Widespread legislative reforms allowing for the legal sale and use of cannabis for medical and non-medical (e.g., recreational) purposes has greatly expanded access to cannabis and resulted in the proliferation of novel cannabis products. Cannabis is being selectively bred to have targeted cannabinoid and terpenoid profiles, which are marketed as having substantively different subjective and medicinal effects. However, these claims are based on anecdote or marketing, rather than controlled scientific discovery. THC is the primary psychoactive constituent of cannabis and has demonstrated therapeutic value (treatment of cachexia and nausea/emesis), but is also associated with many adverse effects. There is a theoretical basis for believing that some effects of THC may be modulated by terpenoids, abundant naturally occurring plant products prevalent within a variety of cannabis strains. The terpenoids of interest in the present project, limonene, myrcene, and pinene are common to human diets and designated Generally Recognized as Safe (GRAS) by the FDA. However, human laboratory research testing the separate and combined effects of THC and terpenoids is scarce to non-existent. The unique effects of limonene (anxiolytic), pinene (cognitive enhancement), myrcene (sedative) that have been elucidated in independent studies suggest that these substances may mitigate or enhance specific effects of THC.
The aim of this project is to systematically evaluate the effects of THC, limonene, myrcene, and pinene, alone, and in combination, to evaluate the validity of the purported cannabis ?entourage? effect (belief that whole plant provides substantively different effects than THC alone). Three double-blind, placebo-controlled within-subjects crossover studies will be completed to evaluate each terpenoid alone and in combination with moderate and high doses of THC. Healthy volunteers who report past, but not current (past month) cannabis use will attend 9 outpatient laboratory sessions and receive the following: 1) Placebo, 2) THC (15mg), 3) THC (30mg), 4) low dose terpenoid, 5) high dose terpenoid, 6) THC (15mg) + low dose terpenoid, 7) THC (15mg) + high dose terpenoid, 8) THC (30mg) + low dose terpenoid, and 9) THC (30mg) + high dose terpenoid. Dose order will be randomized and repeated assessments will characterize behavioral, physiological, cognitive, and subjective effects. The use of two doses of THC and each terpenoid allows for evaluation of THC-terpenoid interactions at different ratios and both maximizes the likelihood of observing targeted THC effects and reduces the likelihood of Type II error. Results will advance our understanding of the behavioral pharmacology of cannabis. Demonstrating an attenuation of THC effects would support the cannabis ?entourage? effect and provide data useful for the development of novel cannabinoid medications that can mitigate adverse effects of THC. In contrast, the absence of THC modulation by these terpenoids would indicate the need to evaluate other targets, and would support use of pharmaceutical cannabinoid products versus plant-based products in medicine.

Public Health Relevance

The cannabis (marijuana) plant is very complex and is made up of hundreds of different chemicals that interact with each other in ways that are not very well understood. In this project, we will study the interactions between THC, the part of the cannabis plant that causes intoxication, and 3 other chemicals in the plant: limonene, pinene, and myrcene. We believe that two of these substances (limonene and pinene) might be able to reduce some of the unwanted side effects of THC (anxiety and memory impairment), and that myrcene might cause additional sedation when combined with THC, but these effects have yet to be studied in controlled experiments.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Su, Shelley
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Johns Hopkins University
Schools of Medicine
United States
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Bonn-Miller, Marcel O; ElSohly, Mahmoud A; Loflin, Mallory J E et al. (2018) Cannabis and cannabinoid drug development: evaluating botanical versus single molecule approaches. Int Rev Psychiatry 30:277-284