(S)-ketamine augments behavioral and physiological responses to Δ9-tetrahydrocannabinol
(S)-ketamine is a fast-acting therapeutic to manage treatment-resistant depression as well as psychiatric emergencies. As the non-prescribed use of ketamine has rapidly increased over the past decade, its possible interactions with other recreational drugs are of increasing interest. Here, we addressed if {Delta}9-tetrahydrocannabinol (THC), the main psychoactive constituent of Cannabis sp., and (S)-ketamine could affect each others psychoactive profile in a pharmacological triad. In healthy male mice, the sequential use of (S)-ketamine followed by THC at human-relevant doses did not result in either synergistic or antagonistic effects acutely. In contrast, THC-induced hypothermia was nearly doubled by subsequent (S)-ketamine administration. THC-induced hypolocomotion was not only prolonged by (S)-ketamine, but axial rotation and stumbling during ambulation in an open field were increased in subjects exposed sequentially to both drugs. Likewise, the performance of subjects exposed to THC and then (S)-ketamine worsened on a rotarod. Combined drug treatment led to unusual epinephrine and corticosterone profiles in blood plasma. We suggest that (S)-ketamine augments adverse THC effects, which at the endocrine level invoke the acute deregulation of the hypothalamus-pituitary-adrenal axis. Our findings support the clinical notion that combining cannabis and (S)-ketamine should be avoided.