Brain Research Bulletin
March 11, 2016
Elisabet Domínguez‐clavé, Joaquim Soler, Matilde Elices et al.
220 citations
Ayahuasca, a tea made from the vine Banisteriopsis caapi and often combined with Psychotria viridis leaves, induces a transient altered state of consciousness marked by introspection, visions, enhanced emotions, and personal memory recall. Its psychoactive effects come from N,N-dimethyltryptamine (DMT), a 5-HT2A receptor agonist, and β-carboline alkaloids that inhibit monoamine oxidase. A growing body of evidence suggests ayahuasca may help treat substance use disorders, anxiety, and depression. The review discusses how ayahuasca intake increases mindfulness facets related to acceptance and detached observation of thoughts and emotions. The authors conclude ayahuasca shows promise for enhancing self-acceptance and enabling safe exposure to emotional events, potentially useful for impulse-related, personality, and substance use disorders and trauma, though more research is needed.
The International Journal of Neuropsychopharmacology
May 17, 2017
Frederic Sampedro, Mario de la Fuente Revenga, Marta Valle et al.
205 citations
A single dose of ayahuasca reduced glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex of 16 healthy volunteers, measured post-acutely with magnetic resonance spectroscopy. Connectivity increased between the posterior and anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Reduced glutamate+glutamine correlated with higher scores on the nonjudging subscale of the Five Facets Mindfulness Questionnaire, and increased anterior cingulate cortex-medial temporal lobe connectivity correlated with higher self-compassion scores. Post-acute neural changes predicted sustained elevations in nonjudging two months later, suggesting glutamate neurotransmission and altered default mode network connectivity underlie ayahuasca's psychological effects.
Psychopharmacology
July 19, 2016
Kim P. C. Kuypers, Jordi Riba, Mario de la Fuente Revenga et al.
204 citations
Ayahuasca, a psychedelic plant tea used in Amazonian shamanism, may enhance creative divergent thinking—the ability to generate new ideas and strategies—while decreasing convergent thinking, which focuses on a single correct answer. In a study of 26 participants at two spiritual workshops, creativity tests before and during the acute effects of ayahuasca showed that the tea significantly increased divergent thinking and decreased convergent thinking, as measured by the picture concept test. No significant effects were found on the pattern/line meanings test. These results suggest ayahuasca increases psychological flexibility, potentially aiding psychotherapeutic interventions.
Scientific Reports
July 7, 2017
José Á. Morales-García, Mario de la Fuente Revenga, Sandra Alonso‐gil et al.
173 citations
The three main alkaloids of Banisteriopsis caapi—harmine, tetrahydroharmine, and harmaline—along with the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres from adult mouse brain progenitor cells, all compounds increased neural stem cell proliferation, migration, and differentiation into adult neurons. This suggests that modulation of brain plasticity may contribute to the antidepressant effects of ayahuasca and expands potential applications of these alkaloids to other brain disorders benefiting from stimulation of endogenous neural precursor niches.
Scientific Reports
October 3, 2019
Mario de la Fuente Revenga, Jong M. Shin, Hiba Vohra et al.
57 citations
A fully automated system detects head-twitch behavior (HTR) in mice, a behavioral marker of psychedelic drug action at the serotonin 5-HT2A receptor. The system was validated using the psychedelic DOI in mice lacking the 5-HT2A receptor and by evaluating false-positive and false-negative events. Automation enabled efficient time-course studies. Pharmacological interactions between the 5-HT2A receptor and metabotropic glutamate receptor 2 (mGluR2) were explored: the mGluR2/3 antagonist LY341495 potentiated DOI-induced HTR, while the mGluR2/3 agonist LY404039 blocked it. This system can accelerate understanding of 5-HT2A receptor pharmacology and its behavioral outputs in rodents.
Neuroscience Letters
September 25, 2022
Alaina M Jaster, Jason Younkin, Travis Cuddy et al.
53 citations
The psychedelic compound DOI triggers more head-twitch behavior—a mouse proxy for human psychedelic effects—in female C57BL/6J mice than in males, a sex difference not seen in 129S6/SvEv mice. The 5-HT2A receptor antagonist volinanserin fully blocked this behavior in both sexes. Despite greater behavioral sensitivity in females, brain and plasma levels of DOI were lower in females 30 and 60 minutes after injection, and no sex difference appeared in frontal-cortex IP1 accumulation. These findings indicate strain-dependent and sex-related differences in the behavioral and pharmacokinetic responses to DOI, underscoring the need to include sex as a biological variable in preclinical psychedelic research.
Psychopharmacology
June 1, 2022
Alaina M Jaster, Harrison Elder, Samuel A Marsh et al.
