Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain

Matthew B. Wall; Tom P. Freeman; Chandni Hindocha; Lysia Demetriou; Natalie Ertl; Abigail M. Freeman; Augustus P.M. Jones; Will Lawn; Rebecca Pope; Claire Mokrysz; Daniel Solomons; Ben Statton; Hannah R. Walker; Yumeya Yamamori; Zixu Yang; Jocelyn L.L. Yim; David J. Nutt; Oliver D. Howes; H. Valerie Curran; Michael A.P. Bloomfield

doi:10.1177/02698811221092506

Individual and combined effects of cannabidiol and Δ⁹-tetrahydrocannabinol on striato-cortical connectivity in the human brain

Matthew B. Wall^*, Tom P. Freeman, Chandni Hindocha, Lysia Demetriou, Natalie Ertl, Abigail M. Freeman, Augustus P.M. Jones, Will Lawn, Rebecca Pope, Claire Mokrysz, Daniel Solomons, Ben Statton, Hannah R. Walker, Yumeya Yamamori, Zixu Yang, Jocelyn L.L. Yim, David J. Nutt, Oliver D. Howes, H. Valerie Curran, Michael A.P. Bloomfield

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

Background: Cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Aims: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). Method: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. Results: Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. Outcomes: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

Original language	English
Pages (from-to)	732-744
Number of pages	13
Journal	Journal of Psychopharmacology
Volume	36
Issue number	6
DOIs	https://doi.org/10.1177/02698811221092506
Publication status	Published - Jun 2022

Keywords

Cannabinoids
cannabis
CBD
fMRI
resting-state
THC

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1177/02698811221092506

Cite this

Wall, M. B., Freeman, T. P., Hindocha, C., Demetriou, L., Ertl, N., Freeman, A. M., Jones, A. P. M., Lawn, W., Pope, R., Mokrysz, C., Solomons, D., Statton, B., Walker, H. R., Yamamori, Y., Yang, Z., Yim, J. L. L., Nutt, D. J., Howes, O. D., Curran, H. V., & Bloomfield, M. A. P. (2022). Individual and combined effects of cannabidiol and Δ⁹-tetrahydrocannabinol on striato-cortical connectivity in the human brain. Journal of Psychopharmacology, 36(6), 732-744. https://doi.org/10.1177/02698811221092506

@article{ef63fdf85850426da9a5576c68c4e56c,

title = "Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain",

abstract = "Background: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Aims: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). Method: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. Results: Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. Outcomes: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.",

keywords = "Cannabinoids, cannabis, CBD, fMRI, resting-state, THC",

author = "Wall, {Matthew B.} and Freeman, {Tom P.} and Chandni Hindocha and Lysia Demetriou and Natalie Ertl and Freeman, {Abigail M.} and Jones, {Augustus P.M.} and Will Lawn and Rebecca Pope and Claire Mokrysz and Daniel Solomons and Ben Statton and Walker, {Hannah R.} and Yumeya Yamamori and Zixu Yang and Yim, {Jocelyn L.L.} and Nutt, {David J.} and Howes, {Oliver D.} and Curran, {H. Valerie} and Bloomfield, {Michael A.P.}",

note = "Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Study 1 was supported by Drug Science and Channel 4 Television. Study 2 was funded by a British Medical Association Foundation for Medical Research Margaret Temple Award to M.A.P.B. M.A.P.B. is funded by a UCL Excellence Fellowship. W.L. is funded by an unrelated Medical Research Council project grant. M.A.P.B., C.H. and H.V.C. are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. T.P.F. was funded by a senior academic fellowship from the Society for the Study of Addiction. Publisher Copyright: {\textcopyright} The Author(s) 2022.",

year = "2022",

month = jun,

doi = "10.1177/02698811221092506",

language = "English",

volume = "36",

pages = "732--744",

journal = "Journal of Psychopharmacology",

issn = "0269-8811",

publisher = "SAGE Publications Ltd STM",

number = "6",

}

Wall, MB, Freeman, TP, Hindocha, C, Demetriou, L, Ertl, N, Freeman, AM, Jones, APM, Lawn, W, Pope, R, Mokrysz, C, Solomons, D, Statton, B, Walker, HR, Yamamori, Y, Yang, Z, Yim, JLL, Nutt, DJ, Howes, OD, Curran, HV & Bloomfield, MAP 2022, 'Individual and combined effects of cannabidiol and Δ⁹-tetrahydrocannabinol on striato-cortical connectivity in the human brain', Journal of Psychopharmacology, vol. 36, no. 6, pp. 732-744. https://doi.org/10.1177/02698811221092506

TY - JOUR

T1 - Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain

AU - Wall, Matthew B.

AU - Freeman, Tom P.

AU - Hindocha, Chandni

AU - Demetriou, Lysia

AU - Ertl, Natalie

AU - Freeman, Abigail M.

AU - Jones, Augustus P.M.

AU - Lawn, Will

AU - Pope, Rebecca

AU - Mokrysz, Claire

AU - Solomons, Daniel

AU - Statton, Ben

AU - Walker, Hannah R.

AU - Yamamori, Yumeya

AU - Yang, Zixu

AU - Yim, Jocelyn L.L.

AU - Nutt, David J.

AU - Howes, Oliver D.

AU - Curran, H. Valerie

AU - Bloomfield, Michael A.P.

N1 - Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Study 1 was supported by Drug Science and Channel 4 Television. Study 2 was funded by a British Medical Association Foundation for Medical Research Margaret Temple Award to M.A.P.B. M.A.P.B. is funded by a UCL Excellence Fellowship. W.L. is funded by an unrelated Medical Research Council project grant. M.A.P.B., C.H. and H.V.C. are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. T.P.F. was funded by a senior academic fellowship from the Society for the Study of Addiction. Publisher Copyright: © The Author(s) 2022.

PY - 2022/6

Y1 - 2022/6

N2 - Background: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Aims: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). Method: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. Results: Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. Outcomes: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

AB - Background: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Aims: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). Method: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. Results: Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. Outcomes: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

KW - Cannabinoids

KW - cannabis

KW - CBD

KW - fMRI

KW - resting-state

KW - THC

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DO - 10.1177/02698811221092506

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