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Cannabis Addiction and the Brain: a Review

December 2018
Journal of Neuroimmune Pharmacology 13(4)

DOI:10.1007/s11481-018-9782-9

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CC BY 4.0

Authors:

Christopher Kure Liu

Touro University California

Peter Manza

National Institutes of Health

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Cannabis is the most commonly used substance of abuse in the United States after alcohol and tobacco. With a recent increase in the rates of cannabis use disorder (CUD) and a decrease in the perceived risk of cannabis use, it is imperative to assess the addictive potential of cannabis. Here we evaluate cannabis use through the neurobiological model of addiction proposed by Koob and Volkow. The model proposes that repeated substance abuse drives neurobiological changes in the brain that can be separated into three distinct stages, each of which perpetuates the cycle of addiction. Here we review previous research on the acute and long-term effects of cannabis use on the brain and behavior, and find that the three-stage framework of addiction applies to CUD in a manner similar to other drugs of abuse, albeit with some slight differences. These findings highlight the urgent need to conduct research that elucidates specific neurobiological changes associated with CUD in humans.

a. Model of neurocircuitry and correlating disruptions in brain function and neurophysiology that contribute to behaviors underlying drug addiction. b. Summary of the changes in neurocircuitry associated with each stage

…

a. Statistical group differences in the effect of methylphenidate on the distribution volume between controls and marijuana abusers. Methylphenidate-induced decreases in distribution volumes were stronger in controls than in marijuana abusers (p < 0.005). There were no regions where marijuana abusers showed greater decreases than controls. b. Individual distribution volume values in putamen after placebo (PL) and after methylphenidate (MP) for marijuana abusers and controls. *p < 0.05, **p < 0.005. (Figure adapted with permission from Volkow et al. 2014a, b, c)

…

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INVITED REVIEW

Cannabis Addiction and the Brain: a Review

Amna Zehra

&Jamie Burns

&Christopher Kure Liu

&Peter Manza

&Corinde E. Wiers

&Nora D. Volkow

1,2

Gene-Jack Wang

Received: 18 January 2018 / Accepted: 7 March 2018 /Published online: 19 March 2018

#The Author(s) 2018

Abstract

Cannabis is the most commonly used substance of abuse in the United States after alcohol and tobacco. With a recent increase in

the rates of cannabis use disorder (CUD) and a decrease in the perceived risk of cannabis use, it is imperative to assess the

addictive potential of cannabis. Here we evaluatecannabis use through the neurobiological model of addiction proposed by Koob

and Volkow. The model proposes that repeated substance abuse drives neurobiological changes in the brain that can be separated

into three distinct stages, each of which perpetuates the cycle of addiction. Here we review previous research on the acute and

long-term effects of cannabis use on the brain and behavior, and find that the three-stage framework of addiction applies to CUD

in a manner similar to other drugs of abuse, albeit with some slight differences. These findings highlight the urgent need to

conduct research that elucidates specific neurobiological changes associated with CUD in humans.

Keywords Substance use disorders .Dopamine .Marijuana .THC

Introduction

Cannabis is the most commonly used substance of abuse in

the United States after alcohol and tobacco (Carliner et al.

2017). In the US, cannabis use increased from 4% to 9.5%

between 2001 and 2002 and 2012–2013 and the prevalence of

Cannabis Use Disorder (CUD) increased from 1.5% to 2.9%

in the same time (Hasin et al. 2015). Despite these increases in

cannabis use and CUD, attitudes towards cannabis use have

softened: adult and adolescent perceptions of cannabis use risk

have decreased since 2001 (Hasin et al. 2015;Carlineretal.

2017). These shifting attitudes have intergenerational conse-

quences as offspring of parents who are early-onset cannabis

users and who meet criteria for CUD are more likely to be-

come early-onset cannabis users themselves (Henry and

Augustyn 2017). Withincreases in cannabis use and decreases

in perceived risk, it is necessary to reevaluate the addictive

potential of cannabis (Carliner et al. 2017; Hasin 2018).

In this review, we explore the nature of cannabis addiction

through a prominent model of drug addiction (Koob and

Vo l k o w 2016). We first explain the model, which proposes a

dysregulation of motivational circuits in three stages of addic-

tion: binge/intoxication, withdrawal/negative affect, and pre-

occupation/anticipation. Second, we summarize empirical ev-

idence for preclinical and human studies on the acute and

long-term effects of cannabis use on the brain and behavior

(similar to those of other drugs of abuse). Third, we review

potential therapeutic agents for CUD that may provide further

evidence for dysregulation in motivational circuits in CUD.

After reviewing the acute and chronic effects of cannabis use

on the brain and behavior and treatment options for cannabis

abusers, we discuss whether there is empirical evidence that

the three stages of addiction apply to CUD (Fig. 1provides an

overview of the current literature supporting this model).

Theoretical Model of Addiction

Koob and Volkow (2016) define drug addiction as a

Bchronically relapsing disorder^marked by compulsive drug

seeking and intake, loss of control in limiting intake, and the

emergence of a negative emotional state when access to a drug

is prevented. This model proposes three stages of addiction

with disturbances in three major neurocircuits: the binge/

intoxication stage driven by changes in the basal ganglia; the

*Gene-Jack Wang

gene–jack.wang@nih.gov

Laboratory of Neuroimaging, National Institute on Alcohol Abuse

and Alcoholism, National Institutes of Health, 10 Center Drive 31,

Room B2L124, Bethesda, MD 20892, USA

National Institute on Drug Abuse, National Institutes of Health,

Bethesda, MD 20892, USA

Journal of Neuroimmune Pharmacology (2018) 13:438–452

https://doi.org/10.1007/s11481-018-9782-9

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

withdrawal/negative affect stage driven by changes in the ex-

tended amygdala; and the preoccupation/anticipation driven

by changes in the prefrontal cortex (PFC). Within these do-

mains, Koob and Volkow (2016) describe neuroadaptations in

18 subsystems including the ascending mesocorticolimbic do-

pamine system, corticotropin-releasing factor (CRF) in the

central nucleus of the amygdala, and corticostriatal glutamate

projections.

The binge-intoxication stage of addiction is characterized

by an excessive impulsivity and compulsivity to use drugs

despite negative consequences associated with such use.

This stage involves hyperactivation of the mesocorticolimbic

dopaminergic reward pathway of the brain associated with the

positive reinforcement of the rewarding effects of drugs. A

hallmark of the binge/intoxication stage is an impairment in

incentive salience, whereby drug-associated cues and contexts

associated with the initial exposure to a drug are attributed

exaggeratedly high rewarding properties and become condi-

tioned to elicit dopamine (DA) release. This incentive salience

dysfunction appears to drive DA signaling to maintain moti-

vation to take the drug upon exposure to conditioned-cues and

even when its pharmacological effects lessen, secondary to the

development of tolerance (Koob and Volkow 2016).

The withdrawal/negative affect stage is then triggered by

opponent-process responses following binge episodes. These

opponent-process responses are marked by within-systems

and between-systems neurobiological changes that drive the

loss of motivation towards non-drug rewards and impaired

emotion regulation seen in this stage. Within-systems

neuroadaptations include changes in the function of brain re-

ward systems including decreased dopaminergic signaling in

the nucleus accumbens (NAcc) and dorsal striatum that result

in an elevation of reward thresholds for non-drug reinforcers,

which contributes to amotivation. Between-systems

neuroadaptations include dysfunction of neurochemical sys-

tems that are not primarily involved in the rewarding effects of

drugs of abuse; this includes changes in brain systems in-

volved in stress responses such as increased CRF release in

the amygdala and HPA-axis dysfunction. The changes

resulting from opponent-processes responses drive character-

istic symptoms of a withdrawal symptom such as increased

anxiety-like responses, chronic irritability, malaise, and dys-

phoria during acute and protracted abstinence from a drug of

abuse (Koob and Volkow 2016).

The preoccupation/ anticipation stage is implicated in the

reinstatement of substance use following abstinence.

Executive control over craving and impulsivity iskey in main-

taining abstinence and is mediated by the PFC. The

preoccupation/anticipation stage is marked by dysregulation

of signaling between the PFC and areas of the brain that

Fig. 1 a. Model of neurocircuitry and correlating disruptions in brain function and neurophysiology that contribute to behaviors underlying drug

addiction. b. Summary of the changes in neurocircuitry associated with each stage

J Neuroimmune Pharmacol (2018) 13:438–452 439

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SECNEREFERYRAMMUSSEGNAHCEGATS

Binge-

intoxication

Behavior THC-induced DA release disrupts incentive salience attribution (Koob and Mason 2016; Bhattacharyya et al.

2012; Wijayendran et al. 2016)

Neurophysiological

Adaptations

Acute THC leads to striatal DA release in animals and humans (Bloomfield et al. 2016; Bossong et al. 2015)

Chronic THC downregulates CB1Rs and blunts striatal DA release in

animals and humans

(Van De Giessen et al. 2017; Volkow et al.

2014; Scherma et al. 2016; Colizzi et al. 2016)

Imaging Correlates Heightened, THC-induced ventral striatal activation to losses in MID task

driven by chronic, relapsing cannabis users.

