Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects
Abstract
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.
LINKED ARTICLES
This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7
Acknowledgments
The author offers appreciation to the following individuals, who provided materials and/or consultation: David Potter, Etienne de Meijer, John McPartland, David Watson, Rob Clarke, Indalecio Lozano, Támas Bíró, José Crippa, Roger Pertwee, Colin Stott, Vincenzo Di Marzo, Luciano De Petrocellis, Patrick McGovern, John Riddle and Elisaldo Carlini. Most of all, I would like to thank Raphael Mechoulam for his example, guidance, friendship, a life of good works and for listening to many ‘crazy ideas’.
Glossary
Abbreviations
2-AG | 2-arachidonoylglycerol |
5-HT | 5-hydroxytryptamine (serotonin) |
AD | antidepressant |
AEA | arachidonoylethanolamide (anandamide) |
AI | anti-inflammatory |
AMPA | α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate |
Ca++ | calcium ion |
CB1/CB2 | cannabinoid receptor 1 or 2 |
CBC | cannabichromene |
CBCA | cannabichromenic acid |
CBD | cannabidiol |
CBDA | cannabidiolic acid |
CBDV | cannabidivarin |
CBG | cannabigerol |
CBGA | cannabigerolic acid |
CBGV | cannabigerivarin |
CNS | central nervous system |
COX | cyclo-oxygenase |
DAGL | diacylglycerol lipase |
ECS | endocannabinoid system |
EO | essential oil |
FAAH | fatty acid amidohydrolase |
FDA | US Food and Drug Administration |
FEMA | Food and Extract Manufacturers Association |
fMRI | functional magnetic resonance imaging |
GABA | gamma aminobutyric acid |
GPCR | G-protein coupled receptor |
GPR | G-protein coupled receptor |
HEK | human embryonic kidney |
IC50 | 50% inhibitory concentration |
i.p | intraperitoneal |
MAGL | monoacylglycerol lipase |
MIC | minimum inhibitory concentration |
MS | multiple sclerosis |
NGF | nerve growth factor |
NIDA | US National Institute on Drug Abuse |
PG | prostaglandin |
PTSD | post-traumatic stress disorder |
RCT | randomized clinical trial |
SPECT | single photon emission computed tomography |
SSADH | succinic semialdehyde dehydrogenase |
Sx | symptoms |
T1/2 | half-life |
TCA | tricyclic antidepressant |
THC | tetrahydrocannabinol |
THCA | tetrahydrocannabinolic acid |
THCV | tetrahydrocannabivarin |
TNF-α | tumour necrosis factor-alpha, TRPV, transient receptor potential vanilloid receptor |
References
- 1. [PubMed]
- 2.
- 3. [PubMed]
- 4. [PubMed]
- 5.
- 6. [PubMed]
- 7. [PubMed]
- 8. [PubMed]
- 9. [PubMed]
- 10. [PubMed]
- 11. [PubMed]
- 12. [PubMed]
- 13. [PubMed]
- 14. [PubMed]
- 15. [PubMed]
- 16. [PubMed]
- 17. [PubMed]
- 18. [PubMed]
- 19.
- 20. [PubMed]
- 21. [PubMed]
- 22.
- 23.
- 24. [PubMed]
- 25. [PubMed]
- 26.
- 27. [PubMed]
- 28. [PubMed]
- 29. [PubMed]
- 30. [PubMed]
- 31. [PubMed]
- 32. [PubMed]
- 33. [PubMed]
- 34.
- 35.
- 36. [PubMed]
- 37.
- 38. [PubMed]
- 39. [PubMed]
- 40. [PubMed]
- 41. [PubMed]
- 42. [PubMed]
- 43. [PubMed]
- 44. [PubMed]
- 45. [PubMed]
- 46. [PubMed]
- 47. [PubMed]
- 48. [PubMed]
- 49. [PubMed]
- 50. [PubMed]
- 51. [PubMed]
- 52. [PubMed]
- 53. [PubMed]
- 54. [PubMed]
- 55. [PubMed]
- 56. [PubMed]
- 57.
- 58. [PubMed]
- 59.
- 60. [PubMed]
- 61. [PubMed]
- 62. [PubMed]
- 63. [PubMed]
- 64.
- 65. [PubMed]
- 66.
- 67. [PubMed]
- 68. [PubMed]
- 69. [PubMed]
- 70. [PubMed]
- 71. [PubMed]
- 72. [PubMed]
- 73.
- 74. [PubMed]
- 75.
- 76. [PubMed]
- 77. [PubMed]
- 78. [PubMed]
- 79. [PubMed]
- 80. [PubMed]
- 81.
- 82. [PubMed]
- 83. [PubMed]
- 84. [PubMed]
- 85. [PubMed]
- 86. [PubMed]
- 87. [PubMed]
- 88. [PubMed]
- 89. [PubMed]
- 90. [PubMed]
- 91. [PubMed]
- 92. [PubMed]
- 93. [PubMed]
- 94. [PubMed]
- 95. [PubMed]
- 96.
