Citation for published version:
Curran, HV, Freeman, TP, Mokrysz, C, Lewis, DA, Morgan, CJA & Parsons, LH 2016, 'Keep off the grass?
Cannabis, cognition and addiction', Nature Reviews Neuroscience, vol. 17, no. 5, pp. 293-306.
https://doi.org/10.1038/nrn.2016.28
DOI:
10.1038/nrn.2016.28
Publication date:
2016
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Download date: 25. Aug. 2022
Keep off the grass? Cannabis, cognition and addiction
H. Valerie Curran*
1
, Tom P. Freeman
1
, Claire Mokrysz
1
, David A. Lewis
2
,
Celia J. A. Morgan
1,3
& Loren H. Parsons
4
1
Clinical Psychopharmacology Unit, University College London, Gower St, London WC1E
6BT, UK.
2
Department of Psychiatry, University of Pittsburgh, 3811 O'Hara St, Pittsburgh PA 15213,
USA.
3
Psychopharmacology and Addiction Research Centre, University of Exeter, Perry Road,
Exeter EX4 4QG, UK.
4
The Scripps Research Institute, 10550 N. Torrey Pines Road, SP30-2001, La Jolla, USA.
*Correspondence to: H.V.C., v.curran@ucl.ac.uk
Abstract
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 prioritised. 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 their
relationship to cognition and addiction.
1. Introduction
For millennia, cannabis has been used medically and for religious purposes, most notably in
China and India. The plant and its many constituent cannabinoids are now becoming
increasingly important in modern medicine, particularly in the treatment of chronic pain and
spasticity
1
. A much more widespread global use is for pleasure
2
: the ‘stoned’ experience varies
widely across individuals but often includes euphoria, a heightened awareness of music and
colour, and the tendencies to eat a lot and to giggle profusely
2
. Despite its pleasurable effects,
most scientific research has focused on adverse consequences of using the drug, such as
addiction, cognitive impairment and possible increased risk of psychotic illness
3, 4
.
We do not know how patterns of use will change as legalisation proliferates, but even a small
percentage increase in the current 182 million users worldwide
5
will mean a considerable surge
in absolute numbers. Are we now able to use existing evidence about the less desirable effects
of cannabis use to help us to look forward to the future?
This article aims to survey our current state of knowledge about the effects of cannabis and
then pinpoint how we should be increasing our understanding of the effects of cannabis, given
its potentially soaring future use. We first summarise the variety of unique ingredients in
cannabis and outline how its use affects cognition, learning and memory. We survey evidence
of how the effects of the drug vary according to the maturational state of the brain and then go
on to discuss cannabis addiction and the mental health problems that are often related to it.
Finally, we identify the important gaps in our current knowledge and look to the future in terms
of both research and the current tide of changes to the legislation of cannabis.
2. Cannabis: a plant with many forms
Purple Haze, Northern Lights, charas, skunk, resin, grass, marijuana, weed… The multitude of
names for cannabis in part reflects variations in genetics, growing conditions, processing, and
constituent cannabinoids and terpenoids in different strains of the plant. Of the roughly 100
unique ingredients in cannabis that are called cannabinoids, most research to date has focused
on the two most prominent of these: delta-9-tetrahydrocannabinol (Δ
9
-THC) and cannabidiol
(CBD). These two compounds appear to have a range of opposing effects on the human brain
and behaviour. For example, Δ
9
-THC acutely impairs learning, produces psychosis-like effects
and increases anxiety
6
, whereas CBD can enhance learning
7
and has antipsychotic
8
and anti-
anxiety
9
properties in humans. When taken together, CBD may ameliorate the harmful effects
of Δ
9
-THC
10, 11
.
Δ
9
-THC acts as a partial agonist at cannabinoid CB
1
receptors (CB1Rs), whereas CBD has a
complex range of pharmacological actions. For example, although CBD has low affinity for
CB
1
R it can attenuate CB
1
agonist effects in brain even at low concentrations (e.g. providing
functional antagonism of CB
1
R signaling)
12
. Conversely, CBD reduces the cellular reuptake
and hydrolysis of the endogenous cannabinoid anandamide (AEA) in brain
12, 13
Neuroimaging
studies have documented opposing effects of Δ
9
-THC and CBD on blood oxygenation level-
dependent (BOLD) signal during performance of several cognitive and emotional tasks,
including striatal response during memory retrieval and amygdala response to fearful faces
14
.
Over the past two decades, the Δ
9
-THC content of street cannabis has risen dramatically,
whereas its CBD content has decreased to negligible levels. For example, in the United States,
the Δ
9
-THC content of street cannabis rose from 4% in 1995 to 12% in 2014
15
. In Europe
16 17
and Australia
18
, high-potency cannabis containing ~15% Δ
9
-THC and less than 0.1% CBD now
dominates the market. Thus, the type of cannabis available years ago differs considerably from
that sold today, limiting the relevance of older longitudinal cohort studies (for example, the
New Zealand Birth Cohort study, see Box 1) to the mental health and cognitive function of
contemporary users. In the United States, the cannabis that the National Institute of Drug Abuse
supplies to researchers for experiments generally has less than 4% Δ
9
-THC, and so findings
from these experiments have limited implications for modern-day cannabis users.
3. Cognition, learning and memory
Endocannabinoids (eCBs) are, in a sense, the brain’s own natural cannabis system, and Δ
9
-
THC and other CB1R agonists alter brain levels of eCBs
19, 20
. eCBs are neuroactive lipids
that participate in a range of physiological processes including reward, motivation, emotional
homeostasis, pain processing, and synaptic plasticity contributing to learning and memory. At
present, the best-characterized eCBs are N-arachidonylethanolamide (anandamide; AEA) and
2-arachidonoylglycerol (2-AG)
21, 22
and both of these lipids exert agonist activity at CB1Rs
and CB2Rs. Owing to their lipid nature, AEA and 2-AG are not stored in vesicles but are
synthesized on an ‘on-demand’ basis, and as such brain eCB levels are critically reliant on the
balance between evoked biosynthesis and subsequent clearance by intracellular enzyme-
mediated hydrolysis. eCBs are crucial in certain forms of neuronal plasticity, and Δ
9
-THC has
been shown to disrupt long-term potentiation (a model for learning and memory) and long-
term depression in preclinical studies
23
. In this section, we consider the acute and longer-term
effects of cannabis on cognition, learning and memory, as well as effects potentially
persisting after an individual has stopped using the drug. We also review evidence on the
impact of starting cannabis use early in adolescence.
Acute effects. Acute effects are transient and seen in the time period during which the
individual is intoxicated with the drug (e.g. feeling ‘stoned’ for around 5-120 minutes when
smoked). A single dose of cannabis or its main active ingredient Δ
9
-THC robustly and dose-
dependently impairs working and episodic memory
24, 25
. Memory impairments occur however
the drug is administered, but the onset of effect is more rapid when it is inhaled or given