EXPRESS: Global Increases in Brain Glucose Metabolism Following Acute N,N-Dimethyltryptamine and Harmine Administration in Healthy Volunteers: A randomised 18 FFDG-PET Study

BACKGROUND: 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 hours. While some neuroimaging studies have characterized effects of DMT on functional connectivity and electroencephalography its impact on cerebral energy metabolism remains largely unexplored. METHODS: We assessed the cerebral metabolic rate for glucose consumption (CMRglc) with 18Ffluorodeoxyglucose positron emission tomography (18FFDG-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). RESULTS: 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. CONCLUSION: 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.