The Development of Cannabinoids as Therapeutic Agents in the United States

Abstract

Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents while underscoring the risks related to interfering with the endogenous system during nonmedical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility to ultimately extend our knowledge of the risks and benefits of cannabinoids for patients and providers. SIGNIFICANCE STATEMENT: This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.

Fig. 1

Cannabinoid types and their inter-relationships. Phytocannabinoids, or cannabinoids from the cannabis plant, may also be produced synthetically from the laboratory, where they are referred to as semisynthetic cannabinoids. Endocannabinoids refer to the endogenous signaling ligands that activate cannabinoid receptors in the body.

Fig. 2

Phytocannabinoid biosynthetic pathways. Two major metabolic pathways are involved in the biosynthesis of phytocannabinoids. In one pathway, CBG-A may be converted to CBG or acidic cannabinoids, including Δ9-tetrahydrocannabinolic acid (Δ9-THC-A), CBD-A, or CBC-A, which, in turn, may be further converted to the neutral compounds Δ9-THC, CBD, or CBC. A second pathway mirrors the first with varinic varieties, resulting in Δ9-THCV, CBDV, and cannabichromevarin (CBCV). The inset shows Δ8-THC for comparison to both Δ9-THC and CBD, the latter from which this compound is primarily derived.

Fig. 3

Endocannabinoid signaling. Excitatory (left) and inhibitory (right) axon terminals synapse onto a dendritic shaft of a principal cortical neuron. Endocannabinoids are released postsynaptically to reach presynaptic cannabinoid receptors to regulate neurotransmission. DGL, diacylglycerol lipase; mGluR, metabotropic glutamate receptor.