(Yip et al. 2014)

Chronic cannabis use associated with blunted DA response to reward

anticipation in the NAcc in MID task

(Martz et al. 2016)

It has been established that hyper-sensitivity to the rewarding properties of

drugs contribute to positive reinforcement, which is driven by disrupted

incentive salience processing

(Filbey et al. 2013)

Therapies Therapies with greatest reduction in binge-intoxication antagonize CB1Rs

and include: rimonabant, which blocks the intoxicating and tachycardic

effects of smoked cannabis

(Crippa et al. 2012, Danovitch and Gorelick

2012)

Partial agonists, which block the reinforcing effects of other drugs of abuse,

have the potential to reduce the effects of cannabis intoxication

(Koob and Mason 2016)

Strains with higher CBD to THC ratios reduce the appetitive effects of

cannabis compared to strains with lower CBD to THC ratios, suggesting

CBD as a potential treatment for acute cannabis intoxication

(Morgan et al. 2010)

Withdrawal-

negative affect

Behavior Presence of withdrawal syndrome marked by: irritability, anxiety decreased

appetite, restlessness, and sleep disturbances

(Karila et al. 2014; Katz et al. 2014; Davis et

al. 2016)

Increase in negative affect after prolonged cannabis use in adults and

adolescents

(Dorard et al. 2008; Katz et al. 2014; Volkow

et al. 2014c; Heitzeg et al. 2015; Davis et al.

2016)

Presence of an amotivational state after prolonged cannabis exposure in

rhesus monkeys and humans

(Volkow et al. 2014a, 2016; Becker et al.

2014; Panlilio et al. 2015; Heitzeg et al. 2015)

Neurophysiological

Adaptations

In rodents, cannabis withdrawal is associated with an increase in CRF in

central nucleus of the amygdala

(Rodriguez de Fonseca et al. 1997; Caberlotto

et al. 2004; Curran et al. 2016)

In human studies, cannabis withdrawal seems to be related to HPA axis

dysfunction

(Somaini et al. 2012; Cuttler et al. 2017)

Imaging Correlates Chronic cannabis use is associated with decreased stimulant-induced DA

reactivity that is associated with greater negative emotionality

(Volkow et al. 2014c)

Chronic cannabis use and cannabis withdrawal are associated with affect

dysregulation related to amygdala functioning

(Filbey et al. 2013; Pujol et al. 2014; Heitzeg

et al. 2015; Spechler et al. 2015; Zimmermann

et al. 2017)

Therapies Therapies with the greatest reduction of withdrawal symptoms target CB1R

and include: oral THC, nabixmol, nabilone all of which have a lower abuse

potential than smoked cannabis

(Balter et al. 2014; Allsop et al. 2015; Tsang

and Giudice 2016; Brezing and Levin 2018)

Therapies that have shown the greatest reduction of withdrawal symptoms

and the lowest rates of relapse include naltrexone (a mu opioid receptor

antagonist), gabapentin (a GABA-a receptor agonist), and N-acetylcysteine

(Brezing and Levin 2018)

Preoccupation-

anticipation

Behavior Preclinical and clinical models demonstrate impaired executive function in

domains of memory and IQ result from acute and chronic cannabis use.

Age-specific effects may be present.

(Koob and Volkow 2016; Renard et al. 2016;

Broyd et al. 2016; Becker et al. 2014; Volkow

et al. 2014a; Caballero and Tseng 2012)

No significant long-term effects of adolescent cannabis use on executive

function was found in several longitudinal co-twin cohort studies. Social

and environmental factors may explain poor executive function among

cannabis users

(Meier et al. 2017; Jackson et al. 2016)

Neurophysiological

Adaptations

Animal studies demonstrate increased glutamate transmission during drug

self-administration while animals receiving glutamate receptor antagonists

show reduced relapse rates.

(Caprioli et al. 2017)

Imaging Correlates Increased BOLD response to cannabis cues compared to naturally hedonic

cues in mesocorticolimbic regions among cannabis users.

(Filbey et al. 2016).

Positive correlations between cue-induced self-rated craving for cannabis

and BOLD responses within the mesocorticolimbic system and the insula.

(Filbey et al. 2016; Norberg et al. 2016)

Therapies N-acetylcysteine is a proposed anticraving agent as it acts on the cysteine-

glutamate antiporter to reduce glutamate neurotransmission that is

upregulated during withdrawal. Preliminary clinical studies have

demonstrated reduced craving and relapse rates in cannabis users.

(Asevedo et al. 2014; Samuni et al. 2013)

Fig. 1 (continued)

440 J Neuroimmune Pharmacol (2018) 13:438–452

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control decision making, self-regulation, inhibitory control

and working memory and might involve disrupted

GABAergic and glutamatergic activity (Koob and Volkow

2016). Behaviorally, this translates into excessive salience at-

tribution to drug-paired cues, decreases in responsiveness to

non-drug cues and reinforcers, and decreases in the ability to

inhibit maladaptive behavior (Koob and Volkow 2016).

Evidence

Acute Effects and Insight into Reinforcing/Addictive

Properties of Cannabis

All drugs of abuse increase DA release —a key neurobiolog-

ical process that generates their reinforcing effects (Koob and

Volkow 2016). Here we evaluate the acute changes in DA

circuitry associated with cannabis intake in preclinical and

clinical studies that provide basis for the reinforcing effects

of cannabis. While the two main constituents of cannabis are

delta9-tetrahydracannabinol (THC) and cannabidiol (CBD),

THC seems to be responsible for cannabis’addictive potential

due to its psychoactive properties and associated effects on

brain dopaminergic function. Acute THC administration

elicits striatal DA release in animals (Ng Cheong Ton et al.

1988) and humans (Stokes et al. 2010; Bossong et al. 2015;

Bloomfield et al. 2016). However, another study found no

evidence for THC-induced DA release (Barkus et al. 2011);

this may be because THC induces quantitatively less DA re-

lease than psychostimulants such as methylphenidate or am-

phetamine (Volkow et al. 1999a). Nonetheless, these findings

suggest that THC increases DA release similar to other drugs

of abuse.

Several animal models of cannabis exposure have been

established in rodents and non-human primates (Panlilio

et al. 2015). In studies with rodents, neurophysiological

methods such as intracranial microinjection, microdialysis,

and single-unit electrophysiological recording techniques are

used to study the acute effects of THC and other cannabinoids

in the brain directly (Oleson and Cheer 2012;Panlilioetal.

2015). Behavioral methods include the use of place condition-

ing, drug discrimination, intracranial self-stimulation, or intra-

venous self-administration to study the reinforcing effects of

cannabinoids in vivo (for further details see: Maldonado and

RodriguezdeFonseca2002; Tanda and Goldberg 2003;

Maldonado et al. 2011; Panlilio et al. 2015;Zandaand

Fattore 2018). Robust intravenous self-administration para-

digms in animals have been difficult to establish. That is, in

rodents THC is unable to sustain intravenous self-

administration (Lefever et al. 2014), whereas squirrel mon-

keys have found to self-administer THC; suggesting differ-

ences in species. However, other behavioral methodologies,

such as drug discrimination and conditioned place preference

paradigms, reveal the rewarding effect of THC and other can-

nabinoids (Maldonado and Rodriguez de Fonseca 2002;

Tanda and Goldberg 2003; Maldonado et al. 2011; Oleson

and Cheer 2012; Panlilio et al. 2015).

In rodents, THC-induced DA release is associated with

increased intracranial self-stimulation in key reward pathways

of the brain (Katsidoni et al. 2013). Likewise, low doses of a

cannabinoid-1 receptor (CB1R) agonist in the PFC increased

spontaneous firing and bursting rates of ventral tegmental area

(VTA) DA neurons, which was associated with potentiated

salience of fear memories in rats (Draycott et al. 2014). THC

elicits striatal DA release by activating CB1R, which are co-

localized with DA receptors in the striatum and substantia

nigra, regions implicated in salience processing

(Wijayendran et al. 2016). This suggests that the

endocannabinoid system (eCS) is involved in regulating DA

release during salience attribution (Bloomfield et al. 2016),

and that acute THC dysregulates the dopaminergic and

endocannabinoid systems which then leads to impairments

in salience processing (Wijayendran et al. 2016). These pre-

clinical findings may provide a biological basis for human

studies which show impaired salience processing after THC

administration. In one study, THC-potent cannabis was found

to increase attentional bias towards cannabis-related stimuli in

cannabis users during a computer-based dot-probe behavioral

task (Morgan et al. 2010). In a separate fMRI task, healthy

participants performed a visual oddball paradigm; THC ad-

ministration resulted in making non-salient stimuli appear

more salient (Bhattacharyya et al. 2012). Together, these

pre-clinical and clinical findings reveal that THC administra-

tion has reinforcing properties that alter salience processing

via increased dopaminergic signaling like other drugs of abuse

(Morgan et al. 2010; Bhattacharyya et al. 2012;Draycottetal.

2014; Wijayendran et al. 2016; Bloomfield et al. 2016).

Long-Term Effects of Cannabis: Behavior

and Cognition

Chronic cannabis use is associated with an increased risk of

developing substance use disorders (SUD); about 9% of

those who use cannabis present with characteristic symp-

toms of dependence according to DSM-IV criteria (Volkow

et al. 2014a). Diagnoses of cannabis abuse and dependence

in the DSM-IV did not include withdrawal due to uncer-

tainty of its diagnostic features (Katz et al. 2014)Inthe

DSM-5, however, cannabis abuse and dependence fall un-

der a diagnosis of CUD which now includes withdrawal

from cannabis. Withdrawal was added as a diagnostic

criteria for CUD as it is often accompanied by increased

functional impairment of normal daily activities similar to

those seen in other SUD (Karila et al. 2014;Katzetal.

2014; Davis et al. 2016). Symptoms of cannabis withdrawal

J Neuroimmune Pharmacol (2018) 13:438–452 441

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also seem to appear in a similar time course and manner as

withdrawal from other substances (Karila et al. 2014).

A clinical diagnosis of cannabis withdrawal includes irrita-

bility, anger or aggression, nervousness or anxiety, sleep dif-

ficulty, decreased appetite or weight loss, restlessness, de-

pressed mood, and physical symptoms causing significant

discomfort such as shakiness or tremors, sweating, fever,

chills, and headaches (Karila et al. 2014;Katzetal.2014).