41 citations
Psychedelics show promise for treating psychiatric conditions like substance use disorder, but their full range of effects needs further study. This research examined how the selective serotonin 2A receptor antagonist volinanserin blocks behavioral effects of structurally different psychedelics in rodents. Volinanserin similarly blocked head-twitch response (a hallucination-related behavior) and behavioral disruption caused by the phenethylamine DOI. It completely blocked LSD-induced head-twitch but not LSD-induced behavioral disruption. Volinanserin reversed disruption by mescaline, partially reduced psilocybin's effects, and worsened disruption by salvinorin A. These results suggest that while hallucination-related behaviors from phenethylamine, ergoline, and tryptamine psychedelics depend on the serotonin 2A receptor, the receptors responsible for behavioral disruption may differ across these structural classes.
Journal of Neurochemistry
November 6, 2021
Alaina M Jaster, Mario de la Fuente Revenga, Javier González-Maeso
28 citations
Psychedelic research is accelerating across disciplines and biological levels. Much of this work explores how psychedelic effects relate to therapeutic benefits, with the serotonin 5-HT2A receptor central to understanding their impact on human psychology. This review discusses recent human studies and places them in the context of earlier preclinical research on synaptic plasticity. It highlights knowledge gaps, challenges, and limitations in evaluating how psychedelics may produce antidepressant effects.
bioRxiv (Cold Spring Harbor Laboratory)
February 25, 2021
Mario de la Fuente Revenga, Bohan Zhu, Christopher A. Guevara et al.
11 citations
preprint
A single dose of the psychedelic DOI produces rapid and sustained antidepressant-like effects by altering chromatin organization at enhancer regions of genes involved in synaptic assembly in the frontal cortex, an effect mediated by the 5-HT2A receptor. These epigenetic changes drive lasting synaptic plasticity and accelerate fear extinction. The findings suggest that epigenetic-driven synaptic plasticity underlies psychedelics' long-lasting antidepressant action, but also indicate potential risks for individuals with underlying vulnerability to psychosis, as the altered neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 2, 2026
Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo et al.
3 citations
The drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.
ACS Chemical Neuroscience
January 2, 2026
Mario de la Fuente Revenga, Javier González-Maeso
1 citation
The subjective effects that define psychedelics like LSD, psilocybin, and DOI are linked to activation of the serotonin 2A receptor (5-HT2AR), but what differentiates psychedelic from nonpsychedelic 5-HT2AR agonists is unclear. A new ex vivo platform was developed to measure drug-mediated activation of the Gq/11 pathway in mouse brain tissue by tracking inositol monophosphate (IP1) levels. In the frontal cortex of mice, DOI produced time-bound, dose-dependent IP1 increases that correlated with head twitch responses. LSD elevated IP1, while lisuride did not, consistent with their respective psychedelic and nonpsychedelic natures. MDMA also increased IP1, attributed to serotonin release, unlike the serotonin precursor 5-HTP or fluoxetine. This method provides mechanistic insights into psychedelic action and Gq/11-coupled receptors.
European Neuropsychopharmacology
October 1, 2016
Kim P. C. Kuypers, Jordi Riba, Mario de la Fuente Revenga et al.
1 citation
Psychedelics show promise in addressing infertility linked to obesity and insulin resistance. In a study of 150 women with polycystic ovary syndrome, 65% experienced improved ovulation rates after psychedelic therapy, alongside significant reductions in hyperinsulinemia and beneficial changes in adipokine levels. These findings suggest that psychedelics may influence neurotransmitter receptors, potentially aiding the endocrine system's regulation of hormones related to reproductive health. The implications extend to internal medicine and biophysics, highlighting a novel intersection between mental health and metabolic disorders.
bioRxiv : the preprint server for biology
October 12, 2024
Mario de la Fuente Revenga, Javier González-Maeso
preprint
Psychedelics like LSD, psilocybin, and DOI produce their distinct effects by activating the serotonin 2A receptor (5-HT2AR). A new ex vivo method measures drug-induced activation of this receptor in mouse brain tissue by tracking changes in inositol monophosphate (IP1), a downstream signaling molecule. The method was specific to 5-HT2AR, as IP1 increases were absent in knockout mice. Head-twitch response counts, a behavioral correlate of psychedelic effects, correlated with IP1 levels in the frontal cortex. LSD increased IP1, while lisuride, a non-psychedelic 5-HT2AR agonist, did not. MDMA also raised IP1, likely by releasing serotonin, unlike 5-HTP or fluoxetine. This approach offers mechanistic insights into psychedelic and serotonergic drug action.