Dopaminergic Function in Cannabis Users and Its Relationship to Cannabis-Induced Psychotic Symptoms

doi:10.1016/j.biopsych.2013.05.027

Biological Psychiatry

Volume 75, Issue 6, 15 March 2014, Pages 470-478

https://doi.org/10.1016/j.biopsych.2013.05.027 Get rights and content

Background

Cannabis is the most widely used illicit drug globally, and users are at increased risk of mental illnesses including psychotic disorders such as schizophrenia. Substance dependence and schizophrenia are both associated with dopaminergic dysfunction. It has been proposed, although never directly tested, that the link between cannabis use and schizophrenia is mediated by altered dopaminergic function.

Methods

We compared dopamine synthesis capacity in 19 regular cannabis users who experienced psychotic-like symptoms when they consumed cannabis with 19 nonuser sex- and age-matched control subjects. Dopamine synthesis capacity (indexed as the influx rate constant ${K_{i}}^{c e r}$ ) was measured with positron emission tomography and 3,4-dihydroxy-6-[¹⁸F]-fluoro-l-phenylalanine ([¹⁸F]-DOPA).

Results

Cannabis users had reduced dopamine synthesis capacity in the striatum (effect size: .85; t₃₆ = 2.54, p = .016) and its associative (effect size: .85; t₃₆ = 2.54, p = .015) and limbic subdivisions (effect size: .74; t₃₆ = 2.23, p = .032) compared with control subjects. The group difference in dopamine synthesis capacity in cannabis users compared with control subjects was driven by those users meeting cannabis abuse or dependence criteria. Dopamine synthesis capacity was negatively associated with higher levels of cannabis use (r = −.77, p < .001) and positively associated with age of onset of cannabis use (r = .51, p = .027) but was not associated with cannabis-induced psychotic-like symptoms (r = .32, p = .19).

Conclusions

These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.

Section snippets

Methods and Materials

The study was approved by the National Research Ethics Service and the Administration of Radioactive Substances Advisory Committee. The study was conducted in accordance with the Declaration of Helsinki. All subjects provided informed written consent to participate.

Subject Characteristics and Scan Parameters

Twenty cannabis users were recruited to the study. Owing to tomograph malfunction during one scan, complete data were available on nineteen users. All cannabis users consumed the drug as a spliff. The mean (SD) age of first cannabis use was 15.5 (1.6) years, and the mean (SD) duration of at least weekly use was 4.7 (3.1) years. The median (interquartile range) time taken to smoke an eighth and lifetime exposure to cannabis was 4.0 (13.5) days and 2340 (6240) spliffs, respectively. Within the

References (92)

T.H. Moore et al.
Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review
Lancet
(2007)
J.C. Wu et al.
Decreasing striatal 6-FDOPA uptake with increasing duration of cocaine withdrawal
Neuropsychopharmacology
(1997)
M. Laruelle
The role of endogenous sensitization in the pathophysiology of schizophrenia: Implications from recent brain imaging studies
Res Brain Res Rev
(2000)
S.K. Bose et al.
Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging
Schizophr Res
(2008)
M. Laruelle et al.
Increased dopamine transmission in schizophrenia: Relationship to illness phases
Biol Psychiatry
(1999)
J. Hietala et al.
Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients
Lancet
(1995)
M.H. Dao-Castellana et al.
Presynaptic dopaminergic function in the striatum of schizophrenic patients
Schizophr Res
(1997)
L.N. Voruganti et al.
Cannabis induced dopamine release: An in-vivo SPECT study
Psychiatry Res
(2001)
E.D. French
Delta9-tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors
Neurosci Lett
(1997)
B. Bosier et al.
Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo
Neuropharmacology
(2012)

M. Navarro et al.

An acute dose of delta 9-tetrahydrocannabinol affects behavioral and neurochemical indices of mesolimbic dopaminergic activity

Behav Brain Res

(1993)

M.A. Gorriti et al.

Chronic (-)-delta9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats

Eur J Pharmacol

(1999)

N.B. Urban et al.

Dopamine release in chronic cannabis users: A [(11)C]raclopride positron emission tomography study

Biol Psychiatry

(2012)

I.H. Akinci et al.

Concordance between verbal report and urine screen of recent marijuana use in adolescents

Addict Behav

(2001)

O.J. Mason et al.

