NEI’s Master Psychopharmacology Program

Cannabinoids and the Developing Brain

Meghan M. Grady

ABSTRACT

The endogenous cannabinoid system plays an integral role in neurodevelopment, both prenatally and during the
critical adolescent time period, when substantial synaptic pruning and restructuring occurs. Given the role of the
endocannabinoid system in neurodevelopment, it seems reasonable that the early use of cannabis may influence
brain maturation and development. Although studying the effects of cannabis is complicated, the limited data
that do exist suggest that early cannabis use can alter neurogenesis and synaptogenesis, and that this may be
associated with increased risk for neuropsychological impairment. Multiple factors may mediate the potential
risks of early cannabis exposure, including the age at initiation; the quantity, frequency, and duration of use; and
the potency of the particular product. Much more research is needed to truly understand the potential long-term
consequences of heavy cannabis use during brain development.

With the widespread use of cannabis both as a
recreational drug and as a potential therapeutic entity, a
major concern for the medical community is: what effect
does early cannabis use have on the developing brain? To
begin to answer that question, we must first understand
the role of the endogenous cannabinoid (CB) system.
Endocannabinoid System
Overview
The endocannabinoid system comprises endogenous
cannabinoids, cannabinoid receptors that are present
throughout the central and peripheral nervous systems,
and the enzymes involved in the synthesis and
degradation of cannabinoids.1-2 It is a neuromodulatory
system that is involved in neurodevelopment, synaptic
plasticity, and homeostatic processes throughout the
nervous system; thus, its regulatory role extends to a
wide range of physiological processes, including immune
function, intraocular pressure, appetite, coordination,
cognitive functioning, pain perception, the emetic reflex,
heart rate, gastrointestinal motility, and even female
reproductive function.2-3
There are two main types of cannabinoid receptors. CB1
receptors are the most abundant and are present at
neuron terminals throughout the central and peripheral
nervous systems. Within the brain, CB1 receptors are
found in the cortex, nucleus accumbens, basal ganglia,
hypothalamus, hippocampus, amygdala, cerebellum, and
brainstem.2 CB2 receptors are not expressed as widely in
the brain, although they are present in glial cells and in
the brainstem. Instead, CB2 receptors are primarily found
in immune cells, where they modulate cell migration
and cytokine release.4 Of the multiple endogenous
cannabinoids, the best understood are anandamide and
2-arachidonoylglycerol (2-AG). Anandamide is a low-
efficacy agonist at CB1 receptors and a very low-efficacy
agonist at CB2 receptors. 2-AG is a high-efficacy agonist
at both CB1 and CB2 receptors.
The endocannabinoid system is unusual among
neurotransmitter systems in more than one way. First, it
functions via retrograde neurotransmission, in which the
endocannabinoids are released from the postsynaptic
neuron and bind to receptors on the presynaptic neuron
to regulate neurotransmitter release there.2,5 Second,
unlike classic neurotransmitters, which are synthesized
and stored in synaptic vesicles, endocannabinoids are

