Salvinorin A, a drug from the plant Salvia divinorum, produces rewarding effects in rats at low to moderate doses but becomes aversive at the highest doses tested. In conditioned place preference tests, doses between 0.1 and 40 micrograms per kilogram given subcutaneously were rewarding, while 160 micrograms per kilogram was aversive. In self-administration tests, doses of 0.1 to 0.5 micrograms per infusion given intracerebroventricularly were rewarding, but 1 microgram per infusion was aversive. The rewarding effect was blocked by pretreatment with either a cannabinoid CB1 receptor antagonist or a kappa-opioid receptor antagonist. Salvinorin A also increased dopamine levels in the shell of the nucleus accumbens by about 150 percent. These findings indicate that the rewarding effects involve interaction between kappa-opioid and endocannabinoid systems.
Salvinorin A, the active hallucinogen in Salvia divinorum, does not sustain stable intravenous self-administration in rats, indicating low abuse potential. Male Lister Hooded and Sprague-Dawley rats were given the drug intravenously for 20 days; neither strain consistently pressed an active lever more than an inactive one, failing to meet the criteria for stable self-administration. Although salvinorin A increased dopamine levels in the nucleus accumbens shell when given systemically (at 40 μg/kg or higher in Lister Hooded rats and 5 μg/kg or higher in Sprague-Dawley rats), direct injection into the ventral tegmental area produced no significant dopamine change in Lister Hooded rats and only brief elevations in Sprague-Dawley rats. Thus, salvinorin A differs from commonly abused drugs: it affects dopamine transmission but cannot sustain self-administration behavior at the doses tested.
Methoxetamine (MXE), a novel psychoactive substance sold as a 'legal high,' is chemically similar to ketamine and phencyclidine and acts as a noncompetitive NMDA receptor antagonist. Recent preclinical data show it also stimulates dopamine neurotransmission in the mesolimbic pathway. This review summarizes MXE's behavioral and toxicological effects, its pharmacology, and the frequent adverse effects seen in a growing number of intoxications. The review notes that MXE's potential rapid antidepressant activity, suggested by its similarity to ketamine and supported by recent preclinical findings, requires further investigation.