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Observational Study
. 2025 Jun 1;82(6):609-617.
doi: 10.1001/jamapsychiatry.2025.0432.

Convergence of Cannabis and Psychosis on the Dopamine System

Jessica Ahrens  1   2 , Sabrina D Ford  3   4 , Betsy Schaefer  3   4 , David Reese  3   4 , Ali R Khan  3   4   5 , Philip Tibbo  6 , Rachel Rabin  1   2 , Clifford M Cassidy  7 , Lena Palaniyappan  2   3   4   7
Affiliations
Observational Study

Convergence of Cannabis and Psychosis on the Dopamine System

Jessica Ahrens et al. JAMA Psychiatry. .

Abstract

Importance: Despite evidence that individuals with a cannabis use disorder (CUD) are at elevated risk of psychosis and that the neurotransmitter dopamine has a role in psychosis, the mechanism linking cannabis use and psychosis remains unclear.

Objective: To use neuromelanin-sensitive magnetic resonance imaging (MRI), referred to as the neuromelanin-MRI signal, a practical, proxy measure of dopamine function, to assess whether a common alteration in the dopamine system may be implicated in CUD and psychosis and whether this alteration can be observed in those with a CUD whether or not they have a diagnosis of first-episode schizophrenia (FES).

Design, setting, and participants: This longitudinal observational cohort study recruited individuals from 2019 to 2023 from an early psychosis service and the surrounding communities in London, Ontario. The sample included individuals with and without CUD, with some in each group also diagnosed with FES.

Exposures: FES and CUD diagnoses from the Structured Clinical Interview for DSM-5.

Main outcomes and measures: Neuromelanin-MRI signals within the midbrain (substantia nigra [SN]/ventral tegmental area [VTA]) including a subregion previously linked to the severity of untreated psychosis (a priori region of interest). Linear mixed-effects analyses were performed relating neuromelanin-MRI signals to clinical measures.

Results: A total of 36 individuals without CUD (mean [SD] age, 22.3 [3.2] years; 29 male [81%]; 12 with FES) and 25 individuals with CUD (mean [SD] age, 24.3 [4.7] years; 22 male [88%]; 16 with FES) participated in the study. One-year follow-up was completed for 12 individuals with CUD and 25 without CUD. CUD was associated with elevated neuromelanin-MRI signal in a set of ventral SN/VTA voxels (387 of 2060 SN/VTA voxels, corrected P = .03, permutation test). CUD was also associated with elevated neuromelanin-MRI signal in the psychosis-related region of interest (t92 = 2.12, P = .04) with a significant dose-dependent association (higher burden of CUD symptoms associated with higher neuromelanin-MRI signal, F1, 96 = 4.89; P = .03). In contrast, participants with FES did not exhibit a significant elevation in neuromelanin-MRI signal (241 SN/VTA voxels had elevated signal, corrected P = .09). There was no association between time and neuromelanin-MRI signal.

Conclusions and relevance: Elevated dopamine function in a critical SN/VTA subregion may be associated with psychosis risk in people with CUD. Cannabis was associated with the hypothesized final common pathway for the clinical expression of psychotic symptoms.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tibbo reported receiving personal fees from Janssen, Otsuka Lundbeck, AbbVie, and Boehringer Ingelheim outside the submitted work. Dr Cassidy reported receiving funding from Terran Biosciences and having a patent for system, method, and computer-accessible medium for neuromelanin-sensitive magnetic resonance imaging as a noninvasive proxy measure of dopamine function in the human brain licensed to Terran Biosciences. Dr Palaniyappan reported receiving personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, and the Canadian Psychiatric Association; grants from Sunovion, Janssen Canada, and Otsuka Canada; and book royalties from Oxford University Press. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
Figure 2.
Figure 2.. Substantia Nigra/Ventral Tegmental Area Neuromelanin-Sensitive Magnetic Resonance Imaging (NM-MRI) Signal in Participants With Cannabis Use Disorder (CUD) and First-Episode Schizophrenia (FES)
A, Visualization template of the midbrain generated by averaging spatially normalized neuromelanin-MRI signal images from study participants. Magnifications show substantia nigra/ventral tegmental area voxels where the neuromelanin-MRI signal was elevated (red) in participants with cannabis use disorder (CUD) compared with individuals without CUD. Psychosis voxels previously shown to correlate with untreated positive symptoms of psychosis are shown in blue (overlap with cannabis-elevated voxels in violet). These voxels were clustered near the cannabis-elevated voxels. Green voxels are where the neuromelanin-MRI signal was reduced in participants with CUD compared with individuals without CUD. B, Dot plots showing the neuromelanin-MRI signal extracted from psychosis voxels in 4 groups, including healthy controls (HCs), those with a CUD, those with FES, and those with both a CUD and FES. Orange dots represent scans collected at baseline and blue dots at follow-up. C, Dot plots showing the neuromelanin-MRI signal extracted from cannabis voxels in 4 groups; orange dots were collected at baseline and blue dots at follow-up. Error bars represent standard error of the mean.
Figure 3.
Figure 3.. Psychosis Voxel Signal and Cannabis Use Disorder (CUD) Severity
Correlation between CUD severity and mean neuromelanin-sensitive magnetic resonance imaging (neuromelanin-MRI) signal in psychosis voxels, corrected for age, sex, diagnosis, and time.
See this image and copyright information in PMC

References

    1. 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. doi:10.1016/S0140-6736(07)61162-3 - DOI - PubMed
    1. Volkow ND, Baler RD, Compton WM, Weiss SRB. Adverse health effects of marijuana use. N Engl J Med. 2014;370(23):2219-2227. doi:10.1056/NEJMra1402309 - DOI - PMC - PubMed
    1. Atakan Z, Bhattacharyya S, Allen P, et al. . Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers. Psychol Med. 2013;43(6):1255-1267. doi:10.1017/S0033291712001924 - DOI - PubMed
    1. Barkus E, Morrison PD, Vuletic D, et al. . Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study. J Psychopharmacol. 2011;25(11):1462-1468. doi:10.1177/0269881110382465 - DOI - PubMed
    1. Nottage JF, Stone J, Murray RM, et al. . Delta-9-tetrahydrocannabinol, neural oscillations above 20 Hz and induced acute psychosis. Psychopharmacology (Berl). 2015;232(3):519-528. doi:10.1007/s00213-014-3684-1 - DOI - PMC - PubMed

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