Importance: verbal learning and memory have been suggested to be the most consistently impaired cognitive functions after both acute and chronic cannabis exposure [1]. Cannabis can induce acute psychotic symptoms [2], and its chronic use may increase the risk of schizophrenia [3] and its relapse [4]. However, no study has investigated its acute effects on psychotic symptoms, human brain function and related verbal memory behaviour depending on previous history of cannabis use. This investigation might help understanding brain function and behaviour upon repeated cannabis exposure in humans. Objective: To examine the neurocognitive effect of acuteadministrationof(−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC, the main active ingredient of cannabis) and its modulation by the extent of previous cannabis exposure, with relevance to the psychotic symptoms manifestation. Design: a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, acute pharmacologicalchallengedesignwasused,withcounterbalanced order of drug administration [5]. On 2 occasions, after administration of Δ9-THC or placebo, volunteers were studied using event-related functional magnetic resonance imaging while performing a verbal paired associate learning task that involved an encoding and a recall condition. Setting: University center. Participants: Twenty-four healthy men with different levels of lifetime cannabis use. Main outcome and measures: Symptom ratings, task performance, and brain activation. Results: compared to non-users, abstinent users (N= 12) showed slower learning process (N=12; P=0.047) and greater right caudate and parahippocampal gyrus activation. Δ9-THC acutely produced anxiety and psychotic symptoms (all P≤0.02), the latter being more pronounced in non-users (P=0.040). In non-users under the placebo condition (control group), the encoding was associated with activation in the right superior temporal gyrus, inferior parietal lobule and precuneus, and deactivation in the parahippocampal gyrus bilaterally, left thalamus, and right posterior cingulate. There was an opposite pattern in non-users exposed to Δ9THC (only acute effect) and in abstinent users under placebo (only residual effect). Users under Δ9-THC (residual and acute cannabis effects) showed brain activity patterns intermediate between the control group and the only residual/only acute effect groups. In nonusers, the Δ9-THC-induced left parahippocampal activation positively correlated with the Δ9-THC-induced psychotic symptoms severity (P=0.036) and learning slowness (P=0.028). Conclusions and relevance: this study has investigated for the very first time whether individuals respond differently to the acute effects of Δ9-THC at a clinical, behavioral, and neurophysiological level depending on their background of cannabis use. Cannabis users may have some residual effect of their cannabis exposure in terms of slower learning and inefficient related brain activity. Also, they seem to have a more blunted response to the acute effects of Δ9-THC administration compared to non-users at both the behavioral and neurophysiological levels. Finally, this study suggests an involvement of the left parahippocampal gyrus in the Δ9-THC-induced psychotic symptoms and cognitive dysfunction among non-users.
Cannabis users are less sensitive to the acute psychotomimetic effects of delta-9-tetrahydrocannabinol administration
Colizzi, M.;
2017-01-01
Abstract
Importance: verbal learning and memory have been suggested to be the most consistently impaired cognitive functions after both acute and chronic cannabis exposure [1]. Cannabis can induce acute psychotic symptoms [2], and its chronic use may increase the risk of schizophrenia [3] and its relapse [4]. However, no study has investigated its acute effects on psychotic symptoms, human brain function and related verbal memory behaviour depending on previous history of cannabis use. This investigation might help understanding brain function and behaviour upon repeated cannabis exposure in humans. Objective: To examine the neurocognitive effect of acuteadministrationof(−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC, the main active ingredient of cannabis) and its modulation by the extent of previous cannabis exposure, with relevance to the psychotic symptoms manifestation. Design: a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, acute pharmacologicalchallengedesignwasused,withcounterbalanced order of drug administration [5]. On 2 occasions, after administration of Δ9-THC or placebo, volunteers were studied using event-related functional magnetic resonance imaging while performing a verbal paired associate learning task that involved an encoding and a recall condition. Setting: University center. Participants: Twenty-four healthy men with different levels of lifetime cannabis use. Main outcome and measures: Symptom ratings, task performance, and brain activation. Results: compared to non-users, abstinent users (N= 12) showed slower learning process (N=12; P=0.047) and greater right caudate and parahippocampal gyrus activation. Δ9-THC acutely produced anxiety and psychotic symptoms (all P≤0.02), the latter being more pronounced in non-users (P=0.040). In non-users under the placebo condition (control group), the encoding was associated with activation in the right superior temporal gyrus, inferior parietal lobule and precuneus, and deactivation in the parahippocampal gyrus bilaterally, left thalamus, and right posterior cingulate. There was an opposite pattern in non-users exposed to Δ9THC (only acute effect) and in abstinent users under placebo (only residual effect). Users under Δ9-THC (residual and acute cannabis effects) showed brain activity patterns intermediate between the control group and the only residual/only acute effect groups. In nonusers, the Δ9-THC-induced left parahippocampal activation positively correlated with the Δ9-THC-induced psychotic symptoms severity (P=0.036) and learning slowness (P=0.028). Conclusions and relevance: this study has investigated for the very first time whether individuals respond differently to the acute effects of Δ9-THC at a clinical, behavioral, and neurophysiological level depending on their background of cannabis use. Cannabis users may have some residual effect of their cannabis exposure in terms of slower learning and inefficient related brain activity. Also, they seem to have a more blunted response to the acute effects of Δ9-THC administration compared to non-users at both the behavioral and neurophysiological levels. Finally, this study suggests an involvement of the left parahippocampal gyrus in the Δ9-THC-induced psychotic symptoms and cognitive dysfunction among non-users.
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