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The why behind the high: determinants of neurocognition during acute cannabis exposure


Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis‐related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.

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Fig. 1: Mesocorticolimbic circuit and salience network activity during THC intoxication.
Fig. 2: Dissociation between the impact of THC on the neurocognitive state and THC blood concentration.
Fig. 3: Moderators of the cannabis-induced neurocognitive state.


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Correspondence to Johannes G. Ramaekers.

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Compounds found in cannabis or that are synthetically produced to mimic naturally occurring cannabinoids.

Psychomotor deficits

Impairments of cognitive and motor functions that interfere with skilled performance.

Psychotomimetic effects

Effects that resemble psychotic symptoms.


Endogenous ligands that bind to cannabinoid receptors.

Xenon-enhanced computed tomography

A neuroimaging method in which the subject inhales xenon gas to assess changes in cerebral blood flow.

Positron emission tomography

A magnetic resonance imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities such as receptor occupancy.

Arterial spin labelling

A non-invasive magnetic resonance imaging technique that uses arterial water as an endogenous tracer to measure cerebral blood flow.

Functional connectivity

A measure of similarity or correlation between brain signals arising from anatomically separated brain regions that indicates that the regions are functionally connected.

Executive network

A frontoparietal brain network involved in sustained attention, complex problem-solving and working memory.

Magnetic resonance spectroscopy

A non-invasive proton imaging technique that allows for the quantitative assessment of regional brain biochemistry.

Functional magnetic resonance imaging

A non-invasive technique for measuring and mapping brain activity based on changes in blood oxygen level-dependent signals that indicate underlying neural activity.

Default mode network

A brain network primarily consisting of the medial prefrontal cortex, the posterior cingulate cortex and the angular gyrus that is active when a person is focused on internal mental state processes and the brain is at wakeful rest.

Inhibitory control

A cognitive process that permits an individual to inhibit their impulses in order to select a more appropriate goal-directed response.

Single-nucleotide polymorphisms

Common genetic variations occurring when a single nucleotide at a single position in the genome differs among people.


A pharmacological concept describing a reduced reaction to a drug following repeated use.


A disorder arising from repeated or continuous substance use characterized by preoccupation with and impaired control over substance use, as well as physiological features such as tolerance and withdrawal.

Trait levels

The quantification of personality traits in an individual.


The disposition of a drug within the body over a period of time as characterized by the four main phases of absorption, distribution, metabolism and elimination.

Field sobriety tests

Tests of balance, coordination and divided attention that are performed by the police to determine whether a driver is impaired.

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Ramaekers, J.G., Mason, N.L., Kloft, L. et al. The why behind the high: determinants of neurocognition during acute cannabis exposure. Nat Rev Neurosci 22, 439–454 (2021).

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