Therapeutic Targets for Cannabinoids

July 2021 | Written in collaboration by Behnoush Kermanshahi (Research Associate – Formulations), Natalia Sannikova (Research and Development Manager) and Andrea Olaizola (Formulations Associate Scientist) at Ascension Sciences

Cannabis sativa has a long history as a medicinal plant given its therapeutic effects. The plant extracts used to be a licensed medicine in the United States for almost a century, between 1850 to 1942, before being dropped from the U.S. pharmacopeia by the Medical Association (1,2).

The term medical cannabis refers to the use of cannabis or cannabinoids to treat diseases or reduce symptoms (3). Cannabis has been shown to be beneficial in treating many complex diseases or rare conditions where there is no effective treatment, and when incumbent methods have detrimental side effects (3). Examples where medical cannabis has gained attention in the last years are multiple sclerosis and central sensitivity syndromes like migraines, and neuropathic pain (3,4,5,6). 

There are hundreds of compounds in cannabis which are suggested to have therapeutic effects.  An increasing amount of research is emerging on the benefits of this plant. The studies have shown improvement in symptoms for chronic pain in several trials and it is worth mentioning that the efficacy of cannabis or cannabinoids is only now becoming more clear, although many risks of bias still exist for some clinical trials in this space.

Endocannabinoids versus Phytocannabinoids

The discovery of the endocannabinoid system in the body has paved the way for cannabinoid research to emerge in targeting the system for therapeutic applications. The endocannabinoid system, including the endogenous ligands, cannabinoid receptors, and enzymes that regulate the biosynthesis of endocannabinoids, have essential roles in central and peripheral nervous system’s functionality (7,8). Phytocannabinoids, which are cannabis plant derivatives, interact with our body in a similar way to endocannabinoids and modulate the endogenous cannabinoid receptors (7,8). Numerous studies have reported phytocannabinoids acting as an analgesic, tranquilizer, antibiotic, antiparasite, nausea suppressant, appetite stimulant, diuretic, anticonvulsant, hypnotic, and expectorant (9). 

Below is a summary of various  clinical study results on cannabinoids and their therapeutic effects classified by the level of evidence.

Conclusive or substantial evidence of effect

Conclusive evidence suggests that there is robust evidence collected from randomized controlled trials to support cannabis or cannabinoids as an effective or ineffective treatment. Substantial evidence is strong and there is no randomness, bias or confounding factors for this evidence (10). 

  • Chronic pain. Chronic pain is one of the most common reasons that patients seek medicinal cannabis (11). Five systematic reviews with fair-to-good quality support the conclusion that there is substantial evidence that cannabis is an effective treatment for adults with chronic pain. Results from 7 clinical trials of smoked cannabis and Nabiximols (Sativex, whole plant extract oromucosal spray) on people with neuropathic pain have shown that plant-derived cannabinoids were able to reduce the pain by 40% compared to the control agent (12).
  • Chemotherapy-induced nausea and vomiting. In a review by Whitening et al. it is reported that from 28 trials on chemotherapy-induced nausea and vomiting (1772 participants), all trials showed greater benefit for cannabinoids compared to the placebo controlled and 2 antiemetic agents such as prochlorperazine and chlorpromazine, which are drugs effective against vomiting and nausea (13). However, the differences were not statistically significant.  In another review by Cochrane, they summarized 23 trials in which the investigators concluded that cannabinoids were highly effective and more efficacious than the conventional antiemetics and placebo (14). Although cannabinoids showed adverse events, patients still preferred them over the placebo and other antiemetics. Dronabinol and nabilone are two cannabinoid drugs that are both on the market for the purpose of treating nausea and vomiting related to chemotherapy and initially were approved in 1985.
  • Spasticity. Results of 3 trials on studying the effect of nabiximols or nabilone on spasticity associated with multiple sclerosis (MS), demonstrated a significant reduction on spasticity compared to placebo (13).  A systematic review by Koppel et al., indicated that nabiximols and oral THC were “probably effective” and oral cannabis extract was “established as effective” in patients with spasticity issues induced by MS (21). In another placebo-controlled crossover trial of nabiximols, patients experienced significant improvement in MS-related spasticity compared to placebo. Although improvements were reported, it was concluded that there is limited evidence for the impact of cannabinoids on spasticity (22).

