Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD.
D. Kelley, Katy Venable, Aspasia Destouni, Gerald Billac, Philip Jesudason Ebenezer, Krisztian Stadler, Charles D. Nichols, Steven A. Barker, Joseph Francis
ACS Chemical Neuroscience January 6, 2022 DOI: 10.1021/acschemneuro.1c00660 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study with in vitro assays Peer reviewed |
|---|---|
| Population | Rats exposed to a 30-day stress regimen |
| Interventions | DMT harmaline |
| Dose | DMT 2 mg/kg IP, harmaline 1.5 mg/kg IP |
| Duration | Every other day for 5 days following a 30-day stress regimen |
| Topics | DMT PTSD |
| Citations | 41 |
| Key points | DMT and pharmahuasca reduce reactive oxygen species production and normalize expression of genes overlapping between a rat stress model and human PTSD. |
Abstract
Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress, and inflammation. Animal models have recapitulated features of PTSD, but no comparative RNA sequencing analysis of differentially expressed genes (DEGs) in the brain between PTSD and animal models of traumatic stress has been carried out. We compared DEGs from the prefrontal cortex (PFC) of an established stress model to DEGs from the dorsolateral PFC (dlPFC) of humans. We observed a significant enrichment of rat DEGs in human PTSD and identified 20 overlapping DEGs, of which 17 (85%) are directionally concordant. N,N-dimethyltryptamine (DMT) is a known indirect antioxidant, anti-inflammatory, and neuroprotective compound with antidepressant and plasticity-facilitating effects. We tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline, and "pharmahuasca" (DMT + harmaline) to reduce reactive oxygen species (ROS) production and inflammatory gene expression and to modulate neuroplasticity-related gene expression in the model. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), pharmahuasca, or vehicle every other day for 5 days, following a 30 day stress regiment. We measured ROS production in the PFC and hippocampus (HC) by electron paramagnetic resonance spectroscopy and sequenced total mRNA in the PFC. We also performed in vitro assays to measure the affinity and efficacy of DMT and harmaline at 5HT2AR compared to 5-HT. DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had mixed effects. Treatments normalized 9, 12, and 14 overlapping DEGs, and pathway analysis implicated that genes were involved in ROS production, inflammation, growth factor signaling, neurotransmission, and neuroplasticity.
Comparable studies
Other preclinical and animal studies on DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Mice and cell lines | 2009 | Experimental study | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by l‐tryptophan or 5‐methoxy‐N,N‐dimethyltryptamine in rats treated with a monoamine oxidase inhibitor Rats | 1971 | Experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study |
Citations in the library
Cited by 31
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment Neuropharmacology January 13, 2023
- Psychedelic-Induced Neural Plasticity: A Comprehensive Review and a Discussion of Clinical Implications. Brain Sciences January 25, 2025
- Exploring DMT: Endogenous role and therapeutic potential. Neuropharmacology May 1, 2025
- The evolution of N, N-Dimethyltryptamine: from metabolic pathways to brain connectivity. Psychopharmacology April 11, 2025
and 26 more in the library
Cites 39
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science February 13, 2009
- Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report Brazilian Journal of Psychiatry March 1, 2015
and 34 more in the library