5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice

Jefferson, Sarah J.; Gregg, Ian; Dibbs, Mark; Liao, Clara; Wu, Hao; Davoudian, Pasha A; Woodburn, Samuel C.; Wehrle, Patrick H; Sprouse, Jeffrey; Sherwood, Alexander M.; Kaye, Alfred; Pittenger, Christopher; Kwan, Alex C.

doi:10.1038/s41386-023-01572-w

Cited by 23 publications

(6 citation statements)

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“…Previous research on the behavioral effects of psilocybin measured HTRs as a dose-dependent indicator of psychedelic drug effects 22,23 . Here, we successfully replicated previous findings of the HTR time-course by manually labeling video for each occurrence of a HTR, after both psilocybin (n=1 mouse) and saline injections (n=1 mouse; figure 4c, supplemental videos S1 and S2).…”

Section: Resultsmentioning

confidence: 99%

Psilocybin biphasically modulates cortical and behavioral activity in mice

Brockett,

Francis

2024

Preprint

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Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted 2-photon imaging experiments in auditory cortex of awake mice and video analysis of mouse behavior, both at baseline and during psilocybin treatment. We found biphasic effects of psilocybin on behavioral and cortical activity. A 2 mg/kg dose of psilocybin initially increased behavioral activity and neural responses to sound. 30 minutes post-dose, mice became behaviorally hypoactive and cortical responses to sound decreased, while neural response variance and noise correlations increased. In contrast, neuronal selectivity for auditory stimuli remained stable during psilocybin treatment. Our results suggest that psilocybin modulates the role of intrinsic versus stimulus-driven activity in sensory cortex, while preserving fundamental sensory processing.

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Section: Resultsmentioning

confidence: 99%

Psilocybin biphasically modulates cortical and behavioral activity in mice

Brockett,

Francis

2024

Preprint

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“… 2 , 143 , 144 Some implicate NMDAR, AMPAR, and Eprhin B2 to be involved in 5‐MeO‐DMT's neuroplastic effects, 64 whereas others hint to the 5‐HT 2A receptor 61 or do not mention any signalling pathways at all. 62 , 63 Recently, preclinical findings with classical serotonergic psychedelics (i.e., psilocybin, LSD, DMT, and DOI) indicate that neuroplasticity primarily involves TrkB and mTor receptors 191 , 192 , 193 and that TrkB‐signalling with psilocybin and LSD is independent of 5‐HT 2A activation. 191 Future research should exemplify whether 5‐MeO‐DMT is involved in TrkB‐signalling due to its promotion of brain‐derived neurotrophic factor and subsequent antidepressant effects following the atypical psychedelic ketamine 194 , 195 and conventional antidepressants.…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, a single dose of 5‐MeO‐DMT was demonstrated to increase dendritic spine density in layer V pyramidal neurons of the PFC in wild‐type mice compared with 5‐HT 2A knockout mice. 61 Others have shown neuroplastic effects in the medial frontal cortex with increases in dendritic spine density lasting for 1 month, 62 whereas others showed both neuroplastic effects and neurogenesis in the dentate gyrus of the hippocampus with more complex dendritic morphology and newborn granule cells, respectively. 63 Moreover, 5‐MeO‐DMT has modulatory effects on proteins in human cerebral organoids with long‐term potentiation and the formation of dendritic spines (i.e., cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization) through several plasticity‐related intracellular pathways, such as NMDAR, AMPAR, and Eprhin B2.…”

Section: Potential Therapeutic Mechanisms Of Action Of 5‐me...mentioning

confidence: 99%

“… 63 Moreover, 5‐MeO‐DMT has modulatory effects on proteins in human cerebral organoids with long‐term potentiation and the formation of dendritic spines (i.e., cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization) through several plasticity‐related intracellular pathways, such as NMDAR, AMPAR, and Eprhin B2. 64 Accordingly, many other authors posit that the neuroplastic effects account for the observed antidepressant effects in human use of 5‐MeO‐DMT, 61 , 62 , 63 particularly due to the widely established observation of structural and functional alterations in key brain regions (i.e., medial frontal cortex and hippocampus) involved in the pathophysiology of MDD 141 , 142 and AUD. 2 , 143 , 144 …”

Section: Potential Therapeutic Mechanisms Of Action Of 5‐me...mentioning

confidence: 99%

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The potential of 5‐methoxy‐N,N‐dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action