The Psychotomimetic States Inventory (PSI): Measuring psychotic-type experiences from ketamine and cannabis

Schizophr Res

(2008)

C. Studholme et al.

Automated 3-D registration of MR and CT images of the head

Med Image Anal

(1996)

A. Egerton et al.

The test–retest reliability of 18F-DOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function

Neuroimage

(2010)

F.E. Turkheimer et al.

Multi-resolution Bayesian regression in PET dynamic studies using wavelets

Neuroimage

(2006)

D.E. Walters et al.

Perinatal exposure to cannabinoids alters neurochemical development in rat brain

Pharmacol Biochem Behav

(1988)

X. Wu et al.

Effects of chronic delta9-tetrahydrocannabinol on rat midbrain dopamine neurons: An electrophysiological assessment

Neuropharmacology

(2000)

H.H. van Hell et al.

Chronic effects of cannabis use on the human reward system: an fMRI study

Eur Neuropsychopharmacol

(2010)

W.P. Melega et al.

Ethological and 6-[¹⁸F]fluro-_L-DOPA-PET profiles of long-term vulnerability to chronic amphetamine

Behav Brain Res

(1997)

B.Y. Glenthoj et al.

Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender

Biol Psychiatry

(2006)

M. Ashtari et al.

Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use

J Psychiatr Res

(2009)

P.R. Stokes et al.

Can recreational doses of THC produce significant dopamine release in the human striatum?

Neuroimage

(2009)

M.O. Maykut

Health consequences of acute and chronic marihuana use

Prog Neuropsychopharmacol Biol Psychiatry

(1985)

E.F. Domino et al.

Regional cerebral blood flow and plasma nicotine after smoking tobacco cigarettes

Prog Neuropsychopharmacol Biol Psychiatry

(2004)

World Drug Report

(2010)

J.C. Anthony et al.

Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: Basic findings from the National Comorbidity Survey

Exp Clin Psychopharmacol

J. Reith et al.

Elevated dopa decarboxylase activity in living brain of patients with psychosis

Proc Natl Acad Sci U S A

(1994)

A. Breier et al.

Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method

Proc Natl Acad Sci U S A

(1997)