Moderate evidence of effect 

There are various good-to-fair quality findings for this level of evidence with very few or no credible opposing findings. There are chance, bias and confounding factors for this evidence, but a general conclusion could be made (10).

  • Sleep disturbance. Approximately 70 million adults in the United States have experienced sleep disorders (10). It is assumed that the endocannabinoid system might help with sleep. In a study with high risk of bias, results showed that dronabinol demonstrated greater benefit compared to placebo for 22 patients with obstructive sleep apnea. In another cross-over trial in 32 patients with fibromyalgia, there was more improvement in insomnia and sleep restfulness with Nabilone compared to amitriptyline. Meta-analysis of 8 trials and 3 trials with cannabinoids (mainly nabiximols) showed greater improvement in sleep quality and sleep disturbance respectively. The improvements seemed to be insignificant (13). In general, it is concluded that there is moderate evidence that cannabinoids, mainly nabiximols, are effective in improving the short-term sleep outcomes in people who have sleep disturbance caused by chronic pain, fibromyalgia, obstructive sleep apnea and multiple sclerosis (10).

Limited evidence of effect

This level of evidence suggests a “supportive finding from fair-quality studies or mixed findings with the most favouring one conclusion” (10). The conclusion is not certain because of chance, bias and confounding factors (10). 

  • Appetite and weight gain. In 4 high risk of bias studies (where dronabinol was compared to placebo and megestrol acetate), in HIV patients, some evidence showed that dronabinol has an effect on weight gain compared to placebo (15,16). There was also some limited evidence for increasing appetite, reducing nausea, increasing body fat percentage, and improving functional status. However, the results were not statistically significant (17,18).
  • Post-traumatic stress disorder (PTSD). There is a single fair-quality crossover trial on 10 male Canadian military personnel suffering from nightmares despite using standard treatments for PTSD (19). Results indicated a significant reduction in PTSD nightmare and improvements in general well-being compared to placebo. There are some ongoing clinical trials evaluating the effect of cannabis and cannabinoids on PTSD which hopefully provide more evidence.
  • Anxiety. A trial on 24 participants with social anxiety disorder where individuals were given a single dose of 600 mg of cannabidiol before a simulated public speaking test showed significant improvement in the anxiety compared to placebo (13). Lack of sufficient trials on this condition has led to the conclusion with limited evidence .
  • Tourette syndrome. Two clinical trials assessing the effect of oral THC (10 mg) in Tourette syndrome suggested an improvement in tic severity compared to placebo (20). Although results are promising, better clinical trials quality with a larger number of patients are needed .

No or insufficient evidence

This level of evidence suggests mixed findings, a single poor study, or health endpoints that have not been investigated. Because of chance, bias and confounding factors, there will be substantial uncertainty and a conclusion cannot be made.

Conditions such as cancer, epilepsy, neurodegenerative disorders, irritable bowel syndrome, and addiction are considered in this level of evidence as there are not enough clinical studies to evaluate these conditions.

Beside all the inconclusive findings from various clinical studies, there are several important areas where they could be improved in various ways. 

Firstly, different administration routes are employed in the existing studies and results are not always directly comparable. Route of administration can dictate the bioavailability and pharmacokinetic profile of an active ingredient or formulation. At the same time, cannabinoids have very low bioavailability which also varies greatly between patients. In many of the aforementioned studies and results, the administration was through smoking or oral oil where the bioavailability varies from 18-50% and 6-20% respectively (23).

Secondly, outcomes of clinical trials can be tainted by the psychoactive properties of cannabinoids. In the strictest sense, placebo-controlled clinical trials for cannabinoids are debatable. The placebo should be designed in a way to have the exact smell, taste and appearance properties of cannabinoids. However, the psychoactive property of cannabinoids is something inevitable and patients quickly realise if they are given cannabinoids or placebo.

