Lisa-Marie Greenwood1,2, Samantha J Broyd3, Hendrika H van Hell3, Juanita Todd4, Alison Jones5, Robin M Murray6, Rodney J Croft3, Patricia T Michie4, Nadia Solowij7,3. 1. Research School of Psychology, Australian National University, Canberra, ACT, Australia. lisa-marie.greenwood@anu.edu.au. 2. The Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), New Lambton Heights, NSW, Australia. lisa-marie.greenwood@anu.edu.au. 3. School of Psychology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia. 4. School of Psychology and Priority Research Centre for Brain and Mental Health, University of Newcastle, Newcastle, NSW, Australia. 5. Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia. 6. Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 7. The Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), New Lambton Heights, NSW, Australia.
Abstract
RATIONALE: Mismatch negativity (MMN) is a candidate endophenotype for schizophrenia subserved by N-methyl-D-aspartate receptor (NMDAR) function and there is increasing evidence that prolonged cannabis use adversely affects MMN generation. Few human studies have investigated the acute effects of cannabinoids on brain-based biomarkers of NMDAR function and synaptic plasticity. OBJECTIVES: The current study investigated the acute effects of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone and in combination on the mismatch negativity (MMN). METHODS: In a randomised, double-blind, crossover placebo-controlled study, 18 frequent and 18 less-frequent cannabis users underwent 5 randomised drug sessions administered via vaporiser: (1) placebo; (2) THC 8 mg; (3) CBD 400 mg; (4) THC 8 mg + CBD 4 mg [THC + CBDlow]; (5) THC 12 mg + CBD 400 mg [THC + CBDhigh]. Participants completed a multifeature MMN auditory oddball paradigm with duration, frequency and intensity deviants (6% each). RESULTS: Relative to placebo, both THC and CBD were observed to increase duration and intensity MMN amplitude in less-frequent users, and THC also increased frequency MMN in this group. The addition of low-dose CBD added to THC attenuated the effect of THC on duration and intensity MMN amplitude in less-frequent users. The same pattern of effects was observed following high-dose CBD added to THC on duration and frequency MMN in frequent users. CONCLUSIONS: The pattern of effects following CBD combined with THC on MMN may be subserved by different underlying neurobiological interactions within the endocannabinoid system that vary as a function of prior cannabis exposure. These results highlight the complex interplay between the acute effects of exogenous cannabinoids and NMDAR function. Further research is needed to determine how this process normalises after the acute effects dissipate and following repeated acute exposure.
RATIONALE: Mismatch negativity (MMN) is a candidate endophenotype for schizophrenia subserved by N-methyl-D-aspartate receptor (NMDAR) function and there is increasing evidence that prolonged cannabis use adversely affects MMN generation. Few human studies have investigated the acute effects of cannabinoids on brain-based biomarkers of NMDAR function and synaptic plasticity. OBJECTIVES: The current study investigated the acute effects of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone and in combination on the mismatch negativity (MMN). METHODS: In a randomised, double-blind, crossover placebo-controlled study, 18 frequent and 18 less-frequent cannabis users underwent 5 randomised drug sessions administered via vaporiser: (1) placebo; (2) THC 8 mg; (3) CBD 400 mg; (4) THC 8 mg + CBD 4 mg [THC + CBDlow]; (5) THC 12 mg + CBD 400 mg [THC + CBDhigh]. Participants completed a multifeature MMN auditory oddball paradigm with duration, frequency and intensity deviants (6% each). RESULTS: Relative to placebo, both THC and CBD were observed to increase duration and intensity MMN amplitude in less-frequent users, and THC also increased frequency MMN in this group. The addition of low-dose CBD added to THC attenuated the effect of THC on duration and intensity MMN amplitude in less-frequent users. The same pattern of effects was observed following high-dose CBD added to THC on duration and frequency MMN in frequent users. CONCLUSIONS: The pattern of effects following CBD combined with THC on MMN may be subserved by different underlying neurobiological interactions within the endocannabinoid system that vary as a function of prior cannabis exposure. These results highlight the complex interplay between the acute effects of exogenous cannabinoids and NMDAR function. Further research is needed to determine how this process normalises after the acute effects dissipate and following repeated acute exposure.
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