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Molecular brain differences and cannabis involvement: A systematic review of positron emission tomography studies
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An increasing number of studies have used positron emission tomography (PET) to investigate molecular neurobiological differences in individuals who use cannabis. This study aimed to systematically review PET imaging research in individuals who use cannabis or have cannabis use disorder (CUD).
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria, a comprehensive systematic review was undertaken using the PubMed, Scopus, PsycINFO and Web of Science databases.
In total, 20 studies were identified and grouped into three themes: (1) studies of the dopamine system primarily found that cannabis use was associated with abnormal striatal dopamine synthesis capacity, which was in turn correlated with clinical symptoms; (2) studies of the endocannabinoid system found that cannabis use and CUD are associated with lower cannabinoid receptor type 1 availability and global reductions in fatty acid amide hydrolase binding; (3) studies of brain metabolism found that individuals who use cannabis exhibit lower normalized glucose metabolism in both cortical and subcortical brain regions, and reduced cerebral blood flow in the lateral prefrontal cortex during experimental tasks. Heterogeneity across studies prevented meta-analysis.
Existing PET imaging research reveals substantive molecular differences in cannabis users in the dopamine and endocannabinoid systems, and in global brain metabolism, although the heterogeneity of designs and approaches is very high, and whether these differences are causal versus consequential is largely unclear.
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Preterm adults without brain injury were shown to have normal striatal dopamine synthesis capacity, and preterm adults with perinatal brain injury showed reduced dopamine synthesis capacity (Froudist-Walsh et al., 2017). This latter contrasts with the increased dopamine synthesis capacity typically observed in psychosis patients (Howes and Murray, 2014); however, another risk factor associated with schizophrenia, notably heavy cannabis use, has also been associated with decreased striatal dopamine (Bloomfield et al., 2014). One possibility is that this may be associated with supersensitivity of the dopamine D2 receptor (Murray et al., 2014), and that disruption of normal dopamine signalling either presynptically or postsynaptically may lead to psychosis (Seeman and Seeman, 2014).
Preterm birth is associated with an elevated risk of developmental and adult psychiatric disorders, including psychosis. In this review, we evaluate the implications of neurodevelopmental, cognitive, motor, and social sequelae of preterm birth for developing psychosis, with an emphasis on outcomes observed in adulthood. Abnormal brain development precipitated by early exposure to the extra-uterine environment, and exacerbated by neuroinflammation, neonatal brain injury, and genetic vulnerability, can result in alterations of brain structure and function persisting into adulthood. These alterations, including abnormal regional brain volumes and white matter macro- and micro-structure, can critically impair functional (e.g. frontoparietal and thalamocortical) network connectivity in a manner characteristic of psychotic illness. The resulting executive, social, and motor dysfunctions may constitute the basis for behavioural vulnerability ultimately giving rise to psychotic symptomatology. There are many pathways to psychosis, but elucidating more precisely the mechanisms whereby preterm birth increases risk may shed light on that route consequent upon early neurodevelopmental insult.
Dopaminergic alterations in populations at increased risk for psychosis: A systematic review of imaging findings
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These findings remained significant after covarying for the use of non-cannabis drugs and were not present in the SMST. When subdividing the cannabis group into individuals who met DSM-IV criteria for cannabis dependence or cannabis abuse and individuals who did not, Bloomfield et al. (2014) reported a significantly lower sDSC in the WS of cannabis users who met the criteria for cannabis dependence/abuse compared with cannabis users who did not meet these criteria and compared with non-using controls. Analyses in the striatal subdivisions only revealed significantly lower sDSC in the AST of cannabis dependency/abuse group compared with non-dependence/non-abuse cannabis users.
Alterations of the dopaminergic system may be important neurobiological correlates of vulnerability and transition to psychosis. We systematically reviewed the evidence for dopaminergic alterations demonstrated by in-vivo imaging studies in humans at increased risk of developing psychosis, covering clinical, genetic, and environmental high-risk groups. All 63 included studies utilized Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), or neuromelanin-sensitive Magnetic Resonance Imaging (NM-MRI) methods to collect data concerning the dopaminergic system during rest and/or following pharmacological, behavioural, or cognitive challenges. The current evidence highlights that 1) striatal dopamine D_2/3 receptor availability is unaltered in all three high-risk groups compared with healthy individuals; 2) striatal dopamine synthesis capacity (sDSC) is increased in some clinical and genetic high-risk individuals relative to controls (e.g. people that meet clinical criteria for being at ultra-high risk of developing psychosis and individuals with 22q11.2 deletion syndrome), while sDSC is decreased in cannabis-using environmental high-risk individuals. It seems likely that all three high-risk groups can be stratified into multiple subgroups, with varying risks to develop psychosis, transition rates, and underlying neurobiology. The present results support the hypothesis that dopaminergic abnormalities occur before high-risk individuals develop psychosis.
Synaptic changes induced by cannabinoid drugs and cannabis use disorder
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These inconclusive results may be due to the relatively low sensitivity of this indirect approach and smaller sample sizes in the (Barkus et al., 2011) and (Stokes et al., 2009) studies. Using PET imaging to measure DA synthesis capacity with the precursor 18F-DOPA, Bloomfield and coworkers found evidence of reduced DA synthesis in striatum of regular cannabis users (Bloomfield et al., 2014) (Table 1). The whole striatal dopamine synthesis capacity was correlated with the rate of cannabis use as well as the age of onset of first cannabis exposure in this study, with early onset and heavy drug associated with greater synthesis impairment.
The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.
How adolescent cannabinoid exposure sets the stage for long-term emotional and cognitive dysregulation: Impacts on molecular and neuronal risk pathways
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Emerging clinical and pre-clinical evidence is providing a convergent understanding of the impacts of adolescent cannabinoid exposure on the developing brain. The correlational limitations of clinical studies are being supplemented with important new mechanistic studies using rodent models of adolescent cannabinoid exposure to reveal the precise underlying neuronal, molecular and behavioral mechanisms related to how neurodevelopmental exposure to cannabinoids such as delta-9-tetrahydrocannabinol (THC) may cause increased risk for serious neuropsychiatric disorders like addiction, anxiety disorders and schizophrenia. In particular, the ability of adolescent cannabinoid exposure to profoundly alter dopamine, GABA and glutamate signaling pathways and their associated molecular effectors, has revealed specific biomarkers related to how adolescent cannabinoid exposure increases long-term risks for neuropsychiatric disorders. This chapter will highlight several lines of pre-clinical evidence revealing how cannabinoid transmission in the mammalian brain can regulate emotional processing and cognition in specific mesocorticolimbic circuits. These findings will be discussed in the context of human clinical findings related to the effects of cannabinoids on neuropsychiatric risk and consider how these pathophysiological sequelae may set the stage for increased vulnerability to these disorders later in life.
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The main psychoactive component detected in cannabis–THC–is a neuromodulator substance that acts on dopaminergic transmission (Bloomfield et al., 2016). Several studies using positron emission tomography have highlighted reduced dopamine synthesis capacity in regular cannabis users (Bloomfield et al., 2014), which may be responsible for the decreased oscillatory potential amplitude in our study. Other results also showed reduced dopamine transporter density in regular cannabis users (Leroy et al., 2012), altered dopamine receptor signal transduction and structural abnormalities in dopaminergic neurons (Spiga et al., 2010).
Cannabis is a neuromodulating substance that acts on central synaptic transmission. Regular cannabis use induces a decreased capacity for dopamine synthesis in the brain. The retina is considered an easy means of investigating dysfunctions of synaptic transmission in the brain. We have previously studied the impact of regular cannabis use on retinal function. Using the N95 wave of the pattern electroretinogram, we found a 6 ms-delayed ganglion cells response. Using the b-wave of the photopic flash electroretinogram, we found a 1 ms-delayed bipolar cells response. Here, we investigated amacrine cells function because these cells are located between the bipolar cells and the ganglion cells and contribute to amplifying the signal between these two layers of the retina. We tested the effect of regular cannabis use on these retinal dopaminergic cells. We assessed the role of these cells in amplifying the delay observed previously.
We recorded dark-adapted 3.0 flash ERG oscillatory potentials in 56 regular cannabis users and 29 healthy controls. The amplitude and implicit time of OP1, OP2, OP3 and OP4 were evaluated.
Cannabis users showed a significant decrease in OP2 amplitude (p = 0.029, Mann-Whitney test) and OP3 amplitude (p = 0.024, Mann-Whitney test). No significant difference was found between the groups for OP1 and OP4 amplitude or for the implicit time of oscillatory potentials.
These results reflect the impact of regular cannabis use on amacrine cells function. They highlight abnormalities in dopaminergic transmission and are similar to those found in Parkinson's disease. Oscillatory potentials could be used as markers of central dopaminergic modulation.

