Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia
Open accessAbstract
Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for at least several months after cessation of treatment. The behaviors are consistent with those observed in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction. In order to elucidate molecular changes that underlie these aberrant behaviors, we chronically treated rats with LSD and performed RNA-Sequencing on the medial prefrontal cortex (mPFC), an area highly associated with both the actions of LSD and the pathophysiology of schizophrenia and other psychiatric illnesses. We observed widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes observed with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering analysis indicates differentially expressed genes are enriched in pathways involving neurotransmission (Drd2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metabolism (Atp5d, Ndufa1) and neuropeptide signaling (Npy, Bdnf), among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia, and genes affected by LSD are enriched with putative schizophrenia genes. Our results provide a relatively comprehensive analysis of mPFC transcriptional regulation in response to chronic LSD, and indicate that the long-term effects of LSD may bear relevance to psychiatric illnesses, including schizophrenia.
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Evidence from in vivo studies investigating subacute and long-term, but not acute, effects of repeated administration of psychedelics (n = 3) show that DMT and LSD stimulate neurogenesis.
“Evidence from in vivo studies investigating subacute and long-term, but not acute, effects of repeated administration of psychedelics (n = 3) show that DMT and LSD stimulate neurogenesis (41, 60, 61).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [61]
The Abstract reports an in vivo rat study of repeated LSD administration and persistent changes in gene expression. The Discussion (§4.1) links those changes to synaptic plasticity, but does not show that LSD stimulates neurogenesis; the paper also does not report a DMT experiment. Its phrase “neurogenetic state” refers here to gene-expression changes, not demonstrated formation of new neurons. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAmong the genes upregulated by chronic LSD in rat mPFC were Bdnf, Egr2, Nor-1, Nr2a, and Npy.
“Among the upregulated genes were Bdnf , Egr2, Nor-1, Nr2a, and Npy.”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [61]
The Discussion (§4.1; page unavailable) explicitly reports increased Bdnf mRNA after chronic LSD. It identifies Nor1 and Npy as regulated, and the Abstract identifies Nr2a as differentially expressed, but those passages do not establish that they were upregulated. The copy also reports an increase in Krox20 mRNA without explicitly identifying it as Egr2. (LLM, conf=0.82)
Experimental — accuracy not yet measuredChronic LSD treatment (0.16 mg/kg i.p., every other day for 90 days) in rats increased the expression of plasticity-related genes in the mPFC 4 weeks after treatment cessation.
“Chronic treatment with LSD (0.16 mg/kg i.p., every other day for 90 days) increased the expression of plasticity-related genes in the mPFC of rats (n = 10), 4 weeks after treatment cessation (61).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [61]
Cortical bdnf mRNA was upregulated by LSD and ayahuasca.
“Cortical bdnf mRNA was upregulated by LSD and ayahuasca (61, 63).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [61]
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References 64 · Cited by 67
Research works printed but not linked: 1
- Freedman DX LSD: The Bridge from Human to Animal 1984 New York Raven Press
- Authors
- Martin, D. A., Marona-Lewicka, D., Nichols, D. E., & Nichols, C. D.
- Affiliations
- Louisiana State University Health Sciences Center New Orleans (US)
- Purdue University West Lafayette (US)
- Corresponding author
- Nichols, David E.
- Nichols, Charles D.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 83
- Pages
- 1-8
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC4098645
- OpenAlex
- W2083534769
- Semantic Scholar
- ead8c2a47d8caa7932a14cc5a8cd37092607a383
- Cited by
- 67
- References
- 64
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 1 · 2022: 9 · 2021: 10 · 2020: 9 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 2
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- School of Medicine, Vanderbilt University
- National Institute of Mental Health (R01MH083689, MH083689)
- National Institute on Drug Abuse (DA 02189, R01DA002189, R56DA002189)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- lysergic acid diethylamide, LSD, chronic drug exposure, schizophrenia, medial prefrontal cortex, gene expression profiling, transcriptional regulation, hyperactivity, anergia, social interaction deficits, synaptic plasticity, neurotransmission, energy metabolism, neuropeptide signaling, DRD2, GABRB1, brain-derived neurotrophic factor, neuropeptide Y, animal models of schizophrenia
- MeSH terms
- Animals, Gene Expression Regulation, Lysergic Acid Diethylamide, Male, Schizophrenia, Gene Expression, Rats, Sprague-Dawley, Prefrontal Cortex, Rats
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