Unpicking the Entourage Effect

OUTLOOK CANNABIS SUSAN BURGHART

EFFICACY and 2-palmitoylglycerol2. Although unable to bind to CB1 and CB2 themselves, the two molecules improved the ability of 2-AG to bind to the receptors and increased effects such as Unpicking the analgesia in the animals. It’s not a big leap to think that this concept could be extended to the chemicals in cannabis, says Ethan Russo, a neurologist and entourage effect director of research and development at the International Cannabis and Cannabinoids Institute in Prague. For example, certain The idea that compounds in cannabis act in synergy to magnify compounds could enhance and heighten the the drug’s effects is intriguing but lacks solid evidence. therapeutic effects of THC, the psychoactive component of cannabis. When Mechoulam’s paper was published, Russo realized that the BY TAMMY WORTH to support it,” says Wiley, a behavioural findings could lend support to his idea that pharmacologist at RTI International, an THC wasn’t the only pharmacological com- enny Wiley was a consultant for the World independent, non-profit research institute in ponent of cannabis. For decades, he had been Health Organization in 2018 when it con- Research Triangle Park, North Carolina. Given hearing anecdotes about strains of cannabis Jducted a major review of cannabis1. The that the cannabis plant is known to contain that affected people in different ways — one committee considered input from various more than 400 types of molecule, including might be good for pain relief whereas another groups of people, including some that were tout- 100 cannabinoids and a range of terpenoids, in could improve sleep. Russo proposed that ing the importance of the entourage effect — a various quantities, the concept is challenging to there were compounds other than THC in purported synergy between the cannabinoids test scientifically. “It is a very complicated idea cannabis that could account for the differences. tetrahydrocannabinol (THC) and cannabidiol and, in some ways, may be unprovable,” she says. After learning about terpenoids, which include (CBD), as well as other molecules found in the compounds known as essential oils that can plant, known as terpenoids. ENTOURAGE ORIGINS be extracted from plants such as lavender and Such groups think that certain combinations The entourage effect was first proposed in peppermint and are purported to have healing of cannabis compounds can boost the potential 1998 by Raphael Mechoulam, a chemist at the properties, he suggested that the compounds medical benefits of THC, such as easing pain Hebrew University of Jerusalem. Mechoulam might be able to enhance the effects of THC. and inflammation, while lessening unwanted and his colleagues were studying the molecule Russo also contends that CBD might work side effects such as memory impairment. But 2-arachidonoylglycerol (2-AG), which binds to enhance THC’s therapeutic effects. As the evidence that the groups provided to sup- to the cannabinoid receptors CB1 and CB2. evidence, he points to a 2010 clinical trial port the claims were mostly anecdotal reports They showed that, in the spleen, brain and gut of Sativex (nabiximols), a botanical drug and communications from patients. of mice, 2-AG is typically found together with that comprises a mixture of THC and CBD “There really isn’t the science out there two other compounds: 2-linoleoylglycerol extracted from cannabis. Developed by

CANNABIS OUTLOOK

GW Pharmaceuticals in Histon, UK, Sativex it as THC acting as a conductor of an orches- is used to treat neuropathic pain in people tra,” she says. “Most of the therapeutic value is with multiple sclerosis. (Russo served as sen- probably derived from THC, but the overall

