Using dopamine research to generate rational cannabinoid drug policy.

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.