Global increases in brain glucose metabolism following acute N,N-dimethyltryptamine and harmine administration in...

Classical psychedelics such as N,N-dimethyltryptamine (DMT) modulate consciousness via serotonergic receptor agonism, and are increasingly investigated for their psychotherapeutic potential. When combined with the monoamine oxidase A (MAO-A) inhibitor harmine-mimicking the pharmacological profile of ayahuasca-oral DMT induces a psychedelic experience lasting 4-5 h. While some neuroimaging studies have characterized effects of DMT on functional connectivity and electroencephalography its impact on cerebral energy metabolism remains largely unexplored. We assessed the cerebral metabolic rate for glucose consumption (CMRglc) with [¹⁸F]fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) and linear graphic analysis following buccal DMT + harmine (90 mg DMT, 120 mg harmine) versus placebo in a single-blind, crossover design in 14 healthy males. Scans were acquired during peak drug effects (100-170 min post-administration). Global CMRglc increased by 12.5% under DMT+harmine versus placebo (t = 2.58, p = 0.011). Vertex- and network-wise analyses revealed widespread cortical increases, particularly in higher-order brain networks. Exploratory analyses found a significant positive correlation between global CMRglc and harmine plasma levels, but not with DMT plasma levels, subjective intensity ratings. A psychedelic dose of DMT + harmine globally increased cerebral glucose metabolism, recapitulating a classic finding for psilocybin, and suggesting a potential metabolic signature of the psychedelic state. Clinical trial registry name and URL incl. registration number: Molecular Imaging Study of Harmine/DMT: a Basic Research Approach (HaD-PET) https://clinicaltrials.gov/study/NCT06252506.