Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of <i>δ</i>-9-THC

Bhattacharyya, Sagnik; Sainsbury, Thomas T J; Allen, Paul; Nosarti, Chiara; Atakan, Zerrin; Giampietro, Vincent; Brammer, Michael; McGuire, Philip

doi:10.1017/s0033291718000387

Cited by 11 publications

(14 citation statements)

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“…Data was normally distributed. Paired t -tests were used to estimate the effects of Δ9-THC on symptoms (focusing on peak changes from the baseline, as we did not expect symptom manifestation by the 2.5-hour time point ( 14 )) and striatal Glx values, and t -tests to compare Δ9-THC-induced Glx changes between subjects sensitive to and those not sensitive to the psychotomimetic effects of Δ9-THC, based on the manifestation of clearly detectable primary symptoms of psychosis (≥ 2-point increase in Positive and Negative Syndrome Scale (PANSS) ( 40 ) delusions, hallucinations, unusual thought content, suspiciousness, and grandiosity items), as drawn from previous factor analytic work ( 49 ) as well as previous work to characterize acute sensitivity to Δ9-THC ( 50 ). Pearson correlation analyses were used to test for an association between changes in striatal Glx values and previous cannabis exposure (SPSS version 22; SPSS Inc, Chicago, Illinois).…”

Section: Methodsmentioning

confidence: 99%

Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis

et al. 2019

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The neurobiological mechanisms underlying the association between cannabis use and acute or long-lasting psychosis are not completely understood. While some evidence suggests altered striatal dopamine may underlie the association, direct evidence that cannabis use affects either acute or chronic striatal dopamine is inconclusive. In contrast, pre-clinical research suggests that cannabis may affect dopamine via modulation of glutamate signaling. A double-blind, randomized, placebo-controlled, crossover design was used to investigate whether altered striatal glutamate, as measured using proton magnetic resonance spectroscopy, underlies the acute psychotomimetic effects of intravenously administered delta-9-tetrahydrocannabinol (Δ9-THC; 1.19 mg/2 ml), the key psychoactive ingredient in cannabis, in a set of 16 healthy participants (7 males) with modest previous cannabis exposure. Compared to placebo, acute administration of Δ9-THC significantly increased Glutamate (Glu) + Glutamine (Gln) metabolites (Glx) in the left caudate head (P = 0.027). Furthermore, compared to individuals who were not sensitive to the psychotomimetic effects of Δ9-THC, individuals who developed transient psychotic-like symptoms (~70% of the sample) had significantly lower baseline Glx (placebo; P 7= 0.023) and a 2.27-times higher increase following Δ9-THC administration. Lower baseline Glx values (r = −0.55; P = 0.026) and higher previous cannabis exposure (r = 0.52; P = 0.040) were associated with a higher Δ9-THC-induced Glx increase. These results suggest that an increase in striatal glutamate levels may underlie acute cannabis-induced psychosis while lower baseline levels may be a marker of greater sensitivity to its acute psychotomimetic effects and may have important public health implications.

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Section: Methodsmentioning

confidence: 99%

Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis

et al. 2019

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“…Whilst no behavioural differences in recall tasks were observed during a verbal paired associative learning task, oral 10mg THC (vs. placebo) abolished the normal decrement in parahippocampal activation during encoding and attenuated ventrostriatal activation during word retrieval ( Bhattacharyya et al, 2009 ). Under placebo conditions participants sensitive to the psychotogenic effects of cannabis had higher hippocampal activation during verbal encoding compared to participants without a psychotogenic response ( Bhattacharyya et al, 2018 ). In keeping with these findings, while THC (6 mg inhaled) reduced activity during encoding in the right insula, the right inferior frontal gyrus, and the left middle occipital gyrus during performance of a pictorial associative memory task, activity during recall was significantly increased in a network of recall-related brain regions, with most prominent effects in the cuneus and precuneus.…”

Section: The Acute Effects Of Cannabis and Thcmentioning

confidence: 99%

The neuropsychopharmacology of cannabis: A review of human imaging studies

Bloomfield

Hindocha

Green

et al. 2019

Pharmacology & Therapeutics

186

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The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.

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“…In this regard, controlled experiments administering 9-THC and other cannabinoids to healthy people are particularly valuable. When implemented in an MRI design, such challenge studies may elucidate how different cannabinoids modulate human behavior by tracking the acute modulation of related neurobiological processes and their genetic, neurophysiological, and neuroreceptor determinants (Bhattacharyya et al, 2012a(Bhattacharyya et al, ,b, 2014(Bhattacharyya et al, , 2017(Bhattacharyya et al, , 2018a.…”

Section: Cannabis Psychosis and Cognitive Dysfunctionmentioning

confidence: 99%

Unraveling the Intoxicating and Therapeutic Effects of Cannabis Ingredients on Psychosis and Cognition

2020

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Research evidence suggests a dose-response relationship for the association between cannabis use and risk of psychosis. Such relationship seems to reflect an increased risk of psychosis not only as a function of frequent cannabis use, but also of highpotency cannabis use in terms of concentration of -9-tetrahydrocannabinol ( 9-THC), its main psychoactive component. This finding would be in line with the evidence that 9-THC administration induces transient psychosis-like symptoms in otherwise healthy individuals. Conversely, low-potency varieties would be less harmful because of their lower amount of 9-THC and potential compresence of another cannabinoid, cannabidiol (CBD), which seems to mitigate 9-THC detrimental effects. A growing body of studies begins to suggest that CBD may have not only protective effects against the psychotomimetic effects of 9-THC but even therapeutic properties on its own, opening new prospects for the treatment of psychosis. Despite being more limited, evidence of the effects of cannabis on cognition seems to come to similar conclusions, with increasing 9-THC exposure being responsible for the cognitive impairments attributed to recreational cannabis use while CBD preventing such effects and, when administered alone, enhancing cognition. Molecular evidence indicates that 9-THC and CBD may interact with cannabinoid receptors with almost opposite mechanisms, with 9-THC being a partial agonist and CBD an inverse agonist/antagonist. With the help of imaging techniques, pharmacological studies in vivo have been able to show opposite effects of 9-THC and CBD also on brain function. Altogether, they may account for the intoxicating and therapeutic effects of cannabis on psychosis and cognition.

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Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of δ-9-THC

Abstract: These results suggest that altered hippocampal activation during verbal encoding may serve as a marker of sensitivity to the acute psychotomimetic effects of THC.

Cited by 11 publications

References 63 publications

Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis

Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis

The neuropsychopharmacology of cannabis: A review of human imaging studies

Unraveling the Intoxicating and Therapeutic Effects of Cannabis Ingredients on Psychosis and Cognition

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