Using dopamine research to generate rational cannabinoid drug policy

Abstract

The recent rise in the recreational use of synthetic cannabinoids (e.g. ‘K2’ and ‘Spice’) has been accompanied by a corresponding increase in regulation. Besides prohibition of specific compounds and general class bans in over forty states, five synthetic cannabinoids (CB) are federally regulated under a ‘temporary’ ban and are currently under a formal review to determine whether to permanently schedule them. Whether through explicit prohibition of specific chemicals, or potential de facto bans of unofficially scheduled compounds through the analogue act, scheduling CBs may significantly impede researching their therapeutic utility and elucidating physiological roles of the endogenous CB system. We argue that a review of neuroscience research suggests that synthetic CBs that act like Δ9-tetrahydrocannabinol (THC) by directly binding to and stimulating CB receptors (i.e. direct agonists), as well as novel drugs that indirectly stimulate these receptors by increasing levels of endogenous CB neurotransmitters (i.e. indirect agonists) have therapeutic value. Specifically, neurochemical research into how CBs influence mesolimbic dopamine release, a reliable and consistent marker of drugs’ rewarding/reinforcing effects, provides the most useful indication of CB abuse liability, and may have implications for the generation of rational drug policy. It demonstrates that direct CB receptor agonists, but not indirect agonists, increase mesolimbic dopamine release. Thus, while direct CB receptor agonists pose an abuse liability, indirect agonists do not. We recommend regulatory agencies revise policies that treat these separate CB classes similarly and to curb regulation aimed at any CB receptor agonists as Schedule I, as this ignores their medicinal properties.

Cannabinoid modulation of drug reward and the implications of marijuana legalization

“…However, CB 1 receptor antagonists, while effective, are associated with significant negative side effects in humans, such as depression and suicidal tendencies (Hill and Gorzalka, 2009). Alternatively, because eCB mobilization occurs only in response to heightened activity, disrupting endogenous activity (e.g., by blocking enzymatic degradation) may more selectively target those synapses that are active during a specific event, such as re-exposure to drug cues (Oleson et al, 2014; Loewinger et al, 2013; Katona and Freund, 2008). This final point highlights that, while cannabinoids have had a pervasive influence on human culture for millennia, the recent discovery of the eCB system has permitted an unprecedented understanding (yet far from incomplete) of how these drugs affect the brain and behavior.…”

Food Addiction: An Evolving Nonlinear Science

“…Finally, given the ability of endocannabinoids (see CB1 in Figure 1 ) to stimulate DA [ 57 ] which can effectuate orexigenic responses in the brain, the usage of marijuana should probably be strongly discouraged in those patients seeking meaningful assistance with either weight loss management or diabesity medical intervention. In addition, given the central importance of de novo production of dopamine in suppressing weight gain through its sympathetic contributions to sympathetic/parasympathetic balance (see Figure 2 ), the withdrawal of dopamine based anorexigenic agents can result in a significant regain in weight [ 14 ].…”

Tales from the dark side: Do neuromodulators of drug withdrawal require changes in endocannabinoid tone?

“…However, the abuse liability associated with drugs like marijuana may limit their therapeutic utility. Even in the early case report by Birch (1889) he cautioned that, “I would insist the necessity of concealing the name of the remedial drug from the patient, lest in his endeavor to escape from one for vice he should fall into another.” Alternatively, elevating endocannabinoid tone provides an approach to treat withdrawal symptoms without posing great risk for potential for abuse (Loewinger et al 2013). The Lichtman group has conducted several studies to test whether increasing specific endocannabinoids might reduce opiate withdrawal symptomatology.…”