Tap

2024

Addiction Biology

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Alcohol use disorder (AUD) remains one of the most prevalent psychiatric disorders worldwide with high economic costs. Current treatment options show modest efficacy and relapse rates are high. Furthermore, there are increases in the treatment gap and few new medications have been approved in the past 20 years. Recently, psychedelic‐assisted therapy with psilocybin and lysergic acid diethylamide has garnered significant attention in the treatment of AUD. Yet, they require significant amounts of therapist input due to prolonged subjective effects (~4–12 h) leading to high costs and impeding implementation. Accordingly, there is an increasing interest in the rapid and short‐acting psychedelic 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT). This paper offers a first look at potential therapeutic mechanisms for AUD by reviewing the current literature on 5‐MeO‐DMT. Primarily, 5‐MeO‐DMT is able to induce mystical experiences and ego‐dissolution together with increases in psychological flexibility and mindfulness. This could decrease AUD symptoms through the alleviation of psychiatric mood‐related comorbidities consistent with the negative reinforcement and self‐medication paradigms. In addition, preliminary evidence indicates that 5‐MeO‐DMT modulates neural oscillations that might subserve ego‐dissolution (increases in gamma), psychological flexibility and mindfulness (increases in theta), and the reorganization of executive control networks (increases in coherence across frequencies) that could improve emotion regulation and inhibition. Finally, animal studies show that 5‐MeO‐DMT is characterized by neuroplasticity, anti‐inflammation, 5‐HT2A receptor agonism, and downregulation of metabotropic glutamate receptor 5 with clinical implications for AUD and psychiatric mood‐related comorbidities. The paper concludes with several recommendations for future research to establish the purported therapeutic mechanisms of action.

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“…During these transformative experiences individuals report enhanced states of awareness that can produce lasting positive effects on subjective well-being, social attitude, and perceived meaning in life (46)(47)(48)(49). Preclinical studies show that these psychoactive substances can modify spine density (50)(51)(52)(53) or synaptic proteins (54-58) in brain structures that are involved in cognitive control as well as learning and memory. Despite abuse liability, data suggest potential beneficial effects of ketamine and psychedelics in the treatment of SUDs caused by alcohol (59-62), cocaine (63)(64)(65)(66)(67) or opioids (68-70).…”

Section: Introductionmentioning

confidence: 99%

Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review

et al. 2023

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BackgroundKetamine and psychedelics have abuse liability. They can also induce “transformative experiences” where individuals experience enhanced states of awareness. This enhanced awareness can lead to changes in preexisting behavioral patterns which could be beneficial in the treatment of substance use disorders (SUDs). Preclinical and clinical studies suggest that ketamine and psychedelics may alter markers associated with synaptic density, and that these changes may underlie effects such as sensitization, conditioned place preference, drug self-administration, and verbal memory performance. In this scoping review, we examined studies that measured synaptic markers in animals and humans after exposure to ketamine and/or psychedelics.MethodsA systematic search was conducted following PRISMA guidelines, through PubMed, EBSCO, Scopus, and Web of Science, based on a published protocol (Open Science Framework, DOI: 10.17605/OSF.IO/43FQ9). Both in vivo and in vitro studies were included. Studies on the following synaptic markers were included: dendritic structural changes, PSD-95, synapsin-1, synaptophysin-1, synaptotagmin-1, and SV2A.ResultsEighty-four studies were included in the final analyses. Seventy-one studies examined synaptic markers following ketamine treatment, nine examined psychedelics, and four examined both. Psychedelics included psilocybin/psilocin, lysergic acid diethylamide, N,N-dimethyltryptamine, 2,5-dimethoxy-4-iodoamphetamine, and ibogaine/noribogaine. Mixed findings regarding synaptic changes in the hippocampus and prefrontal cortex (PFC) have been reported when ketamine was administered in a single dose under basal conditions. Similar mixed findings were seen under basal conditions in studies that used repeated administration of ketamine. However, studies that examined animals during stressful conditions found that a single dose of ketamine counteracted stress-related reductions in synaptic markers in the hippocampus and PFC. Repeated administration of ketamine also counteracted stress effects in the hippocampus. Psychedelics generally increased synaptic markers, but results were more consistently positive for certain agents.ConclusionKetamine and psychedelics can increase synaptic markers under certain conditions. Heterogeneous findings may relate to methodological differences, agents administered (or different formulations of the same agent), sex, and type of markers. Future studies could address seemingly mixed results by using meta-analytical approaches or study designs that more fully consider individual differences.

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5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice

Cited by 23 publications

References 76 publications

Psilocybin biphasically modulates cortical and behavioral activity in mice

Psilocybin biphasically modulates cortical and behavioral activity in mice

The potential of 5‐methoxy‐N,N‐dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action

Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review

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