Typically, symptoms of cannabis withdrawal occur 1 to 2 days

after cessation of heavy use and can last between 7 and 14 days

(Davis et al. 2016). The most common symptoms observed

during cannabis withdrawal include irritability, anxiety, de-

creased appetite, restlessness, and sleep disturbances (Oleson

and Cheer 2012; Panlilio et al. 2015; Curran et al. 2016;Gates

et al. 2016). Sleep disturbances seem to be characterized by

trouble falling asleep, decrease in total sleep time, and the

presence of nightmares and strange dreams (Gates et al.

2016). The severity of withdrawal symptoms was associated

with greater negative impact on normal, daily activities (Davis

et al. 2016) suggesting that the effects of cannabis withdrawal

seem to parallel withdrawal in other drugs of abuse.

Koob and Volkow (2016) posit that the withdrawal stage of

addiction is marked by an increase in negative affect which

also seems to be the case for cannabis addiction (Volkow et al.

2014c). In addition to acute withdrawal-related emotional dis-

turbances such as irritability and anxiety (Katz et al. 2014;

Davis et al. 2016), prolonged cannabis use is associated with

long-term affect dysregulation. In a longitudinal study of ad-

olescents, cannabis users consistently reported greater nega-

tive emotionality than healthy controls between the ages of 13

and 23; moreover, as healthy controls showed a decrease in

negative emotionality with age, negative emotionality

remained elevated for cannabis users during over the same

time (Heitzeg et al. 2015). Another study of adolescents found

that half of a group of adolescents undergoing treatment for

cannabis withdrawal had at least one comorbid diagnosis of

anxiety or depression; additionally, for these adolescents

greater cannabis use was associated with increased depressive

and anxiety-like symptoms (Dorard et al. 2008).

These changes in the affective state after prolonged canna-

bis use may also influence motivation. In both rhesus mon-

keys and humans, withdrawal from cannabis seems to involve

the presence of an amotivational state (Karila et al. 2014;

Panlilio et al. 2015; Volkow et al. 2014a,b,c,2016). The

amotivational state has been previously described as a

Breduced motivation and capacity for usual activities required

for everyday life, a loss of energy and drive to work and

personality deterioration^(Karila et al. 2014). The origin of

this amotivational state is still unknown and may be related to

changes in executive function (Karila et al. 2014) and to re-

duced dopamine signaling after chronic cannabis use

(Bloomfield et al. 2014; Volkow et al. 2014c). In rhesus mon-

keys, chronic cannabis smoke exposure was associated with

lower motivation scores in a place conditioning paradigm,

although these effects disappeared two to three months after

cessation of the cannabis treatment (Paule et al. 1992). In one

study of neurocognition, chronic cannabis users demonstrated

impairments in verbal memory, spatial working memory, spa-

tial planning, and motivated decision-making compared to

healthy controls (Becker et al. 2014). These findings suggest

that the amotivational state during withdrawal may be related

to cognitive dysfunction and to reduced dopamine signaling

after chronic cannabis use.

Cognitive dysfunction, specifically impairments in execu-

tive domains, after chronic cannabis use is a key feature of the

neurobiological model of addiction (Koob and Volkow 2016).

Deficits in executive function after chronic cannabis use have

been shown in both preclinical and clinical studies. In one

preclinical study, chronically administering a synthetic canna-

binoid agonist to adolescent rats impaired short-term working

memory in adulthood (Renard et al. 2016). Specifically, this

chronic cannabinoid exposure altered PFC structure and im-

paired cortical synaptic plasticity from reduced long-term po-

tentiation (LTP) in the hippocampus-PFC circuit. These find-

ings support the theory that adolescent cannabis use causes

lasting deficits in memory. However, they are likely age-

specific effects as preclinical and clinical studies have demon-

strated a lackof long-lasting cognitive impairments from adult

chronic cannabis use (Renard et al. 2016).

Many clinical studies have investigated the long-term ef-

fects of chronic cannabis use on markers of executive function

such as IQ, verbal learning, and memory. The results are

varied and equivocal, as longitudinal studies with controlled

confounds are difficult to establish. Volkow et al. (2014a,b,c)

report that cannabis use during adolescence and young adult-

hood is associated with impaired functional connectivity in the

brain and corresponding declines in IQ. A 2016 systematic

review of 105 papers assessing the acute and chronic effects

of cannabis on human cognition found that memory has been

the most consistently impaired cognitive measure (both after

acute and chronic cannabis use), with the strongest effects in

the verbal domain (Broyd et al. 2016). The evidence for im-

pairments in other domains of executive function such as rea-

soning, problem solving, and planning was less conclusive, as

numerous studies found no significant differences in case-

control comparisons. However, studies examining heavy

users as well as early-onset users reported impaired executive

function, especially when the sample was predominantly older

participants (Becker et al. 2014; Broyd et al. 2016). This may

suggest a conditional effect, unique to adolescent and heavy

cannabis users while moderate and adult users are less vulner-

able to the harmful effects of cannabis on cognition.

Despite earlier findings of impaired executive functioning

in adolescent- and early- onset users, it is important to note

that several recent studies found no significant long-term ef-

fects of adolescent cannabis use on executive function. Meier

442 J Neuroimmune Pharmacol (2018) 13:438–452

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et al. (2018) report a longitudinal co-twin control study that

showed no significant association between adolescent canna-

bis use and neuropsychological decline, and instead suggest

social and environmental factors as explanations for poor ex-

ecutive function among cannabis users. This study was par-

ticularly insightful because of a large sample size (n=1989)

and IQ assessments prior to the onset of cannabis use (IQ

obtained at age 5, 12, and 18). It demonstrated that adolescents

who used cannabis had a lowerchildhood IQ and a lower IQ at

18 than non-users, but that there was no decline in IQ from

pre- to post-cannabis use (Meier et al. 2018). These results are

in line with another co-twin longitudinal study that investigat-

ed two large cohorts of twins and found no significant differ-

ence in IQ change over time between twins discordant for

cannabis use (Jackson et al. 2016). However, lower baseline

IQ was associated with adolescent cannabis use suggesting

that social and environmental factors influence an adolescent’s

subsequent cannabis use (Jackson et al. 2016). Together, these

studies suggest that lower IQ may be a risk factor for cannabis

abuse rather than the use of cannabis resulting in neuropsy-

chological decline. However findings on the effects of canna-

bis exposure during adolescents are controversial and require

investigation with prospective designs that take advantage of

brain imaging technologies. The ABCD study, a prospective

study that aims to follow 10,000 children as they transition

into adulthood with a detailed phenotypic characterization in-

cluding periodic brain imaging, would help clarify what ef-

fects cannabis consumption might have on brain develop-

ment, neurocognitive function and mental illness (Volkow

et al. 2017b).

Long-Term Effects of Cannabis: Neurophysiological

Changes

The chronic relapsing nature of addiction seems to involve

underlying neurophysiological changes in reward, stress, and

executive function circuits (Koob and Volkow 2016). Here we

summarize findings about the effects of chronic cannabis use

on these circuits.

Chronic cannabis abuse is modeled in animals with repeat-

ed treatments of cannabis (through smoke exposure) or THC

and other cannabinoids (typically intravenous injections).

Neurophysiological changes after these different methods of

chronic cannabis treatment are then typically measured

through electrophysiological recordings and microdialysis

(Maldonado and Rodriguez de Fonseca 2002; Tanda and

Goldberg 2003; Maldonado et al. 2011; Oleson and Cheer

2012;Panlilioetal.2015).

In rats, early-life exposure to THC blunts dopaminergic

response to naturally rewarding stimuli that elicit DA release

later in life (Bloomfield et al. 2016). Likewise in rats, adoles-

cent exposure to THC resulted in increased self-administration

of and blunted striatal DA response to CB1R agonists in

adulthood (Scherma et al. 2016). Changes in reward-related

circuitry after chronic cannabis use may be related to changes

in the eCS after prolonged cannabis use. The eCS has been

implicated in reward-processing and reward-seeking behavior

given that CB1 receptors are densely expressed in areas asso-

ciated with reward processing and conditioning including the

amygdala, cingulate cortex, PFC, ventral pallidum, caudate

putamen, NAcc, VTA, and lateral hypothalamus (Parsons

and Hurd 2015; Volkow et al. 2017a). In animals, activation

of CB1 receptors seems to influence the hedonic effects of

natural rewards after THC administration, suggesting that can-

nabis can affect reward sensitivity via activation of CB1 re-

ceptors (Parsons and Hurd 2015).

Chronic THC exposure has further been shown to down-

regulate CB1Rs, providing a neurobiological basis for the

development of tolerance and desensitization to the rewarding

effects of THC (Colizzi et al. 2016). In rodents, chronic ad-

ministration of THC or CB1R agonists leads to tolerance in

most responses as well as a decrease in CB1R availability in

many brain areas (Maldonado and Rodriguez de Fonseca

2002; Tanda and Goldberg 2003; Maldonado et al. 2011). In

cannabis users, withdrawal symptoms have also been associ-

ated with reductions in CB1R availability as assessed by

[

C]OMAR PET imaging (Curran et al. 2016;D’Souza

et al. 2016). Hirvonen et al. (2012) found that cannabis use

downregulates CB1R in cortical regions, potentially altering

the brain’s reward system. However, they also found that after

4 weeks of abstinence, CB1R density returned to normal in

cannabis users in all regions except the hippocampus. This

suggests that some neurobiological changes of chronic canna-

bis use are reversible (Hirvonen et al. 2012).

