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How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.

ABSTRACT: Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-∆(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences.

SUBMITTER: Freeman D

PROVIDER: S-EPMC4332941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Delta-9-tetrahydrocannabinol (?9-THC) is a naturally occurring psychoactive compound derived from the hemp plant Cannabis sativa. In 2015, EFSA established an acute reference dose (ARfD) of 1 ?g/kg body weight (bw) for ?9-THC and assessed acute dietary exposure from milk and dairy products. This resulted at the most 3% and 13% of the ARfD for adults and toddlers, respectively. Following the European Commission Recommendation 2016/2115 on the monitoring of the presence of ?9-THC in food and the issuing of a new mandate, EFSA assessed the acute human exposure to ?9-THC. 'Standard' food categories were used as proxies for consumption of hemp and hemp-based products. Twelve independent scenarios based on single food categories were considered and acute exposure was assessed for consumption days only for all age groups excluding infants. Occurrence data for Total-?9-THC (588 samples in total) were used for this assessment up to the highest reliable percentile for each food category. The EFSA ARfD of 1 ?g/kg bw was exceeded in the adult high consumers of most considered hemp and hemp-containing products, under the lower-bound (LB) and upper-bound (UB) scenario. At the UB, acute exposure in adult high consumers was estimated based on the highest reliable percentile of occurrence, for Hemp seeds (P95, up to 9 ?g/kg bw), Hemp oil (P95, up to 21 ?g/kg bw), Tea (Infusion) (P95, up to 208 ?g/kg bw), Breakfast cereals (P50, up to 1.3 ?g/kg bw), Pasta (Raw) (P75, up to 6.4 ?g/kg bw), Bread and rolls (P75, up to 1.3 ?g/kg bw), Bread and rolls from hemp flour (P90, up to 4.1 ?g/kg bw), Cereal bars (P50, up to 0.3 ?g/kg bw), Fine bakery wares (P75, up to 5.1 ?g/kg bw), Chocolate (Cocoa) products (P75, up to 1.1 ?g/kg bw), Energy drinks (P75, up to 0.2 ?g/kg bw), Dietary supplements (P75, up to 9.9 ?g/kg bw), Beer and beer-like beverages (P90, up to 41 ?g/kg bw). The use of proxies for the consumption of hemp and hemp-containing products, the limited number of occurrence data and the analytical limitations in the quantification of ?9-THC represent the most important sources of uncertainty. Overall, exposure estimates presented in this report are expected to represent an overestimation of acute exposure to ?9-THC in the EU.

Project description:Background and purposeNumerous studies have shown that N-arachidonoylethanolamine (AEA) can inhibit sperm motility and function but the ability of cannabinoids to inhibit sperm motility is not well understood. We investigated the effects of WIN 55,212-2, a CB(1) cannabinoid receptor agonist, and ?(9) -tetrahydracannabinol (?(9) -THC) on the ATP levels and motility of murine sperm in vitro. In addition, the effects of acute administration of ?(9) -THC on male fecundity were determined.Experimental approachEffects of ?(9) -THC on basal sperm kinematics were determined using computer-assisted sperm analysis (CASA). Stop-motion imaging was performed to measure sperm beat frequency. The effect of ?(9) -THC on sperm ATP was determined using a luciferase assay. Male fertility was determined by evaluating the size of litters sired by ?(9) -THC-treated males. KEY RESULTS Pretreatment of sperm for 15 min with 1 µM ?(9) -THC reduced their basal motility and attenuated the ability of bicarbonate to stimulate flagellar beat frequency. Treatment with 5 µM WIN 55,212-2 or 10 µM ?(9) -THC for 30 min reduced sperm ATP levels. In sperm lacking CB(1) receptors this inhibitory effect of WIN 55,212-2 on ATP was attenuated whereas that of ?(9) -THC persisted. Administration of 50 mg·kg(-1) ?(9) -THC to male mice just before mating caused a 20% decrease in embryonic litter size.Conclusions and implications?(9) -THC inhibits both basal and bicarbonate-stimulated sperm motility in vitro and reduces male fertility in vivo. High concentrations of WIN 55,212-2 or ?(9) -THC inhibit ATP production in sperm; this effect of WIN 55,212-2 is CB(1) receptor-dependent whereas that of ?(9) -THC is not. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

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How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.

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