Molecular psychiatry
September 1, 2023
Kat F Kiilerich, Joe Lorenz, Malthe B Scharff et al.
48 citations
Repeated low doses of psilocybin, similar to human microdosing, were tested in rats. The regimen was well tolerated, causing no signs of anhedonia, anxiety, or altered movement, and did not downregulate or desensitize 5-HT2A receptors. The treatment increased resilience to injection stress, reduced self-grooming (a proxy for compulsive actions), and raised 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
Molecules
April 22, 2021
Paul Cumming, Milan Scheidegger, Dario Dornbierer et al.
45 citations
Hallucinogens such as LSD, psilocybin, and mescaline are being re-evaluated for their psychotherapeutic potential. This narrative review covers in vitro and ex vivo binding studies and molecular imaging using PET or SPECT. Early PET work with [11C]-MBL showed that most specific binding is to serotonin 5-HT2A receptors, but interactions with 5-HT1A receptors and other pathways may contribute to the unique experiences. Other important factors include blood-brain barrier permeability, metabolism, and active metabolites. Only a few PET or SPECT studies of radiolabeled hallucinogens exist, most recently using [11C]Cimbi-36. Hybrid imaging combining PET with fMRI is expected to advance future research.
Synapse
July 14, 2004
Pedro Rosa‐neto, Albert Gjedde, Aage Kristian Olsen Alstrup et al.
39 citations
MDMA (Ecstasy) reduces the binding of two different radioligands to dopamine D2-like receptors in the striatum of living pigs, as measured by PET. The binding potential of [11C]raclopride fell by 35% at 45 minutes and 22% at 165 minutes after MDMA infusion, similar to changes caused by d-amphetamine. Unexpectedly, the binding of [11C]NMSP also decreased, by 30% in the first scan and 50% in the second, unlike its typical insensitivity to dopamine release. The simultaneous release of dopamine and serotonin by MDMA may explain the progressive decline in NMSP binding.
Frontiers in Pharmacology
May 2, 2022
Ilana Berlowitz, Klemens Egger, Paul Cumming
32 citations
Monoamine oxidases (MAOs) are enzymes that break down biogenic amines like serotonin, dopamine, and tyramine in the brain and body. Beta-carboline alkaloids, such as harmine and harmane, are MAO inhibitors found in plants including tobacco and Banisteriopsis caapi, a key ingredient in the Amazonian ayahuasca brew. These beta-carbolines may boost the bioavailability of the hallucinogen DMT and might have antidepressant properties. However, the level of MAO inhibition needed to affect neurotransmitter signaling is not yet known. Unlike synthetic antidepressant MAO inhibitors that cause complete and irreversible inhibition, beta-carbolines are reversible and competitive, making complete inhibition unlikely. Many medicinal plants contain MAO inhibitors, but their pharmacological relevance often remains unclear.
Cellular and molecular life sciences : CMLS
September 10, 2024
Klemens Egger, Helena D Aicher, Paul Cumming et al.
30 citations
The potent hallucinogen N,N-dimethyltryptamine (DMT) alters perception, mood, and cognition, presumably through agonism at serotonin 5-HT1A/2A/2C receptors in the brain. DMT is nearly inactive orally due to rapid first-pass metabolism, but co-administration with β-carbolines or synthetic MAO-A inhibitors—as in the Amazonian brew ayahuasca—greatly increases its bioavailability and duration of action. The synergistic effects of DMT and MAOIs may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for depression, addiction, and post-traumatic stress disorder. Neuroimaging reveals alterations in brain activity, functional connectivity, and network dynamics during DMT-induced altered states.
Synapse
April 5, 2007
Paul Cumming, Mette Møller, Kjeld Benda et al.
28 citations
The psychostimulant MDMA (ecstasy) causes degeneration of serotonin nerve endings in the forebrain of rodents, nonhuman primates, and human users. To study this in a large animal without using primates, researchers used PET scans to map serotonin transporters and 5HT1A receptors in the brains of Göttingen minipigs before and after MDMA treatment. Total doses above 20 mg/kg reduced serotonin transporter binding: a mean 42 mg/kg dose caused a 32% decrease in the midbrain and thalamus and a 53% decrease in forebrain structures. This loss did not consistently alter 5HT1A receptor binding. The number of serotonin-producing neurons in the dorsal raphé nucleus (about 95,000 in normal animals) remained unchanged.
Synapse
January 1, 2005
Luciano Minuzzi, George G. Nomikos, Mark Wade et al.
25 citations
LSD reduces the binding potential of a dopamine D2/3 receptor tracer in the striatum of pigs, suggesting a direct interaction with these receptors. In a PET study, the binding potential of [11C]raclopride decreased by 19% four hours after LSD administration, without changes in cerebral blood flow. In vitro experiments showed LSD displaces the tracer from pig brain tissue with an IC50 of 275 nM, and a two-site model indicated a subnanomolar component comprising 20% of binding. Microdialysis in rats found no changes in dopamine or its metabolites. These findings indicate LSD directly occupies a portion of dopamine D2/3 receptors, which may contribute to its psychoactive effects.
Frontiers in pharmacology
January 1, 2023
Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen et al.
17 citations
Co-administration of harmine with DMT in rats increased brain DMT levels by inhibiting its metabolism to indole-3-acetic acid, yet no significant occupancy of serotonin 5-HT2A receptors by DMT was detected, even at brain DMT concentrations up to 11.3 µM. Low doses of DMT and/or harmine did not significantly alter brain glucose metabolism as measured by [18F]FDG-PET. These preliminary findings suggest that the role of MAO-A inhibition in potentiating DMT's psychedelic effects may be more complex than previously assumed, and further dose-response studies are needed.
January 5, 2023
Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff et al.
5 citations
preprint
Repeated low doses of psilocybin, a serotonergic psychedelic drug, were given to rats in a regimen that mimics human microdosing. The rats tolerated the doses well, showing no signs of anhedonia, anxiety, or altered movement. The treatment did not downregulate or desensitize the 5-HT2A receptor. It did impart resilience against stress from repeated injections and reduced self-grooming frequency, a proxy for compulsive actions. Additionally, it increased 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
International review of neurobiology
January 1, 2025
Paul Cumming, Klemens Egger, Gitte M Knudsen
2 citations
Molecular brain imaging techniques such as PET and SPECT have been used since the 1980s to study psychostimulants, and more recently to investigate psychedelics. Most published research involves SPECT studies of cerebral blood flow and PET studies of metabolism and neuroreceptors, particularly the 5-HT2A receptor, which is primarily responsible for the effects of classical psychedelics. Some evidence documents interactions at dopamine D2/3 receptors in the striatum, but many other potential molecular targets remain unexplored. The growing therapeutic use of psychedelics for neurological and psychiatric disorders highlights the need for broader, systematic investigation of their effects on brain function.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
June 1, 2026
Klemens Egger, Robert Bozsak, Helena D Aicher et al.
A psychedelic dose of DMT combined with harmine (mimicking ayahuasca) globally increased cerebral glucose metabolism by 12.5% in 14 healthy males, as measured by FDG-PET scans during peak drug effects. Widespread cortical increases appeared in higher-order brain networks. Global glucose metabolism correlated positively with harmine plasma levels but not with DMT levels or subjective intensity. This recapitulates a classic finding for psilocybin, suggesting a potential metabolic signature of the psychedelic state.