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Archival ReportDopaminergic Function in Cannabis Users and Its Relationship to Cannabis-Induced Psychotic Symptoms

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Subject Characteristics and Scan Parameters

Lancet

Neuropsychopharmacology

Res Brain Res Rev

Schizophr Res

Biol Psychiatry

Lancet

Schizophr Res

Psychiatry Res

Neurosci Lett

Neuropharmacology

Behav Brain Res

Eur J Pharmacol

Biol Psychiatry

Addict Behav

Schizophr Res

Med Image Anal

Neuroimage

Neuroimage

Pharmacol Biochem Behav

Neuropharmacology

Eur Neuropsychopharmacol

Behav Brain Res

Biol Psychiatry

J Psychiatr Res

Neuroimage

Prog Neuropsychopharmacol Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

World Drug Report

Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: Basic findings from the National Comorbidity Survey

Exp Clin Psychopharmacol

Du Haschisch et de l’alienation mentale

The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis

Neuropsychopharmacology

High-potency cannabis and the risk of psychosis

Br J Psychiatry

Addiction: Beyond dopamine reward circuitry

Proc Natl Acad Sci U S A

Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: A combined [18F]DOPA and [18F]DMFP PET study in detoxified alcoholic patients

Am J Psychiatry

Imaging dopamine transmission in cocaine dependence: Link between neurochemistry and response to treatment

Am J Psychiatry

Decreased dopamine activity predicts relapse in methamphetamine abusers

Mol Psychiatry

The dopamine hypothesis of schizophrenia: Version III—the final common pathway

Schizophr Bull

Molecular imaging studies of the striatal dopaminergic system in psychosis and predictions for the prodromal phase of psychosis

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Proc Natl Acad Sci U S A

Archival Report
Dopaminergic Function in Cannabis Users and Its Relationship to Cannabis-Induced Psychotic Symptoms