Lastly, some trials have either investigated a mixture of cannabinoids or a combination of cannabinoids with different drugs. In such cases one should carefully consider how the “entourage effect” or drug-drug interactions affect the toxicity and efficacy of the cannabinoids. Cannabinoid therapeutics can be made more robust using formulations which target tissues or a specific indication.  In either case of mixing APIs, whether for a benefit, or to study toxicity, nanoparticles can be tuned to achieve maximum efficacy while reducing toxicity.

Clearly, there are still a number of opportunities opening for cannabinoid therapeutics, particularly when considering the impact nanoparticles can have on the efficacy of the drug.  The number of discovered cannabinoids continues to grow (we are now at approx. 130), and  each combination or singular compound can benefit from nanoparticle delivery.

Recently, the nanoparticle development for cannabinoids has grown quickly in the research arena, and a number of platforms have emerged on the market due to the clear benefits of increasing the low bioavailability of these compounds. Moreover, nanoparticles can be useful to improve the dosing uniformity which in turn will reduce the pharmacokinetic profile variability between patients and make clinical trial results more consistent.  Therefore, clinical trials using cannabinoid nanoparticles are important to see where therapeutic benefits can be further uncovered or where quality of evidence can be improved on the basis of nano-formulations.

References
  1. Holland, J. The Pot Book: A Complete Guide to Cannabis : Its Role in Medicine, Politics, Science, and Culture. Rochester, VT: Park Street Press, 2010.
  2. Musto, D. F. The Marihuana Tax Act of 1937. Arch. Gen. Psychiatry 26, 101–108 (1972).
  3. National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. In The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. essay, National Academies Press. (2017)
  4. Devinsky, O. et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. New England Journal of Medicine vol. 376 2011–2020 (2017).
  5. Leweke, F. M. et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2, e94–e94 (2012).
  6. Hill, M. N. et al. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the world trade center attacks. Psychoneuroendocrinology 38, 2952–2961 (2013).
  7. Svíženská, I., Dubový, P. & Šulcová, A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures – A short review. Pharmacology Biochemistry and Behavior vol. 90 501–511 (2008).
  8. Di Marzo, V., Bifulco, M. & De Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nat. Rev. Drug Discov. 3, 771–784 (2004).
  9. Zuardi, A. W. History of cannabis as a medicine: A review. Revista Brasileira de Psiquiatria vol. 28 153–157 (2006).
  10. Abrams, D. I. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur. J. Intern. Med. 49, 7–11 (2018).
  11. Sexton, M., Cuttler, C., Finnell, J. S. & Mischley, L. K. A Cross-Sectional Survey of Medical Cannabis Users: Patterns of Use and Perceived Efficacy. Cannabis Cannabinoid Res. 1, 131–138 (2016).
  12. Andreae, M. H. et al. Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J. Pain 16, 1221–1232 (2015).
  13. Whiting, P. F. et al. Cannabinoids for medical use: A systematic review and meta-analysis. JAMA – Journal of the American Medical Association vol. 313 2456–2473 (2015).
  14. Phillips, R. S. et al. Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood. Cochrane Database of Systematic Reviews vol. 2016 (2016).
  15. Struwe, M. et al. Effect of dronabinol on nutritional status in HIV infection. 27, 827–831 (2014).
  16. Timpone, J. G. et al. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Res. Hum. Retroviruses 13, 305–315 (1997).
  17. Beal, J. E. et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J. Pain Symptom Manage. 10, 89–97 (1995).
  18. Abrams, D. I. et al. Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection: A Randomized, Placebo-Controlled Clinical Trial. Ann. Intern. Med. 139, (2003).
  19. Jetly, R., Heber, A., Fraser, G. & Boisvert, D. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology 51, 585–588 (2015).
  20. Müller-Vahl, K. R. Treatment of Tourette syndrome with cannabinoids. Behav. Neurol. 27, 119–124 (2013).
  21. Koppel, B. S. et al. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology vol. 82 1556–1563 (2014).
  22. Leocani, L. et al. Sativex® and clinical–neurophysiological measures of spasticity in progressive multiple sclerosis. J. Neurol. 262, 2520–2527 (2015).
  23. Amar, B. M., Léonard. L. Les psychotropes: pharmacologie et toxicomanie. EBOUND Canada. (2014)
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