s friend’s hair stylist who is now pain-free after going through a long course of pain medications including ablative treatments, physical therapy, and acupuncture and has a physician who does recommend it. Like it or not, cannabidiol and tetrahydrocannabinol are alternative treatment options and are gaining more and more traction. To ignore it is to be complacent with the changing direction and landscape of medicine. As patients become more and more disillusioned by the limitation of conventional treatments, attention is directed towards alternative regimens. It is not just for the yoga-practicing patient looking for more natural methods, one sees the sweet 83-year-old gentleman who must be someone’s grandfather with the chronic hip pain of 50 years who have failed opioids and is simply looking for pain relief.

Is there any evidence that it works?

The endocannabinoid pathway is found naturally in the system. It is responsible for the runner’s sense of wellbeing one gets after a 5-mile run and the pleasant mood you get after a 1-hour work-out with Zumba. There are 2 receptors in the system CB1 receptor which has the highest number of brain cells and the CB2 receptor which is found predominantly in the immune system. There are 2 common cannabinoids cannabidiol and tetrahydrocannabinol which exert various medical effects. Cannabidiol (CBD) has a weak affinity for the CB1 receptor and one needs 100 times the amount to get the same euphoria that one gets from tetrahydrocannabinol, the bane of every ER physician. Unfortunately, the side effects of euphoria of THC have preceded its popularity as a medical product. Little do we know it was once used for hundreds of years as a medication before the psychoactive properties were exploited for recreational purposes. In urologic culture cell lines, it is found that cannabinoids may reduce proliferation of cancer cells and reduce the pro-inflammatory microenvironment that is necessary for metastatic conditions (1). Human studies are still needed to determine a reduction in tumor loads. THC receptors are found in retinal cells and may be found to reduce intraocular pressure in glaucoma (5, 6). Cannabidiol is found to bind to the 5HT1 receptor which reduces anxiety. THC has been well-established in the mouse model to promote the inhibitory control of excitatory pathways in the hippocampus, where seizures commonly arise (8). There is an increase in CB1 receptors after prolonged seizures suggesting a compensatory response.  It has been used in combination and found in several randomized control trials to reduce the frequency of seizures by as much as 36% in medically refractory patients (2). It is well-established that cannabinoids reduce pain refractory to conventional medications (3). It has been found in bench research to be an antioxidant and have anti-inflammatory properties (4, 7). Some studies cite side effects of somnolence, nausea, dysphoria, however, it is not clear what was the quality of cannabinoids or dosages were used. At high doses, while THC can reduce pain it may also result in side effects, which is why it is usually used in combination with CBD which ameliorates the side effects of THC.  In addition, cannabidiol by itself has no euphoria and it takes 100 times the amount to achieve intoxication seen with THC use. Synthetic products will have more side effects than products that are organic meaning only of natural materials.

Given the huge amount of evidence in several different medical conditions (3), the results should overwhelmingly be towards a push in using cannabinoids more frequently. However, because of the cynicism of the public, physicians even of patients, who have been exposed more frequently to the harmful psychoactive side effects, the benefits are far overshadowed. More clinical randomized controlled trials are needed. Most literature cites small numbers of patients enrolled in studies or review multiple medical centers where the conditions are not uniform. In addition, some of the patients that would benefit the most are the least in numbers such as those with rare neurological conditions such as Dravet syndrome or Lennox-Gastuat syndrome.

In conclusion

As it still stands, many states still do not recognize the medicinal value of cannabidiol or tetrahydrocannabinol. In some states, medical physicians are not allowed to recommend it and put themselves at risk for FBI questioning in even suggesting its use. It is not uncommon for patients to move states or order from other states or countries to procure this liquid gold that is supposed to work wonders. Only time will tell if this is a passing fad and if there are long-standing side effects, however, as of current standing, medical marijuana is here to stay. As far as the literature goes, there are beneficial results but it is a cautionary tale as more studies in large human trials are still needed. As with any new preclinical data, the preclinical status may get ahead of itself and human trials do not replicate the desired results. But from the small clinical trials in seizures, pain, nausea, anxiety, and loss of appetite, the results are promising while more research is needed for anti-tumor effects in humans.

As with any medication, there will be clear-cut side effects just as with any other medication which is why more studies are needed to determine the least amount with the least amount of side effects. In some studies,  amounts upwards of 50mg/kg (2) is used the high amounts likely responsible for causing side effects, which is far higher than that cautioned by medical marijuana dispensaries. It will take patients time to wrap their heads around taking guidance from a fresh-faced 20-year-old millennial at the spa-like dispensary which is currently the norm at most dispensaries, who likely knows much more than even most medical professionals. It seems it will take even longer in Congress to understand the potential benefit of cannabinoids from a medical standpoint especially with the present opioid epidemic. Countries in Europe have far surpassed the United States when it comes to cutting-edge treatments. Perhaps, it will take even longer for the medical community to see the medical potential with their exposure to the sinister side of tetrahydrocannabinol seen in patients in the ER for non-medical reasons, which may be one of the most challenging stumbling blocks.

Introduction/Disclaimer

References:

1. Ghandhi, et al, “Systemic review of the potential role of cannabinoids as anti-proliferative agents for urological cancer,” Can. Urol. Assoc. J., 2017, May,-April., 11(3-4):E138-E142.
2. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
3. Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88.
4. Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.
5. ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
6. Jarvinen, T., “Cannabinoids in the treatment of glaucoma,” Pharmacology and Therapeutics, 2002, Aug., 95(2):203-20.
7. Carroll, et al, “9-Tetrahydrocannabinol exerts a direct neuroprotective effect in human cell culture model of Parkinson’s disease,” Neuropathology and Applied Neuropharmacology, 2012, Oct., 38(6):3535-547.
8. Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.