THCA: The Cannabinoid That “Gets No Respect”

Δ9-Tetrahydrocannabinoic acid or THCA, like the late great Rodney Dangerfield, simply “gets no respect” when compared with higher profile cannabinoids like CBD, CBG, or CBN that are highly touted in medical cannabis circles.

THCA is the carboxylated precursor of the psychoactive cannabinoid Δ9-tetrahydrocannabinol or THC. Unlike THC, THCA is not psychoactive and can be found in high concentrations (10%-20%) in certain cannabis strains (1). Interestingly, there is a growing body of evidence that suggest that THCA may possess a variety of medically-beneficial, therapeutic properties.

First, THCA has been reported to possess potent in vitro anti-inflammatory properties similar to those exhibited by COX-2 inhibitors like Celebrex (2). Second, THCA exhibited neuroprotective effects in various tissue culture and animal models of Parkinson’s disease (3). Finally, THCA may possess antiproliferative and anti-tumor effects against prostate cancer (4)

Unfortunately, like most other cannabinoid research, additional studies must be conducted to confirm or refute possible therapeutic benefits of THCA. That said, it is a cannabinoid that deserves more respect than it is currently getting!

References

  1. Baker PB, Taylor BJ, Gough TA. The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products. J. Pharm & Pharmacol. 1981; 33:369-372.
  2. Ruhaak LR, Felth, J, Karlsson PC, Rafer JJ, et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa Biologic and Pharmaceutical Bull; 2011 34:774-778
  3. Moldzio R, Pacher T, Krewenka C, Kranner B, et al. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomed 2012: 19:819-824.
  4. De Pretrocellis L, Ligresti A, Moriello AS, Iappelli M, Verde R, et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br. J. Pharmacol 2013: 168:79-102

What is CBN And Why It May Be Important

Cannabinol or CBN is a weak psychoactive cannabinoid found only in trace amounts in Cannabis (1).  It is mostly a degradation product (metabolite) of Δ-9-tetrahydrocannabinol (THC) [2].

Studies suggest that CBN acts as a weak agonist of CB1 receptors and has a higher affinity for CB2 receptors albeit lower than the affinity of THC for CB2 receptors (3, 4)..

Because CBN is a partially-selective agonist of CB2 receptors it has been suggested to have a plethora of therapeutic benefits including 1) pain relief, 2) sedative effects, 3) anti-inflammatory and antibacterial activity, 4) anticonvulsive properties, 5) bone growth promotion and 6) appetite stimulation (5-9). However, it is important to note that much more research must performed with CBN to validate or refute its potential therapeutic and clinical effects.

References

  1. Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE. (1975) Effects of delta9-tetrahydrocannabinol and cannabinol in man. Pharmacology 1975; 13:502-512.
  2. McCallum ND, Yagen B, Levy S, Mechoulam R. Cannabinol: a rapidly formed metabolite of delta-1- and delta-6-tetrahydrocannabinol. Experientia 1975; 31:520-521.
  3. Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK. Novel cannabinol probes for CB1 and CB2 cannabinoid receptors. Journal of Medicinal Chemistry  2000; 43:3778-3785.
  4. Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC. Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sciences 1998; 63:1-6.
  5. Zymont PM, Andersson DA, Hogestatt ED  Δ-9-tetrahydrocannabinol and cannbiol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism  J Neurosci 2002; 22:4720-4727.
  6. Appendino G, Gibbons S, Giana A, Pagani A et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study.  J Nat Prd 2008; 71:1427-1430.
  7. Ludovic Croxford J Yamamura T. Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J.Neuroimmunol. 2005: 166:3-18.
  8. Farrimond JA, Whalley BJ, Williams CM Cannabinol and cannabidiol exert opposing effects on rat feeding patterns.  Psychopharmacology (Berl) 2012; 223:117-129.
  9. Cannabis 101: What is CBN and what are the benefits of this cannabinoid? https://www.leafly.com/news/cannabis-101/what-is-cbn-and-what-are-the-benefits-of-this-cannabinoid  2015. Accessed August 3, 2017

Cannabis Genomics, Terpenes and the “Entourage Effect”

In addition to pharmacologically active cannabinoids, cannabis resins also contain a variety of terpenes (monoterpenes and sesquiterpenes) that are responsible for the scent of cannabis flowers and contribute to the unique, characteristic flavor qualities of cannabis-derived products. (1)  Over 200 terpenes have been reported in Cannabis sativa (2)

Differences in the medicinal properties of different cannabis strains have been attributed to interactions (or entourage effect) between cannabinoids and various terpenes (2, 3). For example, several cannabis terpenes (most notably, β-Caryophyllene (BCP) have been reported to interact with human cannabinoid receptors (4).  Put simply, terpenes plus cannabinoids—not cannabinoids alone—may be responsible for some of the medicinal benefits attributed to cannabis.  Consequently, it has been proposed that blends of cannabinoids and terpenes could be used in medicinal cannabis preparations to maximize therapeutic benefits via the so-called entourage effect (5). Finally, other research shows that terpenes may contribute to the anxiolytic, antibacterial, anti-inflammatory and sedative effects of Cannabis (2).

While much is known about the phytochemical composition of terpenes for forensic analysis and cannabis breeding, little is know about the molecular biology of terpene biosynthesis in cannabis.  In a recent paper, Booth et al (1) successfully identified nine terpene genes that appear to be involved in all stages of cannabis terpene biosynthesis. The authors suggested that knowledge of the genomics and gene functions of terpene biosynthesis may allow genetic manipulation of cannabis for desirable terpene profiles.  Further, genetic manipulation of terpene biosynthesis may help to scientifically unravel the so-called entourage effect and maximize the medicinal benefits of individual cannabinoids and cannabis-derived pharmaceuticals.

References

  1. Booth JK, Page JE, Bohlmann J. Terpene synthases from Cannabis sativa. PLoSOne 2017; 12:e0173911
  2. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects. British Journal of Pharmacology. 2011; 163: 1344–64
  3. ElSohly MA, editor. Marijuana and the cannabinoids. Springer Science & Business Media; 2007. November 15.
  4. ElSohly MA, editor. Marijuana and the cannabinoids. Springer Science & Business Media; 2007. November 15.
  5. Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009; 16: 97–110