The effects of low doses of delta-9 tetrahydrocannabinol on reinforcement processing in the risky decision-making of young healthy adults.

Research suggests that risky decision-making is sensitive to neuromodulatory influences acting upon corticolimbic circuitry. However, while other evidence attests to effects of delta-9 tetrahydrocannabinol (THC) on the activity of reward pathways, relatively little is known about the possible involvement of cannabinoid activity in risky choice. In this experiment, we examined the effects of a single sublingual 5 mg dose of THC on a test of risky decision-making (requiring choices between simultaneously presented gambles differing in their magnitude of gains, magnitude of losses and the probability with which these outcomes were delivered). Tests of non-normative decision-making involving risk-aversion when deciding between gains and risk-seeking choices when deciding between losses were also included. In all, 15 healthy adults were administered 5 mg THC and placebo in a double-blind, placebo-controlled, within-subject, cross-over design. THC had three principal effects relative to placebo: (i) THC reduced choice of gambles with variable gains and losses, but increased choice of gambles with zero-expected value; (ii) THC reduced participants' attention towards losses when the probability of winning was low (and the probability of losing was high); and (iii) THC speeded participants' responses to gambles with large compared to small potential gains. These results suggest that THC mediates specific motivational processes and the processing of reinforcement cues during risky choice, perhaps reflecting altered CB1 receptor or catecholamine activity within corticolimbic pathways

Low doses of delta-9 tetrahydrocannabinol (THC) have divergent effects on short-term spatial memory in young, healthy adults.

Evidence suggests that manipulating spatial information within working memory depends upon a circuitry organized around the prefrontal cortex (PFC) and the activity of the catecholamine systems. Other evidence attests to the effects of Delta-9 tetrahydrocannabinol (THC) on short-term spatial memory function, most probably involving CB(1) receptor activity within hippocampal circuitries. At the current time, there have been no systematic studies of the effects of THC on spatial working memory in human subjects using tasks known to depend upon frontotemporal neural circuitries. We examined the effects of a single sublingual 5 mg dose of THC on a test of spatial working memory (requiring active manipulation of remembered spatial information for the management of future behavior) and a test of spatial span (requiring only the reproduction of sequences of previously presented spatial cues). In all, 19 healthy adults were administered 5 mg THC and placebo in a double-blind, placebo-controlled, within-subject, crossover design. Male participants performed more accurately than female participants. THC significantly enhanced spatial working memory performance of female participants. By contrast, male and female participants produced more intrusion errors during performance of the Spatial Span task. These results suggest that THC has relatively complex effects on spatial memory in human subjects, perhaps reflecting altered CB(1) receptor activity within frontotemporal circuits or altered activity of mesocortical dopaminergic pathways in PFC areas associated with spatial memory

More Aroused, Less Fatigued: Fatty Acid Amide Hydrolase Gene Polymorphisms Influence Acute Response to Amphetamine

Amphetamine is a stimulant drug that enhances attention and feelings of alertness. Amphetamine's effects are known to be modulated by endogenous cannabinoids, which are degraded by the enzyme fatty acid amide hydrolase (FAAH). In this study we investigated inter-individual differences in mood response to amphetamine in relation to four polymorphisms in the FAAH gene, including the FAAH missense variant rs324420C → A (Pro129Thr), which was previously found to be associated with street drug use and addictive traits. One hundred and fifty-nine healthy Caucasian volunteers participated in a three-session, double-blind crossover study receiving either placebo or oral d-amphetamine (10 and 20 mg). Associations between individual genotypes and levels of self-reported Arousal (Profile of Mood States) after d-amphetamine ingestion were investigated using two-way ANOVAs/ANCOVAs. Association analyses for haplotypes were performed using the adaptive permutation approach implemented in PLINK. Genotypes at rs3766246 and rs2295633 were significantly associated with increased ratings of Arousal (p<0.05) and Fatigue (p<0.01) after the 10-mg dose. Fatigue levels were also found to be associated with the haplotypes CCC and TAT formed from rs3766246, rs324420, and rs2295633 (p<0.05). These data suggest that the endocannabinoid system influences variation in subjective response to amphetamine. This has important implications for understanding the role of endogenous cannabinoids in response to amphetamine, studies of poly-substance abuse, and understanding the genetic determinants of inter-individual differences in stimulant effects and risk of abuse