Chronic cannabis use and administration is also associated

with neurophysiological changes in stress responsivity. In ro-

dents, the neurophysiological changes associated with canna-

bis withdrawal are modeled through precipitated withdrawal

through the use of rimonabant (a selective CB1R blocker)

after repeated cannabinoid treatment (Maldonado et al. 2011;

Oleson and Cheer 2012; Panlilio et al. 2015). Cannabinoid

withdrawal in rodents is associated with an increase in the

stress peptide CRF in the central nucleus of the amygdala

(Rodriguez de Fonseca et al. 1997; Maldonado et al. 2011;

Panlilio et al. 2015; Curran et al. 2016), which suggests the

presence of between-systems changes in brain stress systems,

as described by the Koob and Volkow model (2016). In addi-

tion, the eCS seems to be involved in regulating the stress

response through its action on the amygdala and HPA axis

(Dow-Edwards and Silva 2017; Volkow et al. 2017a). The

eCS modulates interactions between the PFC, amygdala, and

hippocampus which are all involved in emotional memory,

anxiety-related behaviors, and drug cue-induced craving in

SUD (Jasinska et al. 2014). Additionally, endocannabinoids

seem to be required for feedback to normal stress responses:

glucocorticoids increase the endogenous cannabinoids

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anandamide (AEA) and 2-acylglycerol (2-AG) in the

paraventricular nucleus while CB1R antagonists increase

HPA axis output. In rodents, exogenous cannabinoids seem

to create a dysregulation of stress responsivity and anxiety-

related behaviors (Dow-Edwards and Silva 2017).

Moreover, chronic cannabis abuse is associated with the

dysregulation of stress responsivity in humans (Curran et al.

2016). Studies in cannabis users show that chronic cannabis

use is related to both blunted and hyperactive stress responses

(Somaini et al. 2012; Cuttler et al. 2017). Cuttler et al. (2017)

found that healthy controls had an increase in cortisol levels

under a stress-provoking condition compared to baseline but

did not find the same increase in active cannabis users. In

another study, both active and abstinent cannabis users had

persistent hyperactivity of the HPA axis (measured by blood

cortisol and ACTH levels) compared to healthy controls

(Somaini et al. 2012). This pattern of HPA axis dysregulation

is also seen in alcohol users: chronic alcohol use seems to

attenuate the cortisol response to acute psychological stimula-

tion of the HPA axis, but is related to elevated cortisol levels

during alcohol intoxication and abstinence in dependent users

(Stephens and Wand 2012).

In addition to its role in HPA axis dysfunction and reward

processing, the hyperactivation of the eCS may also play a

role in the executive dysfunction sometimes observed in can-

nabis use. The eCS is highly active in adolescent brain devel-

opment, particularly in the PFC, a region that exercises exec-

utive function (Dow-Edwards and Silva 2017). Exogenous

cannabinoids hyperactivate CB1 receptors which are

expressed in pyramidal neurons and GABAergic interneu-

rons, indicative of the regulatory role of the eCS in GABA

and glutamate neurotransmission (Caballero and Tseng 2012;

Volkow et al. 2017a). Activation of presynaptic CB1 receptors

inhibits glutamate transmission onto GABAergic cells in the

PFC, reducing the function of inhibitory prefrontal circuits.

Therefore, hyperactivation by exogenous cannabinoids during

development could disrupt the maturation of GABAergic in-

terneurons in the PFC and desynchronize PFC circuits

(Caballero and Tseng 2012). Thus, adolescent cannabis use

may affect brain development and result in enduring alter-

ations in the GABA/glutamate balance in the PFC (Renard

et al. 2016).

Neuroadaptations in glutamatergic signaling resulting from

repeated cannabis use are likely also implicated in periods of

cannabis abstinence and craving (Samuni et al. 2013). This

theory is supported by a review of animal studies that demon-

strated increased glutamate signaling during drug self-

administration and relapse, offering a potential neurochemical

target for treatment in preventing craving and subsequent re-

lapse. For example, rodent and nonhuman primate models

receiving periodic injections of glutamate receptor antagonists

have shown a reduction in relapse rates (Caprioli et al. 2017).

Nonetheless, these findings need to be corroborated in rodents

since there is conflicting evidence for whether self-

administration in rodent models provides robust evidence of

THC as a behavioral reinforcer (Tanda and Goldberg 2003;

Maldonado et al. 2011;Panlilioetal.2015; Melis et al. 2017).

Long-Term Effects of Cannabis on the Brain:

Neuroimaging Studies

Addiction is a recurring cycle that worsens over time and

involves neuroplastic changes in the brain reward, stress,

and executive function systems (Koob and Volkow 2016).

Previous neuroimaging studies reveal the long-term effects

of chronic cannabis use on several different brain systems

including the reward, endocannabinoid, and stress systems

as well as brain areas involved in emotion processing and

decision making.

Similar to animal models of chronic THC exposure, chron-

ic cannabis use has been shown to blunt DA response to DA-

releasing stimulant drugs in the striatum with both [

C]-(+)-

PHNO and [

C]raclopride PET imaging (Volkow et al.

2014c;Bloomfieldetal.2016; van de Giessen et al. 2017)

and to decrease DA synthesis as assess with PET imaging with

[

F]DOPA (Bloomfield et al. 2014)(Fig.2). This pattern of

decreased stimulant-induced DA release is also seen with

chronic use of other drugs of abuse such as alcohol, cocaine,

and nicotine (Koob and Volkow 2016). However, cannabis

users do not show lower baseline D2/D3 receptor availability

in the striatum compared to healthy controls –a pattern seen in

chronic alcohol, nicotine, cocaine, opiate and methamphet-

amine users (Volkow et al. 1996b,2001,2002,2014b,

2017c;Wangetal.1997;Martinezetal.2012; Tomasi et al.

2015b; Wiers et al. 2016a,2017; Ashok et al. 2017).

Moreover, the stimulant challenge led to significantly lower

self-reported ratings of feeling high (Volkow et al. 2014c), and

decreased brain glucose metabolism in the striatum, thalamus,

andmidbrain(Wiersetal.2016b) in cannabis users versus

controls. Cannabis users had higher negative emotionality

and lower positive emotionality personality scores than con-

trols, and negative emotionality scores were inversely corre-

lated with methylphenidate-induced dopamine increases in

the ventral striatum (Volkow et al. 2014c; Wiers et al.

2016b). These findings offer an explanation for decreased

dopamine reactivity in the striatum during abstinence that

may contribute to negative emotionality, which is consistent

with lower reward sensitivity in cannabis users during the

withdrawal phase of addiction (Volkow et al. 2014c). In an-

other study, a stimulant challenge also led to blunted brain

glucose metabolism in striatal regions, which was associated

with craving (Wiers et al. 2016b). Together these findings

from stimulant challenges indicate functional changes in the

dopaminergic reward system in chronic cannabis users.

Furthermore, fMRI studies have also revealed functional

and structural changes in brain areas involved in reward

444 J Neuroimmune Pharmacol (2018) 13:438–452

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processing after chronic cannabis use. In one study, partici-

pants in a cannabis-dependent group had greater activation in

the ventral striatum in response to losses during a monetary

incentive delay (MID) task compared to healthy controls (Yip

et al. 2014). Compared to controls, the cannabis-dependent

participants also had smaller putamen volumes, a brain region

involved in habit formation. These differences seemed to be

driven by participants who were unable to stay abstinent from

cannabis and were comparable to findings in tobacco smokers

suggesting similar changes in reward functioning in both to-

bacco and alcohol addiction (Yip et al. 2014). In another fMRI

study with the MID task, cannabis users in withdrawal had

greater activation in the ventral striatum in response to posi-

tive incentives compared to healthy controls during the MID

task, similar to findings in alcohol users (Filbey et al. 2013).

Persistent cannabis use also seems to be related to a blunted

response to reward anticipation in the NAcc during the MID

task: in this study, even after controlling for prior and current

use of other drugs, greater cannabis use was related to de-

creased activation in the NAcc during reward anticipation at

baseline, 2 year, and 4 year follow ups (Martz et al. 2016).

Together, these findings suggest that chronic cannabis use

produces functional alterations in areas involved in reward

processing.

A recent fMRI study investigated whether cannabis use

sensitizes and disrupts the mesocorticolimbic reward process-

es during a hedonic cue-reactivity task. A cohort of chronic

cannabis users (requiring 72 h of abstinence) showed greater

BOLD response for cannabis cues compared to natural reward

cues (fruit) in the orbitofrontal cortex (OFC), striatum, anterior

cingulate gyrus, and VTA, regions along the

mesocorticolimbic-reward pathway (Filbey et al. 2016). In

cannabis users, there were also significant positive correla-

tions between cue-induced self-rated craving for cannabis

and BOLD responses within the mesocorticolimbic system

and in the insula. The latter data supports the addictive model

of cannabis as insula activation may serve as a biomarker to

help predict relapse (Filbey et al. 2016). This brain region

contributes to interoceptive awareness of negative emotional

states and is differentially activated during craving (Koob and

Vo l k o w 2016). This is also consistent with prior findings that

the dopaminergic reward system is reactivated during acute

craving episodes (Volkow et al. 1999b,2005;Kooband

Vo l k o w 2016). Moreover, in cannabis abusers, but not in con-

trols, acute THC intoxication elicited activation of brain re-

ward regions as assessed by increases in brain glucose metab-

olism in striatum and orbitofrontal cortex (Volkow et al.

1996a). Overall, these studies demonstrates that chronic can-

nabis use sensitizes the mesocorticolimbic-reward system to

cannabis cues and to THC (Volkow et al. 1996a; Filbey et al.

2016). These findings suggest that chronic cannabis use af-

fects key brain circuits involved in the reward system similar

to other drugs of abuse.

