A promising, yet complex, cannabinoid

Tetrahydrocannabinol (THC) and tetrahydrocannabivarin (THCV) have similar-sounding names but are, in fact, distinct cannabinoids. While both THC and THCV have nearly the same chemical structure, THCV’s side-chain is comprised of a propyl (3-carbon) side chain rather than a pentyl (5-carbon) group [1]. This difference is due to how these chemical structures are synthesized.

THCV is created when geranyl pryophosphate combines with divarinolic acid (instead of olivetolic acid) [2]. Due to this variance in chemical synthesis and structure, THCV also has a higher boiling point and will only cause psychoactive effects at very high doses – in fact, the actions of THCV are entirely dependent on its concentration [1].

At low doses, THCV binds to and blocks the cannabinoid 1 (CB1) (and CB2) receptor, working as an antagonist [3]. However, at high doses, THCV becomes an agonist, boosting the function of CB1 and inducing a psychoactive “high.” But THCV’s peculiarities, and paradoxical effects, do not end there.

In stark contrast to THC and one of its most notorious effects, consumption of THCV actually suppresses appetite. The CB1 receptor mediates eating behavior and appetite regulation, and blocking this receptor can reduce food intake, body weight, and adiposity. Preclinical studies have shown that treatment with a CB1 antagonist, as well as pure THCV, suppresses food intake and causes weight loss [4]. Since TCHV blocks the CB1 receptor at low doses, this cannabinoid may be effective as an anti-obesity treatment.

THCV has additionally been shown to improve fasting plasma glucose and glucose tolerance, as well as insulin sensitivity, in preclinical models of obesity; these effects appear to be mediated through increased energy expenditure [5,6]. And while these results are indeed promising, they are not relegated to animal studies alone, as similar results have also been found in humans.

Rosiglitazone, a CB1 receptor antagonist and anti-diabetic drug, was actually once marketed as an anti-obesity treatment in Europe; however, after evidence showing that the drug was associated with psychiatric effects and later found to increase the risk of cardiovascular disease, it was withdrawn [7]. Although rosiglitazone and THCV are different compounds, clearly, THCV required further study.

A small trial evaluated the safety of THCV administrated over five days in 10 male participants. THCV was well tolerated with no serious side effects; in fact, patients could not distinguish between THCV and placebo [8]. However, one patient did report fatigue.

GW Pharmaceuticals, the medical cannabis company whose pediatric epilepsy drug was granted approval last year, conducted a pilot study on THCV in Type 2 diabetes patients. Sixty-two patients were treated with cannabidiol (CBD), THCV, CBD:THCV formulations, or placebo across 13 weeks [9]. THCV treatment significantly reduced fasting plasma glucose and improved pancreatic function and other lipid-associated factors. While THCV was well tolerated, it did not affect the primary outcome of the study, which was a reduction in high-density lipoprotein.

While these results are encouraging, it is unclear as to the path that THCV might take toward potential approval as a treatment for obesity or diabetes [10]. But, one thing is certain – several more in-human trials must be conducted to better understand its effects on metabolism, as well as rule out any potential safety concerns resulting from its antagonism at the CB1 receptor.

 

References

  1. Pertwee, R.G, Thomas, A., Stevenson, L.A., et al., “The Psychoactive Plant Cannabinoid, Δ9-tetrahydrocannabinol, Is Antagonized by Δ8- and Δ9-tetrahydrocannabivarin in Mice in vivo”, Br J Pharmacol, 2007, Volume 150, pg. 586-594.
  2. Mudge, M., Murch, S.J., Brown, P.M., “Chemometric Analysis of Cannabinoids: Chemotaxonomy and Domestication Syndrome”, Scientific Reports, 2018, Volume 8, pg. 13090.
  3. Thomas, A., Stevenson, L.A., Wease, K.N., et al., “Evidence that the Plant Cannabinoid Δ9-tetrahydrocannabivarin Is a Cannabinoid CB1 and CB2 Receptor Antagonist”, Br J Pharmacol, 2005, Volume 146, pg. 917-926.
  4. Riedel, G., Fadda, P., McKillop-Smith, S., et al., “Synthetic and Plant-derived Cannabinoid Receptor Antagonists Show Hypophagic Properties in Fasted and Non-fasted Mice”, Br J Pharmacol, 2009, Volume 156, pg. 1154-1166.
  5. Ravinet, T.C., Arnone, M., Delgorge, C., et al., “Anti-obesity Effect of SR141716, a CB1 Receptor Antagonist, in Diet-induced Obese Mice”, Am J Physiol Regul Integr Comp Physiol, 2003, Volume 284, pg. R345-353.
  6. Wargent, E.T., Zaibi, M.S., Silvestri, C., et al., “The cannabinoid Δ9-tetrahydrocannabivarin (THCV) Ameliorates Insulin Sensitivity in Two Mouse Models of Obesity”, Nutr Diabetes, 2013, Volume 3, pg. e68.
  7. Nissen, S.E., Wolski, K., “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes”, N Engl J Med, 2007, Volume 356, pg. 2457-2471.
  8. Englund, A., Atakan, Z., Kralj, A., et al., “The Effect of Five Day Dosing with THCV on THC-induced Cognitive, Psychological and Physiological Effects in Healthy Male Human Volunteers: A Placebo-controlled, Double-blind, Crossover Pilot Trial”,
    J Psychopharmacol, 2016, Volume 30, pg. 140-151.
  9. Jadoon, K.A., Ratcliffe, S.H., Barrett, D.A., et al., “Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study”, Diabetes Care, 2016, Volume 39, pg. 1777-1786.
  10. Greenway, F.L., Kirwan, J.P., “Medical Marijuana—An Obesity Problem or Opportunity?”, International Journal of Obesity, 2019, Pg. 1-2.