Cannabis contains more than 100 unique ingredients that are known as 'cannabinoids', and the proportions of these vary widely across different strains of the plant. High-Δ9-tetrahydrocannabinol (Δ9-THC) varieties with negligible levels of cannabidiol (CBD) now dominate many Western markets and are more harmful than lower-Δ9-THC, higher-CBD varieties.
Like other recreational drugs, Δ9-THC increases release of dopamine and opioid peptides (in preclinical studies) and alters endocannabinoid processing in the mesocorticolimbic reward system. Long-term Δ9-THC exposure leads to a downregulation of brain cannabinoid receptor function that reverses following abstinence.
People who try cannabis are ninefold more likely to become addicted to it than to develop psychosis. Cannabis addiction is an increasing problem globally, and no effective pharmacological treatments currently exist — this remains a major unmet clinical need.
The association between cannabis use and psychosis can be influenced by several vulnerability factors, including genetics, environmental factors and the frequency and type of cannabis used. Evidence linking cannabis use with the development of depression and anxiety is less consistent, although these disorders are often comorbid with cannabis addiction.
The acute effects of cannabis on cognitive function are well documented, and the most robust, dose-related decrements are to working and episodic memory. Its long-term cognitive effects remain controversial, are influenced by many confounds and appear to subside a month after stopping use of the drug.
We should ensure that global legislative changes are informed by neuroscience and public health. They should mitigate against adolescent uptake and the availability of highly potent products, including synthetic agents such as 'spice', that act as full cannabinoid receptor agonists.
In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.
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This work was supported by grants from the US National Institutes of Health to L.H.P. (AA020404, AA006420, AA022249 and AA017447) and by grants from the UK Medical Research Council to H.V.C. and C.J.A.M. (G0800268; MR/K015524/1).
C.J.A.M. has been a consultant for Janssen and GlaxoSmithKline. D.A.L. currently receives investigator-initiated research support from Pfizer and in 2012–2014 served as a consultant in the areas of target identification and validation and new compound development for Autifony, Bristol-Myers Squibb, Concert Pharmaceuticals and Sunovion. H.V.C., T.P.F., C.M. and L.H.P. declare no competing interests.
A mental disturbance characterized by aberrant perceptions (hallucinations) and thoughts (delusions) that causes an individual to lose touch with external reality.
- Long-term potentiation
(LTP). A lasting increase in the strength of neurotransmission at a synapse that is implicated in learning and memory.
- Long-term depression
(LTD). An enduring decrease in the strength of neurotransmission at a synapse that is implicated learning and memory.
- Episodic memory
Personal, contextualized autobiographical memory of past experiences.
- Working memory
The capacity to hold information 'online' (maintenance) and manipulate it.
- Cannabis abuse
Cannabis use that is problematic for various aspects of an individual's life (for example, causing occupational, educational or social problems) or that is carried out in dangerous contexts.
- Cannabis dependence
A group of severe consequences of repeated cannabis use, including tolerance to effects, withdrawal symptoms upon cessation, dysregulation of use, increased involvement with cannabis at the expense of other activities, and continued use despite the problems it causes.
A learning process through which particular stimuli or events (such as familiar drug-taking environments, or pleasant drug effects) influence the likelihood or strength of behaviour, such as drug seeking.
- Intracranial self-stimulation
(ICSS). An operant paradigm in which animals perform a behavioural response to receive brief electrical pulses into specific regions in the brain reward pathways.
- Conditioned place preference
A Pavlovian conditioning procedure used to index the motivational properties of drug experience. Typically, the time spent in an environment associated with drug intoxication is compared with that spent in a neutral context.
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Curran, H., Freeman, T., Mokrysz, C. et al. Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 17, 293–306 (2016). https://doi.org/10.1038/nrn.2016.28
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