- 97. [PubMed]
- 98. [PubMed]
- 99.
- 100.
- 101. [PubMed]
- 102. [PubMed]
- 103. [PubMed]
- 104. [PubMed]
- 105. [PubMed]
- 106. [PubMed]
- 107.
- 108. [PubMed]
- 109.
- 110. [PubMed]
- 111. [PubMed]
- 112. [PubMed]
- 113. [PubMed]
- 114. [PubMed]
- 115. [PubMed]
- 116. [PubMed]
- 117. [PubMed]
- 118. [PubMed]
- 119. [PubMed]
- 120. [PubMed]
- 121. [PubMed]
- 122. [PubMed]
- 123.
- 124. [PubMed]
- 125. [PubMed]
- 126. [PubMed]
- 127. [PubMed]
- 128. [PubMed]
- 129. [PubMed]
- 130. [PubMed]
- 131. [PubMed]
- 132. [PubMed]
- 133. [PubMed]
- 134.
- 135. [PubMed]
- 136. [PubMed]
- 137. [PubMed]
- 138. [PubMed]
- 139. [PubMed]
- 140. [PubMed]
- 141. [PubMed]
- 142. [PubMed]
- 143. [PubMed]
- 144. [PubMed]
- 145. [PubMed]
- 146. [PubMed]
- 147. [PubMed]
- 148. [PubMed]
- 149. [PubMed]
- 150. [PubMed]
- 151. [PubMed]
- 152. [PubMed]
- 153. [PubMed]
- 154. [PubMed]
- 155. [PubMed]
- 156.
- 157.
- 158. [PubMed]
- 159. [PubMed]
- 160. [PubMed]
- 161. [PubMed]
- 162. [PubMed]
- 163. [PubMed]
- 164. [PubMed]
- 165.
- 166. [PubMed]
- 167. [PubMed]
- 168. [PubMed]
- 169. [PubMed]
- 170. [PubMed]
- 171. [PubMed]
- 172.
- 173. [PubMed]
- 174. [PubMed]
- 175. [PubMed]
- 176.
- 177. [PubMed]
- 178. [PubMed]
- 179. [PubMed]
- 180. [PubMed]
- 181. [PubMed]
- 182. [PubMed]
- 183. [PubMed]
- 184. [PubMed]
- 185. [PubMed]
- 186. [PubMed]
- 187. [PubMed]
- 188. [PubMed]
- 189.
- 190. [PubMed]
- 191. [PubMed]
- 192. [PubMed]
- 193.
- 194. [PubMed]
- 195. [PubMed]
- 196. [PubMed]
- 197. [PubMed]
- 198.
- 199.
- 200.
- 201. [PubMed]
- 202. [PubMed]
- 203. [PubMed]
- 204. [PubMed]
- 205. [PubMed]
- 206. [PubMed]
- 207. [PubMed]
- 208.
- 209. [PubMed]
- 210. [PubMed]
- 211. [PubMed]
- 212.
- 213. [PubMed]
- 214. [PubMed]
- 215. [PubMed]
- 216. [PubMed]
- 217. [PubMed]
- 218. [PubMed]
- 219. [PubMed]
- 220.
- 221.
- 222. [PubMed]
- 223. [PubMed]
- 224.
- 225. [PubMed]
- 226. [PubMed]
- 227.
- 228.
- 229. [PubMed]
- 230. [PubMed]
- 231. [PubMed]
- 232.
- 233.
- 234. [PubMed]
- 235.
- 236.
- 237. [PubMed]
- 238.
- 239. [PubMed]
- 240. [PubMed]
- 241. [PubMed]
- 242. [PubMed]
- 243. [PubMed]
- 244. [PubMed]
- 245. [PubMed]
- 246. [PubMed]
- 247. [PubMed]
- 248. [PubMed]
- 249.
- 250. [PubMed]
- 251. [PubMed]
- 252. [PubMed]
- 253. [PubMed]
- 254. [PubMed]
- 255.
- 256. [PubMed]
- 257. [PubMed]
- 258. [PubMed]
- 259. [PubMed]
- 260. [PubMed]
- 261.
- 262. [PubMed]
- 263. [PubMed]
- 264. [PubMed]
- 265. [PubMed]
- 266. [PubMed]
- 267.
- 268.
- 269. [PubMed]
- 270.
- 271.
- 272. [PubMed]
- 273.
- 274. [PubMed]
- 275. [PubMed]
- 276. [PubMed]
- 277. [PubMed]
- 278. [PubMed]
- 279. [PubMed]
- 280. [PubMed]
- 281. [PubMed]
- 282. [PubMed]
- 283. [PubMed]
- 284. [PubMed]
- 285. [PubMed]
- 286.
- 287. [PubMed]
- 288. [PubMed]
- 289. [PubMed]
- 290. [PubMed]
- 291.
- 292. [PubMed]
- 293. [PubMed]
- 294. [PubMed]