Severe Cannabis Dependence and Blunted Striatal Dopamine Release: A Comorbidity Independent Effect

Chronic and severe cannabis-dependence is associated with deficits in striatal dopamine release.
Chronic and severe cannabis-dependence is associated with deficits in striatal dopamine release.

The prevalence and use of cannabis is increasing at an alarming rate, in tandem with its legalization in various states and jurisdictions. Recent estimates indicate that, among adults with a cannabis use disorder, approximately 66% of these individuals qualify for cannabis dependence versus cannabis abuse.1,2

Available evidence indicates that cannabis use is associated with elevated risk of developing psychiatric disorders, notably psychosis and depression, which are also frequently accompanied by cognitive impairments. It is not clear, however, whether the release of dopamine (DA) is blunted in the striatum of individuals with severe cannabis dependence. The main psychoactive component of cannabis is ∆9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid receptor (CB1).1,3-5

Studies investigating the underlying consequences of chronic drug use frequently report alterations in DA release, contributing to poor disease course and outcome.5 However, many reports do not exclusively examine the effect(s) of cannabis use on DA release independent of comorbid substance use disorders (eg, nicotine) and/or medical disorders [eg, major depressive disorder (MDD)].5

Accordingly, van de Giessen and colleagues conducted a study to evaluate whether chronic cannabis dependence, independent of nicotine use and other medical comorbidities, leads to striatal and extrastriatal dopaminergic deficits. Their findings were published in Molecular Psychiatry.

Participants included 12 individuals with severe cannabis-dependence that remained as inpatients for 5-7 days to standardize abstinence, and 12 healthy controls.

Individuals in both groups underwent positron emission tomography (PET) scans with [11C]-(+)-PHNO – a dopamine receptor (D3) preferring PET radioligand used to visualize D3 receptors in the human brain in vivo – both before and after oral administration of d-amphetamine.5,6

Cannabis-dependent participants exhibited significantly lower [11C]-(+)-PHNO binding-potential in the striatum (P=0.002, effect size (ES) = 1.48), associative striatum (P=0.003, ES=1.41), and the pallidus (P=0.012, ES=1.16), when compared to that of healthy controls. Deficit in DA release in the associative striatum was reported to correlate with inattention and negative symptoms among cannabis-dependent participants.

Moreover, impairments in cognitive function (ie, working memory and probabilistic category learning performance), in association with decreased DA release in the associative stratum, were observed in cannabis-dependent participants, as well as in healthy controls. Taken together, these results indicate that chronic and severe cannabis-dependence is associated with deficits in striatal dopamine release.5


1. Compton WM, Baler R. The Epidemiology of DSM-5 Cannabis Use Disorders Among U.S. Adults: Science to Inform Clinicians Working in a Shifting Social Landscape. Am J Psychiatry. 2016;173(6):551-553.

2. Wu LT, Zhu H, Swartz MS. Trends in cannabis use disorders among racial/ethnic population groups in the United States. Drug Alcohol Depend. 2016;165:181-190.

3. Moore TH, Zammit S, Lingford-Hughes A et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319-328.

4. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;370(23):2219-2227.

5. van de Giessen E, Weinstein JJ, Cassidy CM et al. Deficits in striatal dopamine release in cannabis dependence. Mol Psychiatry. 2016. doi: 10.1038/mp.2016.21.

6. Tziortzi AC, Searle GE, Tzimopoulou S et al. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy. Neuroimage 2011;54(1):264-277.

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