Cannabinoid type 2 receptors as a therapeutic target for substance use disorders - Project Summary
Drug abuse remains a significant, and escalating, public health problem as rates of drug abuse and
overdose deaths have been accelerating incessantly over the last decade. While opioids have primarily driven
this catastrophic expansion in overdose deaths, a resurgence in mortality associated with the use of stimulant
drugs, and the co-abuse of opioids and stimulant drugs, is evident in recent years. While treatment options for
the management of opioid use disorder exist, they are plagued by poor patient compliance or are themselves
opioid agonists and therefore possess a high risk for dependence, abuse, and death. For stimulant use disorder,
there are currently no approved treatment options. The shortcomings of currently available treatments for opioid
use disorder, and the total lack of any treatment options for stimulant use disorder, clearly indicate the need for
novel options to reduce the abuse-related effects of opioid and stimulant drugs. Cannabinoid type 2 (CB2)
receptor agonists are one potential target that have demonstrated some promise in combating the abuse-related
effects of both opioids and stimulant drugs. However, humans rarely use drugs in isolation indicating the
preclinical study of candidate treatments for substance use disorders on single drugs of abuse does not
accurately reflect the way drugs are used by humans and may not represent their therapeutic potential in real
world scenarios. Therefore, the research proposed in this application aims to examine the effects of CB2 receptor
agonists on the abuse-related effects of opioids, stimulants, and opioid/stimulant mixtures. These studies will
examine the therapeutic potential of CB2 receptor agonists on 2 of the most problematic aspects of substance
use disorders: drug taking behavior, and relapse. Studies in Aim 1 will examine the effects of CB2 receptor
agonists on the self-administration of fentanyl, methamphetamine, and fentanyl/methamphetamine mixtures in
a food versus drug choice procedure. Studies in Aim 2 will examine the effects of CB2 receptor agonists on the
reinstatement of responding previously reinforced by fentanyl, methamphetamine, and
fentanyl/methamphetamine mixtures. These studies will provide the foundation for future research into the
therapeutic utility of CB2 receptor agonists on other problematic effects of opioid, stimulant, and polysubstance
use disorders including their effects on physical dependence and withdrawal, drug taking behavior in physically
dependent subjects, and the ventilatory depressant effects of opioids. Moreover, the postdoctoral training plan
proposed in this application encompasses the acquisition of vital new scientific skills in addition to other
structured activities designed to facilitate the applicants transition from postdoctoral trainee to independent
investigator.