In addition to changes in reward processing, chronic can-

nabis use also seems to affect emotion processing. Several

MRI studies reveal functional and structural differences in

the amygdala –a key brain structure in processing emotions

–after chronic cannabis use. Compared to healthy controls,

adolescents who used cannabis had lower activation in the

amygdala in an emotional arousal word task during fMRI

(Heitzeg et al. 2015). However, in another fMRI study, ado-

lescent cannabis users showed greater amygdala activation to

angry faces compared to controls (Spechler et al. 2015).

Another study of facial emotion recognition found that during

abstinence, cannabis-dependent patients performed signifi-

cantly worse than controls in the identification of negative

emotions suggesting a lasting impact on emotion recognition

after chronic cannabis use (Bayrakçi et al. 2015). Together,

these fMRI findings indicate that chronic cannabis use alters

amygdala function.

Fig. 2 a. Statistical group differences in the effect of methylphenidate on

the distribution volume between controls and marijuana abusers.

Methylphenidate-induced decreases in distribution volumes were stron-

ger in controls than in marijuana abusers (p< 0.005). There were no

regions where marijuana abusers showed greater decreases than controls.

b. Individual distribution volume values in putamen after placebo (PL)

and after methylphenidate (MP) for marijuana abusers and controls.

*p<0.05, **p< 0.005. (Figure adapted with permission from Volkow

et al. 2014a,b,c)

J Neuroimmune Pharmacol (2018) 13:438–452 445

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The association between amygdala structure and cannabis

use is relatively unclear. Some studies have found morpholog-

ical and volumetric differences in the amygdala between

healthy controls and cannabis users in both adolescent and

adult cohorts (Gilman et al. 2014; Lorenzetti et al. 2015). On

the other hand, other studies that controlled for alcohol and

tobacco use found no differences in amygdala volume or

shape between cannabis users and healthy controls (Weiland

et al. 2015; Manza et al. 2018). A longitudinal study with

cannabis users and healthy controls found no volumetric dif-

ferences in gray matter at baseline or a three-year follow up

(Koenders et al. 2016). Despite these inconclusive structural

MRI findings, there is evidence that chronic cannabis use may

contribute to emotional dysregulation through functional

changes in the amygdala (Heitzeg et al. 2015; Spechler et al.

2015).

Further evidence of emotion dysregulation after chronic

cannabis use is seen in fMRI functional connectivity studies

with cannabis users (Pujol et al. 2014; Zimmermann et al.

2018). In one study, cannabis users showed increased

resting-state functional connectivity between posterior cingu-

late cortex (PCC) and other regions of the default mode net-

work (including angular gyri, medial and lateral PFC, ACC

and temporal cortex), and an anticorrelation between PCC

activation and insula activation. These connectivity patterns

were associated with a reduction in anxiety scores suggesting

an alteration of affect state that is related to changes in brain

function during cannabis addiction. As the insula is involved

in integrating interoceptive information for emotion, these

findings suggest that cannabis may enhance visceral sensa-

tions via insula activation to modify affect state (Pujol et al.

2014). Additionally, these resting-state functional connectivi-

ty patterns lasted one month after cessation of cannabis use

suggesting long-lasting changes in brain function after chronic

cannabis use (although functional connectivity patterns in

other networks normalized with abstinence, see Pujol et al.

2014). In another fMRI study, cannabis-dependent subjects

completed task and resting state fMRI 28 days after abstinence

(Zimmermann et al. 2018). During the task, in which partici-

pants were passively exposed to pictures of negative and neu-

tral valence, negative emotional stimuli elicited larger in-

creases in medial orbitofrontal cortex (mOFC) activity in

cannabis-dependent users than in healthy controls; researchers

also found greater functional connectivity between the mOFC

and dorsal striatal region as well as the mOFC and amygdala

compared to healthy controls during the task. Given that the

mOFC is a region implicated in emotional regulation, these

connectivity findings suggest the existence of persistent emo-

tional processing alterations in cannabis-dependent users even

after cessation of cannabis use (Zimmermann et al. 2018).

In addition to contributing to emotion dysregulation, ces-

sation of chronic cannabis use is associated with the develop-

ment of craving (Davis et al. 2016). Cue-reactivity is a

neurobiological metric to evaluate cue-induced craving, a

strong predictor of relapse for substance use (Budney et al.

2008; Wilson and Sayette 2015). A 2016 meta-analysis of

cue-reactivity in regular cannabis users reported moderate to

extreme cue-reactivity despite self-reports of low craving

(Norberg et al. 2016). These results may indicate that cannabis

users underestimate their own excessive salience, suggesting

that self-reports may not accurately reflect cannabis craving

intensity. Thus, excessive salience attribution to cannabis-

related cues appears to be a hallmark of cannabis addiction.

These studies further demonstrate the importance of collecting

objective measures of craving when studying the effects of

chronic cannabis use.

Finally, one of the most consistent neuroimaging findings

in addiction is that of dysregulation of frontal cortical regions

involved with executive function including the dorsolateral

prefrontal cortex, the ACC and the inferior frontal cortex.

Imaging studies investigating brain glucose metabolism,

which serves as a marker of brain function, reported decreased

frontal metabolism in cannabis abusers when compared with

controls (Sevy et al. 2008;Wiersetal.2016b)andin

polysubstance users who consumed cannabis (Moreno-

Lopez et al. 2012).

Treatment Options

Treatments for CUD seem to target aspects of the binge-intox-

ication, withdrawal-negative affect, and preoccupation-

anticipation stages described by Koob and Volkow (2016).

Pharmacological treatments for the binge-intoxication

stage of cannabis addiction have focused on cannabinoid re-

ceptors. One mechanism of action involves direct antagonism

of CB1Rs. CB1R selective antagonists such as rimonabant

have been shown to block the subjective intoxicating and

tachycardic effects of smoked cannabis (Crippa et al. 2012;

Danovitch and Gorelick 2012). Despite the potential acute

benefits, direct antagonism with rimonabant is associated with

anxiety and depression (Taylor 2009; Danovitch and Gorelick

2012). Up to 10% of patients experienced anxiety and depres-

sion following use of rimonabant (Food and Drug

Administration 2007). Another downfall of this therapy is that

in order to avoid precipitated withdrawal, participants are re-

quired to abstain from drug use prior to administration of

antagonist medications, leading to poor compliance rates

(Vandrey and Haney 2009). While partial agonists have been

proposed to block the reinforcing effects of other drugs of

abuse like opioids and nicotine (Koob and Mason 2016), no

partial agonists have been found to reduce cannabis use.

Many different pharmacological treatments have been in-

vestigated for reduction of cannabis withdrawal symptoms,

primarily through modulation of cannabinoid receptors but

also through other neurotransmitter systems including

446 J Neuroimmune Pharmacol (2018) 13:438–452

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glutamate, dopamine, norepinephrine, serotonin, and GABA

(Balter et al. 2014; Levin et al. 2016; Brezing and Levin

2018). In their comprehensive review of the different pharma-

cological treatments for CUD and cannabis withdrawal,

Brezing and Levin (2018) conclude that therapies targeting

specific symptoms of withdrawal (such as anxiety, irritability,

sleep disturbances, and decreased appetite) should be admin-

istered in conjunction with treatments that target reduction in

cannabis use and prevention of relapse. Promising candidates

for treatment of CUD that prevent relapse include naltrexone,

gabapentin, and N-acetylcysteine (NAC) (Mason et al. 2012;

Brezing and Levin 2018). The greatest reduction in multiple

withdrawal symptoms has been shown with treatment using

CB1R agonists such as dronabinol (oral THC), nabixmols (a

combination of THC and CBD), and nabilone (Balter et al.

2014; Brezing and Levin 2018); surprisingly, previous studies

have not shown cannabidiol as a potential treatment for can-

nabis withdrawal despite its anxiolytic effects (Brezing and

Levin 2018). With CB1R agonists as potential treatments, it

is necessary to consider the abuse potential of these drugs.

Dronabinol, nabilone, and nabixmols seem to have a lower

abuse potential than smoked cannabis (Allsop et al. 2015;

Tsang and Giudice 2016), but in one study of cannabinoid

replacement therapy, dronabinol and nabixmol had higher

self-reports of liking than placebo drugs (Allsop et al. 2015).

NAC is being investigated as an anticraving agent in can-

nabis addiction therapy due to its regulatory role in glutamate

and dopamine signaling (Samuni et al. 2013). NAC helps

regulate the intra- and extracellular levels of glutamate

through the cysteine-glutamate antiporter. Increased extracel-

lular glutamate levels activate inhibitory metabotropic gluta-

mate receptors, reducing glutamate neurotransmission

(Samuni et al. 2013). The upregulation of glutamate signaling

during the anticipation/preoccupation phase may be

counteracted with NAC treatment, reducing clinical symp-

toms of craving and therefore reducing relapse rates. A 2014

review article summarizes two studies that evaluated NAC

therapy in CUD. In one study, the placebo cohort reported

twice as many positive urine cannabinoid tests as compared

to the NAC cohort (Asevedo et al. 2014). The other study did

not report group differences in positive urine tests, but did find

a significant reduction in self-reported cannabis craving in the

treatment group (Asevedo et al. 2014). These studies reinforce

the role of glutamate upregulation during cannabis abstinence

on clinical outcomes such as craving and relapse.

Discussion

After examining the acute and long-term effects of cannabis,

CUD appears to conform to the general patterns of changes

described in the Koob and Volkow model of addiction.

Previous preclinical and clinical studies indicate that features

of the three stages of drug addiction described by Koob and

Volkow are also present in cannabis addiction (Fig. 1), al-

though these findings may not be as robust as other drugs of

abuse.

