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What is the entourage effect?

Originally, the so-called entourage effect was specifically mentioned in the context of endocannabinoid interaction that resulted in an effect greater than the sum of its individual components.1 In other words, if you calculate the effect of two compounds acting together, their effect is not worth two, but three compounds, or even more. The authors speculated that this effect could also occur for plant cannabinoids, which had was already been hypothesized in the 1970’s.2 Nowadays, people generally speak of an entourage effect of cannabis compounds that does not necessarily refer to a greater effect, but more to a ‘beneficial effect’. We put that between quotation marks, because what’s beneficial for one person may be harmful for another.

Does the entourage effect exist?

When people discuss the entourage effect, it is always important to explain the perspective from which they look at this term. Let’s discuss this question from several points of view:

Do cannabinoids interact with each other in the body?

Certainly. There are various known interactions between endocannabioids and synthetic cannabinoids.1, 3 Also, plant cannabinoids can influence each other’s effect. An example includes the compound CBD being able to decrease THC-induced anxiety.4

Do cannabinoids give greater effects when combined, as opposed to single compounds?

The answer to this question is debatable. One of the most well-known studies on this topic was conducted in the 1970’s by a Brazilian group of researchers. The researchers collaborated internationally and found that smoking cannabis flower with different cannabinoid consistencies gave relatively larger effects than what could be expected from THC alone.2, 5 These effects were noticed in both animals and humans. Calculation of the effects measured in humans included pulse rate and time estimation. The difference in the effects’ strength between different flower varieties sometimes was two to four times, even when normalizing the THC level. Although this might seem convincing, there are a lot of contrasting findings on this topic. In fact, we found more studies that couldn’t prove the greater effect than the studies that did.6, 7, 8 This does not mean that cannabinoids are unable to induce stronger effects when administered together. On the contrary, it means that this simply might not count for just any compound combination in every organism and in every disease state.

Do cannabinoids give beneficial effects through mutual interaction?

Calling an effect beneficial is subjective: sometimes, an effect can be beneficial for one person, whereas another person can find the exact same effect undesirable. by another. Similarly, the same medicine given to a patient would be beneficial for them, whereas it can cause adverse effects in another person, for example when they are not a patient, but a healthy volunteer. This means that answering the question on beneficial effects of cannabinoids through mutual interaction can be pretty complex. Luckily, there are few examples of scientific publications where the answer is more straightforward. Keep in mind that some of the studies that we’ve reviewed below have been reproduced by other research groups, but this hasn’t happened for all of them yet. Consequentially, we cannot assume that all findings are reliable. One of the examples of the improved effect can be found in a publication by Johnson et all.9 They showed that, compared to placebo, twice as many patients reported pain reduction when CBD was added to THC in their cancer pain treatment. On the other hand, the patients receiving THC-only treatment had results similar to placebo (inactive treatment).9 When it comes to tolerability, adding CBD to THC seems to mitigate the negative side effects of THC. In the example we mentioned already, we saw that adding CBD can reduce anxiety induced by THC, which is a common side-effect of this compound.4 The entourage effect in this instance can potentially enable a higher and more effective dose of THC to be given to treat various symptoms, such as different kinds of pain, while keeping the negative side-effects limited. Future studies will need to provide more insight on this matter. On the other hand, there has been one study in which multiple sclerosis patients reported stronger adverse effects with an oral cannabis sativa plant extract compared to THC alone. In their own words, the authors concluded that:”Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant’s global impression.”. 10 The last two examples might seem to contradict each other, but there are so many factors involved, and there is a lot more research to be done, that it is impossible to come up with a black-and-white answer to the question whether cannabinoids give beneficial effects through mutual interaction. We hope we gave you some insight in the complexity of this issue, and why we need to approach this matter in a well-defined and nuanced manner.

Are there any studies ongoing that teach us about the entourage effect?

Yes, plenty! A noteworthy one is a study that is focused on the potential interaction between cannabinoids and terpenes, the latter being the compounds that are for a large part responsible for giving the cannabis plant their smell. The first small step in trying to understand this interaction better in a structured way is a monstrous study thought out by our friends and researchers Dr. Ethan Russo and Dr. Ryan Vandrey, and conducted by Vandrey’s group at Johns Hopkins University research facilities in Maryland. In three separate studies, the interaction of vaporized THC and the terpenes d-limonene, alpha-pinene, and beta-myrcene will be tested alone and in combination to better understand the interactive effects of these substances on subjective drug effects, mood, cognition, and arousal. While writing this Page, late April 2019, Dr. Vandrey informed us that the first volunteers have been dosed with either THC, limonene, THC + limonene or placebo (inactive treatment). We are eagerly awaiting the first results of this exciting study, which we will include on this Page once the results have been published.References:
  1. Ben-Shabat, Shimon; Fride, Ester; Sheskin, Tzviel; Tamiri, Tsippy; Rhee, Man-Hee; Vogel, Zvi; Bisogno, Tiziana; De Petrocellis, Luciano; Di Marzo, Vincenzo; Mechoulam, Raphael (1998). An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. European Journal of Pharmacology, 353(1), 23-31.
  2. Karniol, I. G.; Carlini, E. A. (1972). The content of (‐)Δ9‐trans‐tetrahydrocannabinol (Δ9‐THC) does not explain all biological activity of some Brazilian marihuana samples. Journal of Pharmacy and Pharmacology, 24(10), 833-835.
  3. Mechoulam, Raphael; Fride, Ester; Hanu, Lumir; Sheskin, Tzviel; Bisogno, Tiziana; Di Marzo, Vincenzo; Bayewitch, Michael; Vogel, Zvi (1997). Anandamide may mediate sleep induction. Nature, 389(6646), 25--26.
  4. Zuardi, A. W.; Shirakawa, I.; Finkelfarb, E.; Karniol, I. G. (1982). Action of cannabidiol on the anxiety and other effects produced by ?9-THC in normal subjects. Psychopharmacology, 76(3), 245--250.
  5. Carlini, E. A.; Karniol, I. G.; Renault, P. F.; Schuster, C. R. (1974). Effects of marihuana in laboratory animals and in man. British journal of pharmacology, 50(2), 299--309.
  6. Wilkinson, J. D.; Whalley, B. J.; Baker, D.; Pryce, G.; Constanti, A.; Gibbons, S.; Williamson, E. M. (2003). Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for all its effects?. The Journal of pharmacy and pharmacology, 55(12), 1687--1694.
  7. Zajicek, J. P.; Sanders, H. P.; Wright, D. E.; Vickery, P. J.; Ingram, W. M.; Reilly, S. M.; Nunn, A. J.; Teare, L. J.; Fox, P. J.; Thompson, A. J. (2005). Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. Journal of Neurology, Neurosurgery & Psychiatry, 76(12), 1664--1669.
  8. Santiago, Marina; Sachdev, Shivani; Arnold, Jonathon C.; McGregor, Iain S.; Connor, Mark (2019). Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors. bioRxiv
  9. Johnson, Jeremy R.; Burnell-Nugent, Mary; Lossignol, Dominique; Ganae-Motan, Elena Doina; Potts, Richard; Fallon, Marie T. (2010). Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. Journal of Pain and Symptom Management, 39(2), 167--79.
  10. Killestein, J.; Hoogervorst, E. L. J.; Reif, M.; Kalkers, N. F.; Van Loenen, A. C.; Staats, P. G. M.; Gorter, R. W.; Uitdehaag, B. M. J.; Polman, C. H. (2002). Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology, 58(9), 1404--7.