Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder

Abstract

Recent clinical and preclinical evidence points towards empathogenic and prosocial effects elicited by psychedelic compounds, notably the serotonin 5-HT2A agonists lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), and their derivatives. These findings suggest a therapeutic potential of psychedelic compounds for some of the behavioural traits associated with autism spectrum disorder (ASD), a neurodevelopmental condition characterized by atypical social behaviour. In this review, we highlight evidence suggesting that psychedelics may potentially ameliorate some of the behavioural atypicalities of ASD, including reduced social behaviour and highly co-occurring anxiety and depression. Next, we discuss dysregulated neurobiological systems in ASD and how they may underlie or potentially limit the therapeutic effects of psychedelics. These phenomena include: 1) synaptic function, 2) serotonergic signaling, 3) prefrontal cortex activity, and 4) thalamocortical signaling. Lastly, we discuss clinical studies from the 1960s and 70s that assessed the use of psychedelics in the treatment of children with ASD. We highlight the positive behavioural outcomes of these studies, including enhanced mood and social behaviour, as well as the adverse effects of these trials, including increases in aggressive behaviour and dissociative and psychotic states. Despite preliminary evidence, further studies are needed to determine whether the benefits of psychedelic treatment in ASD outweigh the risks associated with the use of these compounds in this population, and if the 5-HT2A receptor may represent a target for social-behavioural disorders.

Effects of repeated lysergic acid diethylamide (LSD) on the mouse brain endocannabinoidome and gut microbiome

“…This latter finding is in line with reports that this genus is increased in the cecum of a genetic autism mouse model in association with altered social behaviour (Golubeva et al, 2017). These data also suggest the interesting possibility that LSD treatment of rodent models of autism spectrum disorder, or indeed patients, may induce changes in gut microbiota composition that revert it to that more representative of control animals or healthy humans, in conjunction with improvements in social behaviour (Markopoulos et al, 2021; Sigafoos et al, 2007).…”

“…Bifidobacterium abundance is decreased in the faeces of children diagnosed with autism spectrum disorder (Coretti et al, 2018; Wang et al, 2011), whereas Bifidobacterium‐ and Lactobacillus‐ based probiotics improve autism spectrum disorder and gastrointestinal symptoms by increasing Bifidobacteria (Shaaban et al, 2018) and GABA and decreasing inflammation (Kong et al, 2022). Therefore, the expansion of Bifidobacterium elicited by LSD could represent a mechanism of psychological and gastrointestinal therapeutic improvement in individuals with autism spectrum disorder (Markopoulos et al, 2021; Sigafoos et al, 2007). The Dubosiella genus was also increased by LSD.…”

Examining associations between MDMA/ecstasy and classic psychedelic use and impairments in social functioning in a U.S. adult sample

“…In addition, a pharmacological fMRI study by Preller et al found that classic psychedelics modulate multiple aspects of social cognition via serotonin 2A receptor agonist activity, and these researchers thus suggest that these substances may treat social impairments related to mental health disorders 40 . Further basic and clinical evidence supports the possibility that classic psychedelics might have a role to play in the treatment of social impairments related to mental illness as well 41 , 42 .…”

The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology

“…Furthermore, many clinical studies carried out in the 60s and 70s investigated the possible use of LSD for the treatment of people with ASD and positive evidence emerged. However, this aspect needs to be investigated further with additional studies and clinical trials [ 29 ]. Different clinical trials also reported a positive effect of LSD in the context of alcohol-related disorders; indeed, a meta-analysis of randomized controlled trials concluded that a single dose of LSD is associated with a significant decrease in alcohol misuse [ 244 ].…”

“…To date, there have been promising clinical trials of PAP with LSD, psilocybin and ibogaine to combat drug, alcohol and nicotine addiction [ 25 , 26 , 27 , 28 ]. Recently, potential applications have been found in the treatment of anxiety, obsessive compulsive disorders, major depression, autism spectrum disorders, and, finally, in delaying cognitive decline [ 27 , 29 , 30 , 31 , 32 , 33 ].…”