As described in the Koob and Volkow model (2016), most

drugs of abuse result in the hyperactivation of the

mesocorticolimbic dopaminergic reward pathway in the

binge-intoxication stage of addiction. This hyperactivation

seems to be present in cannabis addiction but to a lower ex-

tent. Acute THC administration elicits striatal DA release in

animals (Bloomfield et al. 2016) and THC challenges were

shown to increase striatal DA transmission in humans (Stokes

et al. 2010; Bossong et al. 2015); although other studies have

found no THC-induced increases in striatal DA (Barkus et al.

2011; Urban et al. 2012). Additionally, there are no baseline

differences in dopamine D2/D3 receptor availability between

cannabis users and healthy controls (Volkow et al. 2014c;van

de Giessen et al. 2017), a finding that does not parallel addic-

tion to other drugs of abuse (including cocaine, alcohol, meth-

amphetamine, nicotine, or heroin) which is associated with

substantial reductions in D2R availability in the ventral stria-

tum (Wang et al. 1997; Volkow et al. 2001,2014c,2017c;

Martinez et al. 2012;Albrechtetal.2013;Tomasietal.

2015a; Wiers et al. 2016a; Ashok et al. 2017). Nonetheless,

as with other drugs of abuse, chronic cannabis use still results

in blunted dopamine reactivity to a stimulant challenge

(Volkow et al. 2014c; van de Giessen et al. 2017).

This blunted stimulant-induced dopamine reactivity has

been associated with negative emotionality (Volkow et al.

2014c) a key feature of withdrawal/negative affect stage de-

scribed by Koob and Volkow (2016). With the addition of

withdrawal as a symptom of CUD, it is evident that the devel-

opment of cannabis addiction parallels addiction to other

drugs of abuse. In addition, chronic cannabis use has been

associated with affect dysregulation that may involve changes

in amygdala functioning (Filbey et al. 2013; Heitzeg et al.

2015; Spechler et al. 2015). As with other drugs of abuse,

cannabis seems to disrupt HPA axis function (Somaini et al.

2012; Cuttler et al. 2017), another key neuroadaptation of the

withdrawal/negative affect stage described by Koob and

Vo l k o w ( 2016).

Chronic cannabis use is also associated with the presence

of cannabis cue-induced craving after abstinence (Filbey et al.

2016; Norberg et al. 2016), a hallmark of the preoccupation/

anticipation stage of the Koob and Volkow framework (2016).

The presence of cannabis cue-induced craving seems to be

related to the loss of executive control over excessive salience

for cannabis (Norberg et al. 2016). In addition, chronic can-

nabis use has been linked to impaired memory and IQ, sug-

gesting changes in executive functioning after chronic canna-

bis use. However, IQ deficits appear to be present before ini-

tiation of cannabis use which may suggest that lower IQ could

be a risk factor for cannabis addiction (Jackson et al. 2016).

J Neuroimmune Pharmacol (2018) 13:438–452 447

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Interestingly, chronic cannabis use is associated with a

downregulation of CB1R –THC’s target receptor –that is

restored after 4 weeks of abstinence in humans (Hirvonen

et al. 2012). This pattern of abstinence-induced changes in

target receptor density is also seen after abstinence from other

drugs of abuse such as heroin, stimulants, and alcohol (in

humans and animals) but with some caveats: the changes

found are not consistent across brain regions for every drug

and abstinence periods are not congruent between studies

(Wang et al. 2012; Seip-Cammack et al. 2013; Ashok et al.

2017; Volkow et al. 2017c). Future studies should examine to

whether changes in target receptors after abstinence are com-

parable across brain regions and if they follow the same time

course in CUD and other SUD.

Future studies should also investigate if there are other

features of the addiction framework proposed by Koob and

Volkow in cannabis addiction. Specifically, more longitudinal

studies should investigate behavioral and mood changes (such

as changes in IQ or the presence of a mood disorder) before

and after the onset of cannabis use to determine whether var-

iations in behavior and mood are risk factors or the result of

cannabis addiction rather than a consequence. Additionally,

with the increasing potency of THC in street cannabis

(ElSohly et al. 2016), it is necessary to evaluate whether

long-term changes may be related to the THC content of can-

nabis. Future studies should also investigate the specific

neurocircuitry Koob and Volkow (2016) implicate in the three

stages of addiction: specifically, how cannabis use impacts

glutamate signaling in the VTA (disrupted during binge/intox-

ication) and PFC (disrupted during preoccupation/craving)

and acetylcholine signaling in the habenula (disrupted during

withdrawal/negative affect).

Future research should also consider whether THC’s ef-

fects on neurons and microglia are related to addiction.

Previous research indicates that chronic THC exposure in an-

imals seems to activate microglia and produce neuroinflam-

mation that may underlie some of the cognitive deficits asso-

ciated with CUD (Melis et al. 2017); additionally, changes in

neuron and glia morphology after chronic cannabis exposure

may also contribute to the persistent cognitive and behavioral

deficits linked to CUD (Cutando et al. 2013;Kolbetal.2018).

Therefore, future studies should investigate whether chronic

THC exposure in animals and humans is linked to changes in

various cell types in the brain that contribute to cannabis ad-

diction through neuroinflammation. THC has also been

shown to have immunosuppressant properties in animals

(Suarez-Pinilla et al. 2014) while cannabis use has been asso-

ciated with adverse cardiovascular effects in humans (Pacher

et al. 2017; Goyal et al. 2017; Thomas et al. 2018); these

peripheral effects could be another line of future research.

Although further research is necessary (Box 1), the find-

ings summarized here indicate that neurobiological changes in

CUD seem to parallel those in other addictions, albeit to a

lesser extent in some brain systems. This is critical in light

of recent findings demonstrating an increase in cannabis use

and CUD and a corresponding decrease in the perceived risk

of cannabis (Carliner et al. 2017;Hasin2018).

Box 1. Questions for future research

•Do changes in CBIR density after abstinence from cannabis parallel

changes in target receptors of other drugs of abuse?

•Are behavioral and mood variations associated with cannabis use a risk

factor or consequence of cannabis addiction?

•Are long-term behavioral and neurophysiological changes related to the

THC content in cannabis?

•Is cannabis use associated with long-term changes in glutamate

signaling as seen in other drugs of abuse?

•Is cannabis use associated with disruptions in the amygdala and

habenula as seen with other drugs of abuse?

Funding The project was supported by NIH Intramural Research

Program of the National Institute on Alcoholism and Alcohol Abuse,

Z01AA3009 (AZ, JB, CKL, PM, CW, NDV, GJW).

Compliance with Ethical Standards

Conflicts of Interest The authors report no biomedical financial interests

or potential conflicts of interest.

Open Access This article is distributed under the terms of the Creative

Commons Attribution 4.0 International License (http://

creativecommons.org/licenses/by/4.0/), which permits unrestricted use,

distribution, and reproduction in any medium, provided you give appro-

priate credit to the original author(s) and the source, provide a link to the

Creative Commons license, and indicate if changes were made.

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Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review

Article

Full-text available

Feb 2023
BSRCCS

Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components—tetrahydrocannabinol (THC) and cannabidiol (CBD)—or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.

A male mouse model of WIN 55,212–2 self-administration to study cannabinoid addiction

Article

Full-text available

Mar 2023

We have established for the first time a mouse model of cannabinoid addiction using WIN 55,212–2 intravenous self-administration (0.0125 mg/kg/infusion) in C57Bl/6J mice. This model allows to evaluate the addiction criteria by grouping them into 1) persistence of response during a period of non-availability of the drug, 2) motivation for WIN 55,212–2 with a progressive ratio, and 3) compulsivity when the reward is associated with a punishment such as an electric foot-shock, in agreement with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5). This model also allows to measure two parameters that have been related with the DSM-5 diagnostic criteria of craving, resistance to extinction and reinstatement, and two phenotypic traits suggested as predisposing factors, impulsivity and sensitivity to reward. We found that 35.6% of mice developed the criteria of cannabinoid addiction, allowing to differentiate between resilient and vulnerable mice. Therefore, we have established a novel and reliable model to study the neurobiological correlates underlying the resilience or vulnerability to develop cannabinoid addiction. This model included the chemogenetic inhibition of neuronal activity in the medial prefrontal cortex to the nucleus accumbens pathway to assess the neurobiological substrate of cannabinoid addiction. This model will shed light on the neurobiological substrate underlying cannabinoid addiction.

Maternal high-fat diet decreases milk endocannabinoids with sex-specific changes in the cannabinoid and dopamine signaling and food preference in rat offspring

Article

Full-text available

Feb 2023

Introduction Maternal high-fat (HF) diet during gestation and lactation programs obesity in rat offspring associated with sex-dependent and tissue-specific changes of the endocannabinoid system (ECS). The ECS activation induces food intake and preference for fat as well as lipogenesis. We hypothesized that maternal HF diet would increase the lipid endocannabinoid levels in breast milk programming cannabinoid and dopamine signaling and food preference in rat offspring. Methods Female Wistar rats were assigned into two experimental groups: control group (C), which received a standard diet (10% fat), or HF group, which received a high-fat diet (29% fat) for 8 weeks before mating and during gestation and lactation. Milk samples were collected to measure endocannabinoids and fatty acids by mass spectrometry. Cannabinoid and dopamine signaling were evaluated in the nucleus accumbens (NAc) of male and female weanling offspring. C and HF offspring received C diet after weaning and food preference was assessed in adolescence. Results Maternal HF diet reduced the milk content of anandamide (AEA) ( p<0.05 ) and 2-arachidonoylglycerol (2-AG) ( p<0.05 ). In parallel, maternal HF diet increased adiposity in male ( p<0.05 ) and female offspring ( p<0.05 ) at weaning. Maternal HF diet increased cannabinoid and dopamine signaling in the NAc only in male offspring ( p<0.05 ), which was associated with higher preference for fat in adolescence ( p<0.05 ). Conclusion Contrary to our hypothesis, maternal HF diet reduced AEA and 2-AG in breast milk. We speculate that decreased endocannabinoid exposure during lactation may induce sex-dependent adaptive changes of the cannabinoid-dopamine crosstalk signaling in the developing NAc, contributing to alterations in neurodevelopment and programming of preference for fat in adolescent male offspring.

