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Anxiety disorders (ADs) represent the sixth leading cause of disability worldwide, resulting in a significant global economic burden. Over 50% of individuals with ADs do not respond to standard therapies, making the identification of more effective anxiolytic drugs an ongoing research priority. In this work, we review the preclinical literature concerning the effects of lysergic acid diethylamide (LSD) on anxiety-like behaviors in preclinical models, and the clinical literature on anxiolytic effects of LSD in healthy volunteers and patients with ADs. Preclinical and clinical findings show that even if LSD may exacerbate anxiety acutely (both in "microdoses" and "full doses"), it induces long-lasting anxiolytic effects. Only two randomized controlled trials combining LSD and psychotherapy have been performed in patients with ADs with and without life-threatening conditions, showing a good safety profile and persisting decreases in anxiety outcomes. The effect of LSD on anxiety may be mediated by serotonin receptors (5-HT1A/1B, 5-HT2A/2C, and 5-HT7) and/or transporter in brain networks and circuits (default mode network, cortico-striato-thalamo-cortical circuit, and prefrontal cortex-amygdala circuit), involved in the modulation of anxiety. It remains unclear whether LSD can be an efficacious treatment alone or only when combined with psychotherapy, and if "microdosing" may elicit the same sustained anxiolytic effects as the "full doses". Further randomized controlled trials with larger sample size cohorts of patients with ADs are required to clearly define the effective regimens, safety profile, efficacy, and feasibility of LSD for the treatment of ADs., (© 2023. Springer Nature Switzerland AG.)

Aim: Psychedelic compounds elicit relief from mental disorders. However, the underpinnings of therapeutic improvement remain poorly understood. Here, we investigated the effects of repeated lysergic acid diethylamide (LSD) on whole-genome DNA methylation and protein expression in the mouse prefrontal cortex (PFC)., Methods: Whole genome bisulphite sequencing (WGBS) and proteomics profiling of the mouse prefrontal cortex (PFC) were performed to assess DNA methylation and protein expression changes following 7 days of repeated LSD administration (30 μg/kg/day); a treatment we previously found to potentiate excitatory neurotransmission and to increase dendritic spine density in the PFC in mice. qRT-PCR was employed to validate candidate genes detected in both analyses., Results: LSD significantly modulated DNA methylation in 635 CpG sites of the mouse PFC, and in an independent cohort the expression level of 178 proteins. Gene signaling pathways affected are involved in nervous system development, axon guidance, synaptic plasticity, quantity and cell viability of neurons and protein translation. Four genes and their protein product were detected as differentially methylated and expressed, and their transcription was increased. Specifically, Coronin 7 (Coro7), an axon guidance cue; Penta-EF-Hand Domain Containing 1 (Pef1), an mTORC1 and cell cycle modulator; Ribosomal Protein S24 (Rps24), required for pre-rRNA maturation and biogenesis of proteins involved with cell proliferation and migration, and Abhydrolase Domain Containing 6, Acylglycerol Lipase (Abhd6), a post-synaptic lipase., Conclusions: LSD affects DNA methylation, altering gene expression and protein expression related to neurotropic-, neurotrophic- and neuroplasticity signaling. This could represent a core mechanism mediating the effects of psychedelics., Competing Interests: Declaration of Competing Interest D.D.G. is a consultant at Diamond Therapeutics Inc., Toronto, ON, Canada. D.D.G. and G.G. are inventors of a pending patent on the method-of-use of LSD., (Copyright © 2022. Published by Elsevier Inc.)

Background: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive., Methods: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose-response effects of cumulative LSD doses (5-160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex., Results: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose-response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D 2 ) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex., Conclusion: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D 2 -mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases., (Copyright © 2021 the authors.)

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT 2A , but not N -methyl-D-aspartate (NMDA) and 5-HT 1A , synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons ( Raptor f/f :Camk2alpha-Cre ), the prosocial effects of LSD and the potentiation of 5-HT 2A /AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC ( Raptor f/f :Gad2-Cre ), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT 2A /AMPA receptors and mTOR signaling. The activation of 5-HT 2A /AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder., Competing Interests: Competing interest statement: G.G. is a consultant at Diamond Therapeutics Inc, Toronto, ON, Canada. G.G. and D.D.G. are inventors of a provisional patent regarding the use of LSD., (Copyright © 2021 the Author(s). Published by PNAS.)

Depression and anxiety are psychiatric diagnoses commonly associated with low quality of life and low percentage of responsiveness by patients treated with currently available drugs. Thus, research into alternative compounds to treat these disorders is essential to guarantee a patient's remission. The last decade has witnessed a revamped interest for the application of psychedelic medicine for the treatment of mental disorders due to anecdotal reports and clinical studies which show that low doses of d-lysergic acid diethylamide (LSD) and psilocybin may have antidepressant effects. LSD and psilocybin have demonstrated mood-modulating properties likely due to their capacity to modulate serotonergic (5-HT), dopaminergic (DA) and glutamatergic systems. LSD, belonging to the category of "classic halluginogens," interacts with the 5-HT system through 5HT 1A , and 5HT 2A receptors, with the DA system through D 2 receptors, and indirectly also the glutamatergic neurotransmission thought the recruitment of N-methyl-d-aspartate (NMDA) receptors. Randomized clinical studies have confirmed its antidepressant and anxiolytic effects in humans. Thus, in this chapter, we will review the pharmacology of psychedelic drugs, report the most striking clinical evidence which substantiate the therapeutic potentials of these fascinating compounds in mood disorders, and look into the horizon of where psychedelic medicine is heading., (© 2018 Elsevier B.V. All rights reserved.)

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles' reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD's mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT 2A receptor as a partial agonist and 5-HT 1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D₂, Trace Amine Associate receptor 1 (TAAR₁) and 5-HT 2A . More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD's effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR₁ receptors., Competing Interests: The authors declare that they have no competing interest.

d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT 1 and 5-HT 2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5-20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT 2A and D 2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30-120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D 2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT 1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR 1 ) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT 1A, D 2 and TAAR 1 receptors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Purpose: Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro‐immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown. Experimental Approach: Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid‐like mediators and metabolites were quantified via high‐pressure liquid chromatography with tandem mass spectrometry (HPLC‐MS/MS). Neurotransmitter levels were assessed via HPLC‐UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing. Key Results: LSD increased social preference and novelty and decreased hippocampal levels of the N‐acylethanolamines N‐linoleoylethanolamine (LEA), anandamide (N‐arachidonoylethanolamine) and N‐docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2‐docosahexaenoylglycerol (1/2‐DHG); the prostaglandins D2 (PGD2) and F2α (PGF2α); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline‐treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9. Conclusions and Implications: The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome. [ABSTRACT FROM AUTHOR]