THCV is a phytocannabinoid analogous to THC. THCV have different interactions with CB1 and CB2 compared to THC, and yields some opposite effects like the suppression of appetite. In addition, THCV is reported to have anti-epileptic and anti-psychotic effects and shows potential to help in a wide list of diseases, like type 2 diabetes or Obesity.

Chemical Name: 
tetrahydrocannabivarin
IUPHAR entry: 
Wikipedia entry: 
Synthetic Pathways: 

THCV is synthesized through decarboxylation of tetrahydrocannabivarinic acid (THCVA). THCVA is synthesized from cannabigerovarin (CBGV) by acid synthase. CBGV is synthesized through decarboxylation of cannabigerovaric acid (CBGVA). CBGVA is synthesized from divarinolic acid and geranyl-pyrophosphate.

Degradation Pathways: 

THCV is degraded through oxydation to cannabivarin (CBV).

Literature Discussion: 

Receptors

THCV binds to CB1 and CB2 receptors. It acts as a partial agonist of CB2 receptor. However, it is not clear how specifically interacts with CB1. In vitro studies show antagonist effects while in vivo studies suggest neutral receptor antagonist effects (McPartland, Duncan, Di Marzo, & Pertwee, 2015; Morales, Hurst, & Reggio, 2017; Thomas et al., 2005).

THCV acts as antagonist of TRPM8 and also activates TRPV1, TRPV2, TRPV3 and TRPV4, suggesting several potential therapeutic effects, including acne treatment and gastrointestinal inflammation (L. De Petrocellis et al., 2012; Luciano De Petrocellis et al., 2011; Oláh et al., 2016)

THCV inhibits l-α-lysophosphatidylinositol (LPI), which activates GPR55, involved in pain transmission (Anavi-Goffer et al., 2012)

Pharmacokinetics

THCV intraperitoneal administration leads to higher brain concentrations of THCV compared to oral administration (Deiana et al., 2012)

cannabinoid interactions

THCV modulates and can counteract some of the THC effects (Booker, Naidu, Razdan, Mahadevan, & Lichtman, 2009; Englund et al., 2015)

Anxiety

Rimonabant also induces anxiogenic effects in contrast to THCV, probably because THCV acts as a neutral CB1 receptor antagonist while Rimonabant acts as inverse agonist (O’Brien et al., 2013).

Bladder Dysfunction

THCV showed potential to treat bladder dysfunctions (Pagano et al., 2015)

COPD

In one study THCV reduced inflammatory leukocyte recruitment (Makwana et al., 2015)

Functional Gastro-Intestinal Disorders 

Apart from THC, (relatively) non-psychotropic cannabinoids such as THCVCBD and CBG were found to have anti-inflammatory effects in experimental intestinal inflammation (Alhouayek and Muccioli, 2012).

Liver Damage

Synthetic THCV showed protective effects against liver damage (Bátkai et al., 2012)

Eczema

A comparative study into the topical anti-inflammatory activity of cannabinoids (on croton oil-inflamed skin in mice) showed that Δ8THC, Δ9THC and THCV are about half as effective in reducing inflammation as Indometacin (a commonly used Non-steroid anti-inflammatory drug), but approximately 5 times more effective than CBCV and CBDCBC and CBDV had no appreciable anti-inflammatory activity (Tubaro et al., 2010).

Epilepsy

THCV significantly reduced epilepsy seizure incidence starting with doses of 0.25 mg/kg in animal models. THCV shows antiepileptiform and anticonvulsant properties, probably related to its activity in CB1 receptors  (Gaston & Friedman, 2017; Hill et al., 2010).

In healthy human volunteers, 10 mg oral THCV reduced functional network connectivity in the brain (measured by fMRI)(Rzepa et al., 2015).

Inflammation

THCV inhibits nitrite production, showing anti-inflamatory and immunomodulatory effects (Bolognini et al., 2010; Romano et al., 2016)

Obesity

THCV induced hypophagia and reduction in body weight at low doses (from 3mg/kg), suggesting a possible treatment for Obesity and metabolic syndrome. THC combination with THCV would delete these effects, but they are rescued by combining them with CBD (Riedel et al., 2009; Silvestri et al., 2015; Wargent et al., 2013).

In contrast to Rimonabant, THCV does not cause nausea but maintains the anti-Obesity potential (Rock, Sticht, Duncan, Stott, & Parker, 2013). Oral dose administration of 10mg of THCV reduces resting state functional connectivity in brain areas that are usually overactivated in obese individuals. Also, it activates areas which have reduced activity linked to Obesity (Rzepa, Tudge, & McCabe, 2015). The same dose was used in another study showing increased brain activity in Obesity related areas when presenting different types of food stimuli, suggesting also a possible therapeutic potential to treat Obesity (Tudge, Williams, Cowen, & McCabe, 2015).