Measuring white matter microstructure in 1,457 cannabis users and 1,441 controls: A systematic review of diffusion-weighted MRI studies

Article

Full-text available

Mar 2023

Alexandra Gaillard

Cannabis is the most widely used regulated substance by youth and adults. Cannabis use has been associated with psychosocial problems, which have been partly ascribed to neurobiological changes. Emerging evidence to date from diffusion-MRI studies shows that cannabis users compared to controls show poorer integrity of white matter fibre tracts, which structurally connect distinct brain regions to facilitate neural communication. However, the most recent evidence from diffusion-MRI studies thus far has yet to be integrated. Therefore, it is unclear if white matter differences in cannabis users are evident consistently in selected locations, in specific diffusion-MRI metrics, and whether these differences in metrics are associated with cannabis exposure levels. We systematically reviewed the results from diffusion-MRI imaging studies that compared white matter differences between cannabis users and controls. We also examined the associations between cannabis exposure and other behavioral variables due to changes in white matter. Our review was pre-registered in PROSPERO (ID: 258250; https://www.crd.york.ac.uk/prospero/). We identified 30 diffusion-MRI studies including 1,457 cannabis users and 1,441 controls aged 16-to-45 years. All but 6 studies reported group differences in white matter integrity. The most consistent differences between cannabis users and controls were lower fractional anisotropy within the arcuate/superior longitudinal fasciculus (7 studies), and lower fractional anisotropy of the corpus callosum (6 studies) as well as higher mean diffusivity and trace (4 studies). Differences in fractional anisotropy were associated with cannabis use onset (4 studies), especially in the corpus callosum (3 studies). The mechanisms underscoring white matter differences are unclear, and they may include effects of cannabis use onset during youth, neurotoxic effects or neuro adaptations from regular exposure to tetrahydrocannabinol (THC), which exerts its effects by binding to brain receptors, or a neurobiological vulnerability predating the onset of cannabis use. Future multimodal neuroimaging studies, including recently developed advanced diffusion-MRI metrics, can be used to track cannabis users over time and to define with precision when and which region of the brain the white matter changes commence in youth cannabis users, and whether cessation of use recovers white matter differences. www.crd.york.ac.uk/prospero/, identifier: 258250.

Trends of the Global Burden of Disease Attributable to Cannabis Use Disorder in 204 Countries and Territories, 1990–2019: Results from the Disease Burden Study 2019

Article

Full-text available

Feb 2023
Int J Ment Health Addiction

Unlabelled: Cannabis is the fourth psychoactive substance to be legalized which are of far-reaching significance to the world. We analyzed data from the 2019 Global Burden of Disease Study (GBD) to estimate the incidence and prevalence of cannabis use disorder (CUD) and calculated the disease burden of CUD in 204 countries and territories and 21 regions over the past three decades. We reported disease burden due to CUD in terms of disability-adjusted life years (DALYs), age-standardized rate (ASR), estimated annual percentage change (EAPC), and analyzed associations between the burden of CUD and sociodemographic index (SDI) quintiles. Globally, the number of incidence cases of CUD was estimated to be increasing by 32.3% from 1990 to 2019 and males are nearly double higher than that of female. DALYs increase 38.6% from 1990. Young people aged 20-24 years old with cannabis use disorder have the highest DALYs in 2019, followed by those younger than 20 years old. India, Canada, USA, Qatar, Kenya, and high SDI quintile areas showed a high burden of disease. Nearly 200 million individuals are cannabis users worldwide, and CUD is a notable condition of GBD. The global cultivation of cannabis, rooted in different cultures, diversified access to cannabis, legalization in controversy, the promotion of medical cannabis, and many other factors promote the global cannabis industry is constantly updated and upgraded. It deserves more discussion in the future in terms of pathophysiological mechanisms, socioeconomics, law, and policy improvement. Supplementary information: The online version contains supplementary material available at 10.1007/s11469-022-00999-4.

Endocannabinoid System: Chemical Characteristics and Biological Activity

Article

Full-text available

Jan 2023

The endocannabinoid system (eCB) has been studied to identify the molecular structures present in Cannabis sativa. eCB consists of cannabinoid receptors, endogenous ligands, and the associated enzymatic apparatus responsible for maintaining energy homeostasis and cognitive processes. Several physiological effects of cannabinoids are exerted through interactions with various receptors, such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered G-protein-coupled receptors (GPR55, GPR3, GPR6, GPR12, and GPR19). Anandamide (AEA) and 2-arachidoylglycerol (2-AG), two small lipids derived from arachidonic acid, showed high-affinity binding to both CB1 and CB2 receptors. eCB plays a critical role in chronic pain and mood disorders and has been extensively studied because of its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities for eCB and are relevant to the treatment of several neurological diseases. This review provides a description of eCB components and discusses how phytocannabinoids and other exogenous compounds may regulate the eCB balance. Furthermore, we show the hypo- or hyperfunctionality of eCB in the body and how eCB is related to chronic pain and mood disorders, even with integrative and complementary health practices (ICHP) harmonizing the eCB.

Deletion of Cryab increases the vulnerability of mice to the addiction-like effects of the cannabinoid JWH-018 via upregulation of striatal NF-κB expression

Article

Full-text available

Mar 2023

Synthetic cannabinoids have exhibited unpredictable abuse liabilities, especially self-administration (SA) responses in normal rodent models, despite seemingly inducing addiction-like effects in humans. Thus, an efficient pre-clinical model must be developed to determine cannabinoid abuse potential in animals and describe the mechanism that may mediate cannabinoid sensitivity. The Cryab knockout (KO) mice were recently discovered to be potentially sensitive to the addictive effects of psychoactive drugs. Herein, we examined the responses of Cryab KO mice to JWH-018 using SA, conditioned place preference, and electroencephalography. Additionally, the effects of repeated JWH-018 exposure on endocannabinoid- and dopamine-related genes in various addiction-associated brain regions were examined, along with protein expressions involving neuroinflammation and synaptic plasticity. Cryab KO mice exhibited greater cannabinoid-induced SA responses and place preference, along with divergent gamma wave alterations, compared to wild-type (WT) mice, implying their higher sensitivity to cannabinoids. Endocannabinoid- or dopamine-related mRNA expressions and accumbal dopamine concentrations after repeated JWH-018 exposure were not significantly different between the WT and Cryab KO mice. Further analyses revealed that repeated JWH-018 administration led to possibly greater neuroinflammation in Cryab KO mice, which may arise from upregulated NF-κB, accompanied by higher expressions of synaptic plasticity markers, which might have contributed to the development of cannabinoid addiction-related behavior in Cryab KO mice. These findings signify that increased neuroinflammation via NF-κB may mediate the enhanced addiction-like responses of Cryab KO mice to cannabinoids. Altogether, Cryab KO mice may be a potential model for cannabinoid abuse susceptibility.

Substance Use and Addiction

Chapter

Apr 2023

When experiencing mental health challenges, we all deserve treatments that actually work. Whether you are a healthcare consumer, student, or mental health professional, this book will help you recognize implausible, ineffective, and even harmful therapy practices while also considering recent controversies. Research-supported interventions are identified in this book and expanded upon in a companion volume. Chapters cover every major mental disorder and are written by experts in their respective fields. Pseudoscience in Therapy is of interest to students taking courses in psychotherapy, counseling, clinical psychology, and behavior therapy, as well as practitioners looking for a guide to proven therapeutic techniques.

The Reward System: What It Is and How It Is Altered in Cannabis Users

Chapter

Jun 2022

Determining impacts of prenatal cannabis exposure on cannabis vapor self-administration using a novel response-contingent vapor model in pregnant rat dams

Article

Feb 2023

Altered orbitofrontal activity and dorsal striatal connectivity during emotion processing in dependent marijuana users after 28 days of abstinence

Article

Full-text available

Mar 2018
PSYCHOPHARMACOLOGY

Rationale: Intact cognitive and emotional functioning is vital for the long-term success of addiction treatment strategies. Accumulating evidence suggests an association between chronic marijuana use and lasting alterations in cognitive brain function. Despite initial evidence for altered emotion processing in dependent marijuana users after short abstinence periods, adaptations in the domain of emotion processing after longer abstinence remain to be determined. Objective and methods: Using task-based and resting state fMRI, the present study investigated emotion processing in 19 dependent marijuana users and 18 matched non-using controls after an abstinence period of > 28 days. Results: Relative to the control subjects, negative emotional stimuli elicited increased medial orbitofrontal cortex (mOFC) activity and stronger mOFC-dorsal striatal and mOFC-amygdala functional coupling in dependent marijuana users (p < 0.022, FWE-corrected). Furthermore, mOFC-dorsal striatal functional connectivity was increased at rest in marijuana users (p < 0.03, FWE-corrected). Yet, processing of positive stimuli and subjective ratings of valence and arousal were comparable in both groups. Conclusions: Together, the present findings provide the first evidence for persisting emotion processing alterations in dependent marijuana users. Alterations might reflect long-term neural adaptations as a consequence of chronic marijuana use or predisposing risk factors for the development of marijuana dependence.

