Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids

Dennis J Sholler¹, Marilyn A Huestis², Benjamin Amendolara³, Ryan Vandrey⁴, Ziva D Cooper⁵

Affiliations

¹ Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: dsholle1@jhmi.edu.
² Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, USA.
³ UCLA Cannabis Research Initiative, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁴ Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ UCLA Cannabis Research Initiative, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.

PMID: 33086126
PMCID: PMC7725960
DOI: 10.1016/j.pbb.2020.173059

Review

Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids

Dennis J Sholler et al. Pharmacol Biochem Behav. 2020 Dec.

. 2020 Dec:199:173059.

doi: 10.1016/j.pbb.2020.173059. Epub 2020 Oct 18.

Authors

Dennis J Sholler¹, Marilyn A Huestis², Benjamin Amendolara³, Ryan Vandrey⁴, Ziva D Cooper⁵

Affiliations

¹ Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: dsholle1@jhmi.edu.
² Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, USA.
³ UCLA Cannabis Research Initiative, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁴ Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ UCLA Cannabis Research Initiative, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.

PMID: 33086126
PMCID: PMC7725960
DOI: 10.1016/j.pbb.2020.173059

Abstract

The phytocannabinoid Δ⁹-tetrahydrocannabinol (THC) was isolated and synthesized in the 1960s. Since then, two synthetic cannabinoids (SCBs) targeting the cannabinoid 1 (CB1R) and 2 (CB2R) receptors were approved for medical use based on clinical safety and efficacy data: dronabinol (synthetic THC) and nabilone (synthetic THC analog). To probe the function of the endocannabinoid system further, hundreds of investigational compounds were developed; in particular, agonists with (1) greater CB1/2R affinity relative to THC and (2) full CB1/2R agonist activity. This pharmacological profile may pose greater risks for misuse and adverse effects relative to THC, and these SCBs proliferated in retail markets as legal alternatives to cannabis (e.g., novel psychoactive substances [NPS], "Spice," "K2"). These SCBs were largely outlawed in the U.S., but blanket policies that placed all SCB chemicals into restrictive control categories impeded research progress into novel mechanisms for SCB therapeutic development. There is a concerted effort to develop new, therapeutically useful SCBs that target novel pharmacological mechanisms. This review highlights the potential therapeutic efficacy and safety considerations for unique SCBs, including CB1R partial and full agonists, peripherally-restricted CB1R agonists, selective CB2R agonists, selective CB1R antagonists/inverse agonists, CB1R allosteric modulators, endocannabinoid-degrading enzyme inhibitors, and cannabidiol. We propose promising directions for SCB research that may optimize therapeutic efficacy and diminish potential for adverse events, for example, peripherally-restricted CB1R antagonists/inverse agonists and biased CB1/2R agonists. Together, these strategies could lead to the discovery of new, therapeutically useful SCBs with reduced negative public health impact.

Keywords: Cannabidiol; Cannabinoid receptor; Cannabinoids; Cannabis; Synthetic cannabinoids; Δ(9)-Tetrahydrocannabinol.

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Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids

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Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids

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