Blunted highs: Pharmacodynamic and behavioral models of cannabis tolerance

J.G. Ramaekers*, N.L. Mason, E.L. Theunissen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

Acute exposure to cannabis comes with neurocognitive impairment, leading to increased risk of human error and injury. Evidence however indicates that such acute effects are less prominent in chronic users, suggesting cannabis tolerance. Models of cannabis tolerance stress the importance of neurobiological or behavioral adaptations following repeated cannabis exposure. The pharmacodynamic model relates neuroadaptive changes in the brain to a blunted response to cannabis. Downregulation of CB1 receptors in chronic cannabis users has been associated with a normalization of dopaminergic output from the ventral tegmental area to the mesolimbic circuit, and a reduction of impairment during acute cannabis exposure. Such neuroadaptions are absent in occasional users, who show strong increments of dopamine and glutamate levels in the striatum, a loss of functional connectivity within the mesolimbic circuit and neurocognitive impairments when exposed to cannabis. Evidence for a behavioral model of cannabis tolerance that poses that users can have volitional control to overcome functional impairment during cannabis intoxication is relatively weak, and at best shows limited control over a limited number of behavioral functions. Cannabis tolerance is most likely to occur in users that consume high doses of cannabis continuously, at a high pace, for a prolonged period of time. Knowledge on frequency, dose and duration of cannabis use that is needed to achieve, maintain or lessen tolerance however is very limited, but will be of importance in the context of cannabis therapeutics and in legal settings when evaluating the impact of cannabis exposure on human function.

Original languageEnglish
Pages (from-to)191-205
Number of pages15
JournalEuropean Neuropsychopharmacology
Volume36
Early online date31 Jan 2020
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Behavioural compensation
  • Cannabis
  • DELTA(9)-TETRAHYDROCANNABINOL THC
  • DOPAMINE RELEASE
  • FREQUENT
  • HEAVY
  • IMPULSE CONTROL
  • Impairment
  • Neuroadaptation
  • ORAL DELTA(9)-TETRAHYDROCANNABINOL
  • RECEPTOR ADAPTATION
  • SMOKED MARIJUANA
  • TETRAHYDROCANNABINOL
  • Tolerance
  • USERS

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