Subcortical Local Functional Hyperconnectivity in Cannabis Dependence

Article

Full-text available

Nov 2017

Background Cannabis abuse has been associated with psychopathology, including negative emotionality and a higher risk of psychosis, particularly with early age of initiation. However, the mechanisms underlying this association are poorly understood. Because aberrant dopamine (DA) signaling is implicated in cannabis-associated psychopathology, we hypothesized that regular cannabis abuse (CA) would be associated with altered resting functional connectivity in dopamine midbrain-striatal circuits. Methods We examined resting brain activity of subcortical regions in 441 young adults from the Human Connectome Project, including 30 CA meeting DSM criteria for dependence, and 30 controls matched on age, sex, education, BMI, anxiety, depression, and alcohol/tobacco usage. Results Across all subjects, local functional connectivity density (lFCD) hubs in subcortical regions were most prominent in ventral striatum, hippocampus, amygdala, dorsal midbrain, and the posterior-ventral brainstem. As hypothesized, CA showed markedly increased lFCD relative to controls in ventral striatum (where nucleus accumbens is located) and midbrain (where substantia nigra/ventral tegmental nuclei are located) but also in brainstem and lateral thalamus. These effects were observed in the absence of significant differences in subcortical volumes, and were most pronounced in the individuals who began cannabis use earliest in life and who reported high levels of negative emotionality. Conclusions Together, these findings suggest that chronic cannabis abuse is associated with changes in resting brain function, particularly in dopaminergic nuclei implicated in psychosis but that are also critical for habit formation and reward processing. These results shed light on neurobiological differences that may be relevant to psychopathology associated with cannabis use.

The Conception of the ABCD Study: From Substance Use to a Broad NIH Collaboration

Article

Full-text available

Oct 2017

Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day.

Effect of Novel Allosteric Modulators of Metabotropic Glutamate Receptors on Drug Self-administration and Relapse: A Review of Preclinical Studies and Their Clinical Implications

Article

Full-text available

Sep 2017
BIOL PSYCHIAT

Results from preclinical rodent studies during the last 20 years implicated glutamate neurotransmission in different brain regions in drug self-administration and rodent models of relapse. These results, along with evidence for drug-induced neuroadaptations in glutamatergic neurons and receptors, suggested that addiction might be treatable by medications that inhibit glutamatergic responses to drugs of abuse, drug-associated cues, and stressors. This idea is supported by findings in rodent and primate models that drug self-administration and relapse are reduced by systemic injections of antagonists of ionotropic glutamate receptors or metabotropic glutamate receptors (mGluRs) or orthosteric agonists of mGluR2/3. However, these compounds have not advanced to clinical use because of potential side effects and other factors. This state of affairs has led to the development of positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) of mGluRs. PAMs and NAMs of mGluRs, either of which can inhibit evoked glutamate release, may be suitable for testing in humans. We reviewed results from recent studies of systemically injected PAMs and NAMs of mGluRs in rodents and monkeys, focusing on whether they reduce drug self-administration, reinstatement of drug seeking, and incubation of drug craving. We also review results from rat studies in which PAMs or NAMs of mGluRs were injected intracranially to reduce drug self-administration and reinstatement. We conclude that PAMs and NAMs of mGluRs should be considered for clinical trials.

U.S. Epidemiology of Cannabis Use and Associated Problems

Article

Full-text available

Aug 2017

Deborah S. Hasin

This review provides an overview of the changing U.S. epidemiology of cannabis use and associated problems. Adults and adolescents increasingly view cannabis as harmless, and some can use cannabis without harm. However, potential problems include harms from pre-natal exposure and unintentional childhood exposure; decline in educational or occupational functioning after early adolescent use, and in adulthood, impaired driving and vehicle crashes; cannabis use disorders (CUD), cannabis withdrawal, and psychiatric comorbidity. Evidence suggests national increases in cannabis potency, prenatal and unintentional childhood exposure; and in adults, increased use, CUD, cannabis-related emergency room visits and fatal vehicle crashes. Twenty-nine states have medical marijuana laws (MML) and of these, 8 have recreational marijuana laws (RML). Many studies indicate that MML or their specific provisions did not increase adolescent cannabis use. However, the more limited literature suggests that MML have led to increased cannabis potency, unintentional childhood exposures, adult cannabis use, and adult CUD. Ecological-level studies suggest that MML have led to substitution of cannabis for opioids, and also possibly for psychiatric medications. Much remains to be determined about cannabis trends and the role of MML and RML in these trends. The public, health professionals and policy makers would benefit from education about the risks of cannabis use, the increases in such risks, and the role of marijuana laws in these increases.

Associations between Adolescent Cannabis Use and Neuropsychological Decline: A Longitudinal Co-Twin Control Study: Adolescent Cannabis Use and IQ Decline

Article

Full-text available

Jul 2017
ADDICTION

Aims: This study tested whether adolescents who used cannabis or met criteria for cannabis dependence showed neuropsychological impairment prior to cannabis initiation and neuropsychological decline from before to after cannabis initiation. Design: A longitudinal co-twin control study. Setting and participants: Participants were 1,989 twins from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative birth cohort of twins born in England and Wales from 1994-1995. Measurements: Frequency of cannabis use and cannabis dependence were assessed at age 18. Intelligence quotient (IQ) was obtained at ages 5, 12, and 18. Executive functions were assessed at age 18. Findings: Compared with adolescents who did not use cannabis, adolescents who used cannabis had lower IQ in childhood, prior to cannabis initiation, and had lower IQ at age 18, but there was little evidence that cannabis use was associated with IQ decline from age 12-18. For example, adolescents with cannabis dependence had age-12 and age-18 IQ scores that were 5.61 (t=-3.11, p=.002) and 7.34 IQ points (t=-5.27, p<.001) lower than adolescents without cannabis dependence, but adolescents with cannabis dependence did not show greater IQ decline from age 12-18 (t=-1.27, p=.20). Moreover, adolescents who used cannabis had poorer executive functions at age 18 than adolescents who did not use cannabis, but these associations were generally not apparent within twin pairs. For example, twins who used cannabis more frequently than their co-twin performed similarly to their co-twin on 5 of 6 executive function tests (ps>.10). The one exception was that twins who used cannabis more frequently than their co-twin performed worse on one working memory test (Spatial Span Reversed; β=-0.07, p=.036). Conclusions: Short-term cannabis use in adolescence does not appear to cause IQ decline or impair executive functions, even when cannabis use reaches the level of dependence. Family background factors explain why adolescent cannabis users perform worse on IQ and executive function tests.

Old and new synthetic cannabinoids: lessons from animal models

Article

Jan 2018

Synthetic cannabinoids have long been studied for their therapeutic potentials. However, during the last decade, new generations of synthetic cannabinoid agonists appeared on the drug market. These new psychoactive substances are currently sold as ‘marijuana-like’ products as they claim to mimic the effects of the psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC). Yet, their effects are more intense and potent than THC, typically last longer and are often associated to serious psychiatric consequences. Animal models of drug addiction are frequently used in preclinical research to assess the abuse potential of new compounds, evaluate drug positive reinforcing effects and analyze drug-induced behaviors. Some of these protocols have been used recently to study the newly synthesized cannabinoid agonists and have started elucidating their pharmacology and actions in the brain. The aim of this review is to summarize the major findings reported by animal studies that tested synthetic cannabinoids of first, second, and third generation by using self-administration and reinstatement models, drug discrimination and conditioned place preference procedures. Altogether, behavioral studies clearly indicate that synthetic cannabinoids possess abuse liability, are likely to activate the brain reward circuit and induce positive subjective and reinforcing effects.

THC alters alters morphology of neurons in medial prefrontal cortex, orbital prefrontal cortex, and nucleus accumbens and alters the ability of later experience to promote structural plasticity

Article

Nov 2017
SYNAPSE

Psychoactive drugs have the ability to alter the morphology of neuronal dendrites and spines and to influence later experience-dependent structural plasticity. If rats are given repeated injections of psychomotor stimulants (amphetamine, cocaine, nicotine) prior to being placed in complex environments, the drug experience interferes with the ability of the environment to increase dendritic arborization and spine density. Repeated exposure to Delta 9-Tetrahydrocannabinol (THC) changes the morphology of dendrites in medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc). In order to determine if drugs other than psychomotor stimulants will also interfere with later experience-dependent structural plasticity we gave Long-Evans rats THC (0.5 mg/kg) or saline for 11 days before placing them in complex environments or standard laboratory caging for 90 days. Brains were subsequently processed for Golgi-Cox staining and analysis of dendritic morphology and spine density mPFC, orbital frontal cortex (OFC), and NAcc. THC altered both dendritic arborization and spine density in all three regions, and, like psychomotor stimulants, THC influenced the effect of later experience in complex environments to shape the structure of neurons in these three regions. We conclude that THC may therefore contribute to persistent behavioral and cognitive deficits associated with prolonged use of the drug. This article is protected by copyright. All rights reserved.

Cardiovascular effects of marijuana and synthetic cannabinoids: The good, the bad, and the ugly

Article

Mar 2018

Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.

The Current State of Pharmacological Treatments for Cannabis Use Disorder and Withdrawal

Article

Sep 2017
NEUROPSYCHOPHARMACOL

Cannabis use disorder (CUD) commonly occurs and carries a notable economic and functional burden at both individual and societal levels. While there are no clearly efficacious medication treatments for CUD, twenty years of committed and high quality research in the human laboratory and clinical settings have resulted in medications with demonstrated effectiveness in the treatment of cannabis withdrawal, the ability to reduce cannabis use, and results that point to promising future work. The current state of pharmacology research for CUD highlights the need to consider particular characteristics of patients, such as gender, impulsivity, and severity of cannabis use, when selecting a medication in the off-label treatment of CUD or cannabis withdrawal. As a field, the body of work also exposes some areas in need of improvement in study design, selection of outcome measures, interpretation of results, and the overall process of evaluating candidate medications. Coming to a consensus as a field and addressing these gaps in future research will likely lend itself to further advances in improving the lives of patients with CUD.Neuropsychopharmacology accepted article preview online, 06 September 2017. doi:10.1038/npp.2017.212.