ISTOCK/GETTY ior medical adviser to GW Pharmaceuticals in orchestra experience is really valuable.” 2003–14.) The study3 involved 177 people experiencing SCIENTIFIC SCEPTICS pain from cancer and compared three Wiley is sceptical about whether Mechoulam’s approaches: one group of participants received work in mice translates to plants. a placebo, another was given a drug contain- Mechoulam realized that the molecules ing high levels of THC and a third group was he was studying in the brain and gut had an treated with Sativex. Participants were asked important role — to help regulate the body’s to score their pain throughout the two-week cannabinoid system. But plants are not pro- study and to confirm at the end by how much ducing terpenoids to make cannabis a more their pain had lessened, if at all. A reduction effective medicine — they serve other pur- in pain of 30% or more was considered clini- poses, including deterring predators. “It’s an cally important. Around 40% of the people idea, or theory, that has been co-opted from treated with Sativex reported this level of pain what it was never meant to cover,” Wiley says. relief — almost twice as many as those who Connor also finds little evidence to support received either placebo or THC alone. the entourage effect. The small number of Mark Connor, a pharmacologist at studies conducted so far haven’t been able to Macquarie University in Sydney, Australia, determine the concentrations of terpenoids Trichomes on leaves and buds produce the says that the Sativex trial does not prove the that reach the brain when someone consumes cannabis plant’s active compounds. existence of the entourage effect. However, it cannabis, he says. Essentially, no one knows might be the first step in showing that drugs how much reaches its target or how terpenoids effect is real. The debate is becoming a “contest comprising variable ratios of natural prod- might work when they do get there. “There between the scientific method and anecdotal ucts such as cannabinoids — as opposed to could be something there,” Connor says, “but and personal experience”, Wiley says, and she single compounds, which is the norm among we are always looking for what the molecular is concerned that the effect will be used as a pharmaceuticals — can yield benefits. basis might be — and at this point we can’t say.” marketing tool — a reason for people to keep Other research that Russo cites in support To gain a better understanding of how trying new strains of cannabis until one works of the entourage effect is a 2018 meta-analysis cannabis works in the body, Connor investi- for them. that studied 670 people with treatment- gated how six common terpenoids interacted Connor and Wilson-Poe think that cannabis resistant epilepsy, who received either purified with THC in cells. In will keep its place in the market as a natural 4 CBD or CBD-rich cannabis extracts . Sev- a March preprint, he “When I hear option for easing pain, inflammation and enty-one per cent of those taking the extracts found no evidence that ‘the entourage sleep until researchers can demonstrate or reported an improvement in the frequency of the compounds could effect’, I think disprove its therapeutic value. And the active seizures, compared with 46% of people who activate CB1 and CB2 or components of cannabis might work together were given purified CBD. However, there modify THC-induced of it as THC to produce beneficial effects in ways that are was no difference in the proportion of either signalling9. He is quick acting as a tricky to pinpoint using current methods. group who saw at least a 50% reduction in the to note, however, that conductor of Russo agrees, but hopes that the entourage frequency of their seizures. his results don’t rule an orchestra.” effect will increase the pharmaceutical value “We’ve got some proof at this point,” Russo out the possibility that of cannabis. Treatments for cancer commonly says, although he concedes that it might not be terpenoids and THC interact in other ways. involve cocktails of drugs that are designed to enough to “satisfy the masses”. For instance, terpenoids could interact with tackle several aspects of the disease. Combi- proteins other than cannabinoid receptors, nations of terpenoids, THC and CBD might TEMPERING AND ENHANCING which his experiment didn’t address. This is similarly be tailored to symptoms such as Russo has collated evidence to suggest that the case for opioid drugs, as Connor explains: spasticity, pain or anxiety. “For complex condi- terpenoids have the potential to reduce the “When I started working, we thought there tions, you need to do multiple things at once,” psychosis and memory problems that THC was one receptor,” he says. “Now we know he says. “That can come from different drugs can produce5. And such compounds might there is potential for drug-binding sites at or one properly designed botanical.” ■ also augment THC’s more positive properties. other places.” Studies suggest that myrcene can improve Tammy Worth is a freelance health-care sleep in people with chronic pain6, and that THE ENTOURAGE PROMISE reporter in Kansas City, Missouri. 7 limonene might help to alleviate anxiety . Proponents and doubters agree that further 1. World Health Organization. WHO Expert Committee When used in concert, terpenoids, THC and research, including double-blind clinical trials, on Drug Dependence: Fortieth Report. WHO Tech. CBD therefore provide an opportunity to fine- is needed to confirm whether the entourage Rep. Ser. No. 1013 (WHO, 2018). 2. Ben-Shabat, S. et al. Eur. J. Pharmacol. 353, 23–31 tune medications more effectively to fit the effect exists and, if so, to understand how it (1998). individual needs of patients, he says. works. “That way, you are taking out bias and 3. Johnson, J. R. et al. J. Pain Symptom Mgmt 39, Some terpenoids have been shown to have expectation,” Wilson-Poe says. 167–179 (2010). 8 4. Pamplona, F. A., da Silva, L. R. & Coan, A. C. antioxidative and analgesic properties , says Wiley agrees. “We have to have specified Front. Neurol. 9, 759 (2018). Adie Wilson-Poe, a neuroscientist at the quantities and look at interactions one by one,” 5. Lewis, M. A., Russo, E. B. & Smith, K. M. Planta Med. Legacy Research Institute in Portland, Oregon, she says. But she worries that such work will 84, 225–233 (2018). 6. Baron, E. P., Lucas, P., Eades, J. & Hogue, O. and chief executive of Smart Cannabis, a not stop the attention being given to anecdotal J. Headache Pain 19, 37 (2018). cannabis company also in Portland. But she claims of interactions. At the moment, many 7. Fukumoto, S. et al. Stress Health 24, 3–12 (2008). concedes that there has been no research on upholders of the entourage effect are people 8. Russo, E. B. & Marcu, J. Adv. Pharmacol. 80, 67–134 (2017). finding appropriate combinations of molecules who smoke or ingest cannabis — they notice 9. Santiago, M., Sachdev, S., Arnold, J. C., for various symptoms. that different strains produce varied effects McGregor, I. S. & Connor, M. Preprint at bioRxiv “When I hear ‘the entourage effect’, I think of and take that as evidence that the entourage https://doi.org/10.1101/569079 (2019).