Global Increases in Brain Glucose Metabolism Following Acute N,N-Dimethyltryptamine and Harmine Administration in Healthy Volunteers: An [¹⁸F]FDG-PET Study

Classical psychedelics such N,N-dimethyltryptamine (DMT), psilocybin, and lysergic acid diethylamide (LSD) 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 neuroimaging studies have examined changes in brain activity, connectivity, and cerebral perfusion under psychedelics, their effects on cerebral glucose metabolism remain largely unexplored. Here, we used positron emission tomography with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG-PET) to assess the cerebral metabolic rate for glucose consumption (CMRglc) following buccal DMT + harmine (90 mg DMT, 120 mg harmine) versus placebo in a single-blind, placebo-controlled, crossover design in (n = 14) healthy males. Scans were acquired during peak drug effects, i.e., 100–170 min post-administration. Global CMRglc increased by 12% under DMT + harmine compared to placebo (t = 2.57, p < 0.05), with relatively greater activation in the right hemisphere. Vertex- and network-wise analyses revealed widespread cortical increases, with localized effects in the default mode, frontoparietal, and attentional networks. Exploratory correlational analyses found a significant positive correlation between global CMRglc and harmine plasma levels (area under the curve (AUC); r = 0.61, p = 0.021) in the DMT + harmine condition, but not with DMT AUC, subjective intensity ratings, or regional serotonin-2A receptor (5-HT2AR) density derived from a publicly available PET atlas. These findings advance the mechanistic understanding of psychedelics by demonstrating that DMT + harmine increases cerebral glucose metabolism, particularly in higher-order networks, and augment pioneering work indicating increased brain glucose metabolism as a potential metabolic signature of the psychedelic state.