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Preliminary in vivo evidence of lower hippocampal synaptic density in cannabis use disorder

Molecular Psychiatry volume 26, pages 3192–3200 (2021)Cite this article

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Abstract

Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pre- and post-synaptically. Whether similar alterations exist in human cannabis users, has not yet been demonstrated in vivo. Positron emission tomography (PET) and [11C]UCB-J, a radioligand for the synaptic vesicle glycoprotein 2A (SV2A), were used to study hippocampal synaptic integrity in vivo in an equal number (n = 12) of subjects with DSM-5 cannabis use disorder (CUD) and matched healthy controls (HC). Arterial sampling was used to measure plasma input function. [11C]UCB-J binding potential (BPND) was estimated using a one-tissue (1T) compartment model with centrum semiovale as the reference region. Hippocampal function was assessed using a verbal memory task. Relative to HCs, CUDs showed significantly lower [11C]UCB-J BPND in the hippocampus (~10%, p = 0.008, effect size 1.2) and also performed worse on the verbal memory task. These group differences in hippocampal BPND persisted after correction for volume differences (p = 0.013), and correction for both age and volume (p = 0.03). We demonstrate, for the first time, in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. These results are consistent with the microstructural findings from experimental studies with cannabinoids in animals, and studies of hippocampal macrostructure in human with CUD. Whether the lower hippocampal synaptic density resolves with abstinence warrants further study.

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Fig. 1: Comparison of Hippocampal synaptic density ([11C]UCB-J BPND) between Cannabis Use Disorder (CUD) and healthy controls (HC).

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Acknowledgements

The authors would like to acknowledge the efforts of Kim Forselius-Bielen, Alex Selloni, and Harsimar Kaur working in the Schizophrenia Neuropharmacology Research Group at Yale (SNRGY), and staff at the Yale PET Center.

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U.S. National Institute of Drug Abuse.

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  1. These authors contributed equally: Deepak Cyril D’Souza, Rajiv Radhakrishnan

Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Deepak Cyril D’Souza, Rajiv Radhakrishnan, Suhas Ganesh, Mohini Ranganathan, Jose Cortes-Briones & Patrick Skosnik

  2. Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA

    Deepak Cyril D’Souza, Rajiv Radhakrishnan, Mohini Ranganathan, Jose Cortes-Briones & Patrick Skosnik

  3. Schizophrenia Neuropharmacology Research Group at Yale (SNRGY), New Haven, CT, USA

    Deepak Cyril D’Souza, Rajiv Radhakrishnan, Mohini Ranganathan, Jose Cortes-Briones & Patrick Skosnik

  4. Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, USA

    Deepak Cyril D’Souza, Rajiv Radhakrishnan, Suhas Ganesh, Mohini Ranganathan, Jose Cortes-Briones & Patrick Skosnik

  5. Department of Radiology and Biomedical Engineering, Yale University School of Medicine, New Haven, CT, USA

    Mika Naganawa, Nabeel Nabulsi, Soheila Najafzadeh, Jim Ropchan, Yiyun Huang & Richard E. Carson

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Supplementary information

Supplemental Table 1: Effect sizes for group differences in [11C]UCB-J BPND (Rank ordered)

Supplemental Table 2: Effect sizes for group differences in [11C]UCB-J - VT (Rank ordered)

Supplemental Figure 1: Schematic representation of proteins located in the synaptic vesicle membrane

Supplemental Figure 2: Hippocampal [11C]UCB-J binding CUD vs. HC With Partial Volume Correction

41380_2020_891_MOESM5_ESM.pdf

Legend Supplemental Figure 2: Hippocampal [11C]UCB-J binding potential (BPND) in CUD compared to HC With Partial Volume Correction

41380_2020_891_MOESM6_ESM.pdf

Supplemental Figure 3: Relationship between ↓ in Hippocampal [11C]UCB-J binding and ↓ in Total Immediate Recall in CUD (change from HC)

41380_2020_891_MOESM7_ESM.pdf

Legend Supplemental Figure 3: Correlation between Hippocampal [11C]UCB-J binding and AVLT Total Immediate Recall in CUD (change from HC)

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D’Souza, D.C., Radhakrishnan, R., Naganawa, M. et al. Preliminary in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. Mol Psychiatry 26, 3192–3200 (2021). https://doi.org/10.1038/s41380-020-00891-4

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