Parkinson´s

Antioxidant effects of THCV have been related to an attenuation of motor inhibition through CB2 receptors in animal models of Parkinson´s Disease (PD), suggesting an interesting approach to ameliorate PD symptoms and even to delay disease progression (García et al., 2011).

Schizophrenia

THCV could have antipsychotic properties through the activation of 5HT1A receptors as shown in rat models for Schizophrenia (Cascio, Zamberletti, Marini, Parolaro, & Pertwee, 2015)

References

Alhouayek, M., and Muccioli, G.G. (2012). The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity. Trends Mol. Med. 18, 615–625.

Anavi-Goffer, S., Baillie, G., Irving, A. J., Gertsch, J., Greig, I. R., Pertwee, R. G., & Ross, R. A. (2012). Modulation of L-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. The Journal of Biological Chemistry, 287(1), 91-104. https://doi.org/10.1074/jbc.M111.296020

Bátkai, S., Mukhopadhyay, P., Horváth, B., Rajesh, M., Gao, R. Y., Mahadevan, A., … Pacher, P. (2012). Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. British Journal of Pharmacology, 165(8), 2450-2461. https://doi.org/10.1111/j.1476-5381.2011.01410.x

Bolognini, D., Costa, B., Maione, S., Comelli, F., Marini, P., Di Marzo, V., … Pertwee, R. G. (2010). The plant cannabinoid Δ9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. British Journal of Pharmacology, 160(3), 677-687. https://doi.org/10.1111/j.1476-5381.2010.00756.x

Booker, L., Naidu, P. S., Razdan, R. K., Mahadevan, A., & Lichtman, A. H. (2009). Evaluation of prevalent phytocannabinoids in the acetic acid model of visceral nociception. Drug and Alcohol Dependence, 105(1-2), 42-47. https://doi.org/10.1016/j.drugalcdep.2009.06.009

Cascio, M. G., Zamberletti, E., Marini, P., Parolaro, D., & Pertwee, R. G. (2015). The phytocannabinoid, Δ 9 -tetrahydrocannabivarin, can act through 5-HT 1 A receptors to produce antipsychotic effects. British Journal of Pharmacology, 172(5), 1305-1318. https://doi.org/10.1111/bph.13000

De Petrocellis, L., Ligresti, A., Moriello, A. S., Allarà, M., Bisogno, T., Petrosino, S., … Di Marzo, V. (2011). Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. British Journal of Pharmacology, 163(7), 1479-1494. https://doi.org/10.1111/j.1476-5381.2010.01166.x

De Petrocellis, L., Orlando, P., Moriello, A. S., Aviello, G., Stott, C., Izzo, A. A., & Di Marzo, V. (2012). cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiologica (Oxford, England), 204(2), 255-266. https://doi.org/10.1111/j.1748-1716.2011.02338.x

Deiana, S., Watanabe, A., Yamasaki, Y., Amada, N., Arthur, M., Fleming, S., … Riedel, G. (2012). Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology, 219(3), 859-873. https://doi.org/10.1007/s00213-011-2415-0

Englund, A., Atakan, Z., Kralj, A., Tunstall, N., Murray, R., & Morrison, P. (2015). 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. Journal of Psychopharmacology (Oxford, England). https://doi.org/10.1177/0269881115615104

García, C., Palomo-Garo, C., García-Arencibia, M., Ramos, J., Pertwee, R., & Fernández-Ruiz, J. (2011). Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease. British Journal of Pharmacology, 163(7), 1495-1506. https://doi.org/10.1111/j.1476-5381.2011.01278.x

Gaston, T. E., & Friedman, D. (2017). Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy & Behavior: E&B. https://doi.org/10.1016/j.yebeh.2016.11.016

Hill, A. J., Weston, S. E., Jones, N. A., Smith, I., Bevan, S. A., Williamson, E. M., … Whalley, B. J. (2010). Δ9-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia, 51(8), 1522-1532. https://doi.org/10.1111/j.1528-1167.2010.02523.x

Makwana, R., Venkatasamy, R., Spina, D., and Page, C. (2015). The effect of phytocannabinoids on airway hyperresponsiveness, airway inflammation and cough. J. Pharmacol. Exp. Ther.