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synthesized on demand in response to postsynaptic
neuron activation.2,5 That is, precursors to the
endocannabinoids are stored in the lipid membrane
of the postsynaptic neuron. When that neuron is
activated, either via depolarization or the presence
of a neurotransmitter binding to a G-protein-coupled
receptor, this triggers an enzymatic reaction to form and
release the endocannabinoid, which then binds to a
presynaptic cannabinoid receptor, causing the inhibition
of neurotransmitter release (Figure 1).
Role in neurodevelopment
One of the most important aspects of the
endocannabinoid system is the role it plays in
neurodevelopment. Prenatally, CB1 receptors are
present in high density in white matter. They dramatically
increase during childhood in the frontal cortex, striatum,
and hippocampus, and reach their maximum density
in adolescence before dropping off in adulthood.6
Anandamide also increases gradually throughout
childhood, reaching its maximum level by the end of
adolescence and dropping off during adulthood.6
Figure 1. The Endocannabinoid System: Retrograde Neurotransmission
A B
A. Endocannabinoid (EC) precursors are present in lipid membranes
B. Neurotransmitter binding (or depolarization) triggers enzymatic reaction to form and release EC
C. Released EC binds to presynaptic CB1 or CB2 receptors
D. EC binding inhibits release of inhibitory and excitatory neurotransmitters
Prenatally, the endocannabinoid system is involved in
neural stem cell survival, proliferation, and migration of
immature neurons.1,7-9 Endocannabinoid signaling also
activates cascades that promote synapse formation,
including neurite outgrowth, direction of axonal growth,
and positioning of cortical gamma aminobutyric acid
(GABA) interneurons (Figure 2).7-8 The formation of
synapses occurs at a furious rate until the age of 6. Then
during pubescence and adolescence, a period known as
competitive elimination occurs, with extensive synaptic
pruning and restructuring.5
In particular, adolescence is a critical time period for the
pruning of asymmetric excitatory glutamate synapses
and for the proliferation of GABA inhibitory circuits.9 An
appropriate balance of excitatory-inhibitory synapses
is essential to proper late-stage brain maturation, and
the endocannabinoid system seems to be involved in
this process.9 Specifically, the endocannabinoid system
regulates the inhibition of glutamate neurotransmission,
which is important for synaptic pruning, influences the
positioning of GABA interneurons, and is involved in white
C D
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matter development (Figure 2). In fact, there is evidence
for a correlation between CB1 receptor density in a certain
brain region and its particular critical period.6,9
Cannabis and the Developing Brain
Cannabis: more than just THC
Given the role of the endocannabinoid system in
neurodevelopment, it seems reasonable that the use of
cannabis during this critical time period may influence
brain maturation. Studying its effects, however, is
complicated. There are two well-known and relatively well-
studied exogenous cannabinoids: (1) tetrahydrocannabinol
(THC), which is psychoactive and binds as a partial
agonist at CB1 and CB2 receptors, causing inhibition of
neurotransmitter release; and (2) cannabidiol, which is not
psychoactive and for which the binding at CB receptors is
not entirely clear, although it does seem to interact with
other neurotransmitter systems, such as the serotonin
system.3,10 However, there are as many as 500 chemicals
within the cannabis plant, and approximately 60 to 100 of
those are cannabinoids that potentially compete with or
Figure 2. Pre- and Postnatal Neurodevelopment: Role of Endocannabinoid System
migration
neural stem
cell survival
stem cell
immature
neuron
neurogenesis selection migration
proliferation
mimic the effects of the endogenous cannabinoids.3 Each
strain of cannabis may contain a different combination of
cannabinoids, some of which may be agonists while others
are antagonists.11 In addition, the extraction processes can
affect potencies.11 Thus, it can be difficult to predict what
the effects will be of any particular cannabis product. The
Schedule I status of cannabis has made it very difficult to
study in controlled trials, and the controlled data that do
exist are for purified formulations or synthetic compounds
and cannot necessarily be extrapolated to other strains or
compounds.
Bearing in mind the limitations noted above, the
aggregate data that do exist show that chronic
heavy cannabis use is associated with changes in the
endocannabinoid system, including reduced anandamide
in cerebrospinal fluid,12 reduced CB1 receptor
expression,13 and abnormalities in brain regions high in
CB1 receptors, such as the hippocampus and prefrontal
cortex.14 This suggests that heavy cannabis use during
early development may have relevant effects on the brain.
direct
axonal
growth
white matter
development
eliminated
promote
neurite
outgrowth
eliminated
differentiation synaptogenesis competitive elimination
position cortical inhibition of
GABA interneurons glutamate
release
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Cannabis use during prenatal development
Not surprisingly, there is limited research on the effects
of exogenous cannabinoids during human prenatal
development. Preliminary findings include subtle
impairments in executive functions, such as learning,
memory, and attention; increased impulsivity; and
increased externalizing behavior.9,15 There is some
suggestion of possible volumetric changes; specifically,
reduced cortical grey matter.16 In animal models,
prenatal treatment with CB1 receptor ligands has shown
decreased neurogenesis and altered development of
major neurotransmitter systems, including misrouting
of migrating GABA interneurons, altered synapse
distribution, and errors in axonal growth and connections.8
Cannabis use during adolescence
Heavy cannabis use during adolescence is associated with
downregulated CB1 receptors in white matter, disrupted
glutamate neurotransmission, and alterations in prefrontal
cortex volume and function.9,17 A small longitudinal
study demonstrated differences in resting functional
connectivity between healthy controls and treatment-
seeking adolescents with cannabis use disorder.18 In a
later longitudinal study by the same group, alterations
in intrinsic functional connectivity were also seen in
nontreatment-seeking young adults with cannabis use
disorder.19 In a rat model, adolescent exposure to THC
induced premature synaptic pruning and allostatic atrophy
of dendritic arborization.17
Behaviorally, animal studies have shown persistent deficits
in learning, working memory, and object recognition;
disruption in social behavior; more depressive-like
behaviors; reduced consumption of palatable food;
passive response to acute stress; impaired prepulse
inhibition; and increased locomotor activity.6,8-9
Although somewhat limited, there are also studies
in humans that illustrate the potential long-term
behavioral effects of cannabis use during adolescence,
including impaired motivation,20 blunted reward
response,21 neuropsychological deficits,22 and cognitive
impairment.18,23-24 For example, in a large longitudinal
study assessing the association between persistent
cannabis use and neuropsychological decline, individuals
who were cannabis-dependent before age 18 showed a
significant decline in IQ at age 38 compared to those who
began using cannabis later in life.23 Just as concerning,
stopping cannabis use did not restore neuropsychological
functioning among those who were dependent before
age 18. Heavy early cannabis use is also associated with
a lower likelihood of high school completion and degree
attainment.20 However, a recent meta-analysis of studies in
young adults showed that although there was a small but
statistically significant effect of heavy, frequent cannabis
use on cognition, the effect was not mediated either by
age or age at onset of first use.25
Of great concern is whether or not early cannabis use may
induce neurodevelopmental changes that can actually
increase the risk of developing a psychotic disorder. It
is well established that cannabis intoxication can cause
acute psychosis.26-27 In a meta-analysis of studies involving
patients at ultra-high risk for psychosis, only those
who met criteria for cannabis dependence (i.e., heavy,
chronic use) were significantly more likely to transition
to psychosis.28 Nonetheless, the number of confounding
variables makes it difficult to determine the extent to
which heavy cannabis use in adolescence may increase
risk for a psychotic disorder.
Conclusion
The endocannabinoid system plays an important role
in neurodevelopment, suggesting that cannabis use
during this time period could influence brain maturation.
Preliminary evidence suggests that early cannabis use can
alter neurogenesis and synaptogenesis, and that this may
be associated with increased risk for neuropsychological
impairment. However, data are relatively limited, and
several factors may mediate any potential risks of early
cannabis exposure, including the age at initiation; the
quantity, frequency, and duration of use; and the potency
of the particular product. Much more research is needed
to truly understand the potential long-term consequences
of heavy cannabis use during brain development.
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