The papers in this Special Issue address important questions surrounding the medicinal use of cannabis by reviewing the literature on (1) the impact of cannabis on neurocognition across the lifespan, (2) the therapeutic potential of cannabis, and (3) putative harms associated with cannabis use.
In the last few years, record numbers of Americans continue to support the legalization of cannabis, with some surveys reporting ∼60% approval of legalization compared to ∼30% a decade ago (Gallup, May 2019; https://news.gallup.com/poll/1657/Illegal-Drugs.aspx). Of those who support legalization, an astounding majority (86%) do so for its potential therapeutic benefits. Indeed, use of cannabis for medicinal purposes has dated as far back as 2700 BC. This begs the question of whether public opinion is supported by empirical research.
Because the primary psychoactive ingredient in cannabis, tetrahydrocannabinol (THC), exerts its effects via modulation of cannabinoid 1 receptors that are ubiquitous in the brain and underlie several brain functions, hundreds of studies have investigated the putative effects of cannabis on neurocognition. In this Special Issue, Duperrouzel and colleagues reviewed this vast, yet largely mixed literature from meta-analyses of these studies across different cannabis using populations. While the associations between cannabis and brain alterations in adult cannabis users are largely disparate across studies, findings are relatively consistent in adolescent or adolescent-onset populations. This important literature is presented by Chye et al., who described widely replicated findings of structural and functional brain alterations in areas important for reward and inhibitory control in adolescents. Whether these alterations are age-limited effects or general effects of cannabis, however, remain unknown. It may, therefore, be useful to ascertain age-related changes by examining cannabis users across the lifespan. To date, however, the vast majority of studies have excluded cannabis users in older age—defined as >55 years old. The review by Yoo et al. attempted to summarize this sparse literature by characterizing the interactions between mechanisms related to cannabis and aging across multiple biological systems. This review highlights the limited knowledge on how cannabis use might affect the aging population, thereby, restricting its clinical efficacy in this growing population.
What does the current literature show in terms of the clinical applications of cannabis? In populations who use cannabinoids for medicinal purposes, a large majority (i.e., 40%) utilize cannabis for pain (Gallup, June 19–July 12, 2019). To date, the unresolved and complex relationship between the analgesic effects of cannabinoids and their psychoactive effects limit the application of cannabinoids for the treatment and management of pain. An understanding of these two separate mechanisms in the central and peripheral nervous system is provided in the review by Milligan et al. based on the pre-clinical literature. Following pain, alleviation of stress and anxiety is the second most reported motivation for the use of cannabis for medicinal purposes. Hindocha reviewed the evidence on the efficacy of cannabinoids in the treatment of these symptoms in post-traumatic stress disorder (PTSD) that appear to hold promise for cannabinoids in the reduction of PTSD global symptoms. Although pain, and, stress and anxiety are the most common ailments associated with cannabis self-medication, the first FDA-approved cannabis-based prescription drug is indicated for the treatment of pediatric epilepsy. In 2018, the FDA-approved Epidiolex, a CBD solution for Lennox–Gastault syndrome and Dravet syndrome following promising findings from large, double-blind, placebo-controlled studies sponsored by the drug’s manufacturer, GW Pharmaceuticals. In the timely review of the use of cannabinoids for the treatment of epilepsy, Harvey and Doyle provided a review of clinical studies from the first of its kind in 1949–2018, indicating concordant findings of seizure control following cannabinoid treatment in epilepsy.
As in other therapeutic compounds, unwanted side effects are important to consider. The literature is unequivocal in that the risk for side effects of cannabis exposure is especially high during adolescence. A principal side effect is cannabis’ abuse liability. In the review by Karoly et al., they addressed the predominant co-use of cannabis and alcohol in adolescents and described the mixed evidence in the literature across neuropsychological, brain imaging, and psychosocial outcomes. Another concern during adolescent development is cannabis use and its relation to conduct disorder, a psychiatric disorder marked by antisocial behavior in adolescents. Blair evaluated this relationship through a review of existing longitudinal studies as well as studies of risk factors. In a similar vein, Sideli and colleagues reviewed the body of work on the relationship between cannabis use and psychosis and mood disorders, including suicidality. The authors highlighted that the role of cannabis in the development of psychosis is consistent, and, identified important factors that mediate this relationship, such as increased THC potency.
In conclusion, given the profound changes in attitudes toward cannabis that stem from its putative therapeutic potential, the burden on the scientific community is in determining how we may harness its therapeutic benefits while minimizing harmful effects.