McPartland, J. M., Duncan, M., Di Marzo, V., & Pertwee, R. G. (2015). Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. British Journal of Pharmacology, 172(3), 737-753. https://doi.org/10.1111/bph.12944

Morales, P., Hurst, D. P., & Reggio, P. H. (2017). Molecular Targets of the Phytocannabinoids-A Complex Picture. Progress in the chemistry of organic natural products, 103, 103-131. https://doi.org/10.1007/978-3-319-45541-9_4

O’Brien, L. D., Wills, K. L., Segsworth, B., Dashney, B., Rock, E. M., Limebeer, C. L., & Parker, L. A. (2013). Effect of chronic exposure to rimonabant and phytocannabinoids on Anxiety-like behavior and saccharin palatability. Pharmacology, Biochemistry, and Behavior, 103(3), 597-602. https://doi.org/10.1016/j.pbb.2012.10.008

Oláh, A., Markovics, A., Szabó-Papp, J., Szabó, P. T., Stott, C., Zouboulis, C. C., & Bíró, T. (2016). Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment. Experimental Dermatology, 25(9), 701-707. https://doi.org/10.1111/exd.13042

Pagano, E., Montanaro, V., Di Girolamo, A., Pistone, A., Altieri, V., Zjawiony, J. K., … Capasso, R. (2015). Effect of Non-psychotropic Plant-derived cannabinoids on Bladder Contractility: Focus on Cannabigerol. Natural Product Communications, 10(6), 1009-1012.

Riedel, G., Fadda, P., McKillop-Smith, S., Pertwee, R. G., Platt, B., & Robinson, L. (2009). Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. British Journal of Pharmacology, 156(7), 1154-1166. https://doi.org/10.1111/j.1476-5381.2008.00107.x

Rock, E. M., Sticht, M. A., Duncan, M., Stott, C., & Parker, L. A. (2013). Evaluation of the potential of the phytocannabinoids, cannabidivarin (CBDV) and Δ9-tetrahydrocannabivarin (THCV), to produce CB1 receptor inverse agonism symptoms of nausea in rats. British Journal of Pharmacology, 170(3), 671-678. https://doi.org/10.1111/bph.12322

Romano, B., Pagano, E., Orlando, P., Capasso, R., Cascio, M. G., Pertwee, R., … Borrelli, F. (2016). Pure Δ9-tetrahydrocannabivarin and a Cannabis sativa extract with high content in Δ9-tetrahydrocannabivarin inhibit nitrite production in murine peritoneal macrophages. Pharmacological Research, 113, Part A, 199-208. https://doi.org/10.1016/j.phrs.2016.07.045

Rzepa, E., Tudge, L., & McCabe, C. (2015). The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers. The International Journal of Neuropsychopharmacology, 19(2). https://doi.org/10.1093/ijnp/pyv092

Silvestri, C., Paris, D., Martella, A., Melck, D., Guadagnino, I., Cawthorne, M., … Di Marzo, V. (2015). Two non-psychoactive cannabinoids reduce intracellular lipid levels and inhibit hepatosteatosis. Journal of Hepatology, 62(6), 1382-1390. https://doi.org/10.1016/j.jhep.2015.01.001

Thomas, A., Stevenson, L. A., Wease, K. N., Price, M. R., Baillie, G., Ross, R. A., & Pertwee, R. G. (2005). Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. British Journal of Pharmacology, 146(7), 917-926. https://doi.org/10.1038/sj.bjp.0706414

Tubaro, A., Giangaspero, A., Sosa, S., Negri, R., Grassi, G., Casano, S., Della Loggia, R., and Appendino, G. (2010). Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins. Fitoterapia 81, 816–819

Tudge, L., Williams, C., Cowen, P. J., & McCabe, C. (2015). Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers. The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 18(6). https://doi.org/10.1093/ijnp/pyu094

Wargent, E. T., Zaibi, M. S., Silvestri, C., Hislop, D. C., Stocker, C. J., Stott, C. G., … Cawthorne, M. A. (2013). The cannabinoid Δ9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of Obesity. Nutrition & diabetes, 3(5), e68. https://doi.org/10.1038/nutd.2013.9

Clinical Trials: 

diabetes

In a pilot clinical study, doses of 5mg of THCV showed efficacy and safety in glycemic control in type 2 diabetes (Jadoon et al., 2016)

References

Jadoon, K. A., Ratcliffe, S. H., Barrett, D. A., Thomas, E. L., Stott, C., Bell, J. D., … Tan, G. D. (2016). 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, 39(10), 1777-1786. https://doi.org/10.2337/dc16-0650