A Brief History of Cannabis Research

Cannabidiol (CBD) was first isolated from cannabis in 1940 by Roger Adams and its chemical structure was elucidated in the 1960s.  Around this time, the structure of THC was also elucidated, another interesting compound also found in cannabis.  In the 1940s and 1950s, pharmacological experiments were conducted on cannabinoids with researchers concluding that THC displayed psychotropic activity (this is what gives people a “high”) whereas CBD lacked this effect.  An interesting area of research around this time period was that CBD and its metabolites had an effect on cytochrome P450 (CYP) enzymes.  These enzymes are heavily involved in the metabolization of endogenous and exogenous chemicals in the body, about 75% of drug metabolism is done by these enzymes.  In the 1960s and 70s because of the rise in popularity of recreational marijuana usage most pharmacological studies focused on the psychoactive properties of marijuana and less research was done on the therapeutic benefits.  In the 1980s researchers learned more about the existence of cannabinoid receptors in the human body.  The cannabinoid receptors play a role in a wide range of processes affecting things like pain-sensation, appetite, mood, and memory.  The 1990s saw a focus on researching if the body produced cannabinoids endogenously.  In humans, during exercise certain plasma endocannabinoid levels actually, rise, this is associated with the euphoric feeling some people get during exercise (think a “runner’s high”).  Most recently, research on CBD has focused on its potential role as an analgesic for pain relief.

Chronic Pain Epidemic

If you’ve been following the news at all lately, it’s easy to understand why researchers have keyed in on the pain relief potential of cannabis based drugs.  In a study of European populations they found that chronic musculoskeletal pain was a common condition in 25% of elderly people [1]  The number was even higher for those in nursing homes.   A CDC publication stated that about 20% of US adults were dealing with chronic pain [2]

A study on 8 subjects with neuropathic chronic pain receiving a dosage of 25 mg/day of THC resulted in 7 subjects suffering from side effects resulting in the premature arrest of the drug in 5 of them [3]  Another study also in subjects with neuropathic pain reciving the same 25 mg/day dosage of THC, except this time over the course of an average of 55 days resulted in 5 out of the 7 patients withdrawing from the study because of side effects (sedation and asthenia). [4]  Whereas a study using 40 mg daily dosages of CT-3 a THC analogue, did show differences in pain scale ratings 3 hours after drug admission. [5]  A study on Nabilone, a synthetic cannibinoid being given to 20 chronic noncancer pain patients for an average of 1.5 years, showed improved ratings of subjective overall pain in 15 subjects and reduced pain intensity in 9 subjects. [6]

A study on Sativex (a THC-CBD 1:1 ratio) drug’s effects on 125 patients with neuropathic pain over the course of 5 weeks was conducted.  The mean reduction in pain intensity sources was greater in the Sativex group than the placebo.  However, of all subjects in the study 18% on sativex and 3% on placebo withdrew from the study. [7]  

Researchers wanted to analyze the effects of the therapuetic use of cannabis, THC-CBD, and synthetic THC on the treatment of chronic neuropathic pain in adults.  They included 16 studies with 1750 participants that ranged from 2 weeks to 26 weeks.   From the data, the researchers found cannabis-based medicine increased the number of people achieving 50% or greater pain relief compared to placebo.  However, more participants in the studies also withdrew from the studies due to adverse events with cannabist based medicines than with placebo. [8]

A different group of researchers conducted a systematic review of studies examining the effect of cannabinoids in the treatment of chronic non-cancer pain.  Researchers looked at the effects of cannabis and synthetic cannabinoids.  The researchers concluded that in 15 of the 18 trials that met inclusion, a significant analgesic effect was seen for cannabinoids compared to placebo and there were no serious adverse effects. [9]

So what’s the verdict?

In the report The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, an expert, ad hoc committee of the National Academies of Sciences, Engineering, and Medicine examined over 10,000 studies and concluded that there’s conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of chronic pain. [10]

Something to consider is that there’s not a lot of consistency among the studies on the substances used, some are using the entire plant, some studies use either a combination of THC-CBD (or one of those compounds by itself), and others are using synthetic analogs.  Some studies are using an inhaled plant, others sprays, and others are consumed orally.  It’ll be interesting to see what delivery method and what form of cannabinoids end up being most successful as more studies are conducted.  

References

[1] Frondini, C., Lanfranchi, G., Minardi, M., & Cucinotta, D. (2007). Affective, behavior and cognitive disorders in the elderly with chronic musculoskelatal pain: The impact on an aging population. Archives of Gerontology and Geriatrics, 44, 167-171. doi:10.1016/j.archger.2007.01.024

[2] Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, Kerns R, Von Korff M, Porter L, Helmick C. Prevalence of chronic pain and high impact chronic pain among adults – United States, 2016. MMWR. September 14, 2018. 

[3] Attal, N., Brasseur, L., Guirimand, D., Clermond-Gnamien, S., Atlami, S., & Bouhassira, D. (2004). Are oral cannabinoids safe and effective in refractory neuropathic pain? European Journal of Pain,8(2), 173-177. doi:10.1016/s1090-3801(03)00084-3

[4] Clermont-Gnamien, Sabine & Atlani, Sophie & Attal, Nadine & Le Mercier, Franck & Guirimand, Frédéric & Brasseur, Louis. (2002). The therapeutic use of D9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain. Presse médicale (Paris, France : 1983). 31. 1840-5. 

[5] Karst, M., Salim, K., Burstein, S., Conrad, I., Hoy, L., & Schneider, U. (2003). Analgesic Effect of the Synthetic Cannabinoid CT-3 on Chronic Neuropathic Pain. Jama, 290(13), 1757. doi:10.1001/jama.290.13.1757

[6] Berlach, D. M., Shir, Y., & Ware, M. A. (2006). Experience with the Synthetic Cannabinoid Nabilone in Chronic Noncancer Pain. Pain Medicine, 7(1), 25-29. doi:10.1111/j.1526-4637.2006.00085.x

[7] Nurmikko, T. J., Serpell, M. G., Hoggart, B., Toomey, P. J., Morlion, B. J., & Haines, D. (2007). Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial. Pain, 133(1), 210-220. doi:10.1016/j.pain.2007.08.028

[8] Gupta, A. (2018). What are the effects of cannabis-based medicines for adults with chronic neuropathic pain? Cochrane Clinical Answers. doi:10.1002/cca.2117

[9] Lynch, M. E., & Campbell, F. (2011). Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British Journal of Clinical Pharmacology, 72(5), 735-744. doi:10.1111/j.1365-2125.2011.03970.x

[10] The Health Effects of Cannabis and Cannabinoids. (2017). doi:10.17226/24625