Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder

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.


INTRODUCTION
Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting 1-2% of the global population (Chiarotti and Venerosi, 2020). ASD is often diagnosed in childhood, with individuals displaying characteristic atypicalities in social communication and interaction, as well as repetitive patterns of behaviour and restricted interests (American Psychiatric Association, 2013). These features are highly heterogeneous in ASD and are often accompanied with co-occurring diagnoses of depression and anxiety (Rai et al., 2018;Hollocks et al., 2019). At present, there is a lack of selective medications targeting the major phenotypes of ASD: impaired social behaviour and communication.
Psychedelics are currently experiencing a resurgence of scientific investigation, following in the footsteps of pioneering mid-twentieth century research. Although the term "psychedelic" encompasses a variety of compounds, the present review focuses on the serotonergic, or "classical," psychedelics, which produce their hallucinogenic effects via the serotonin 5-HT 2A receptor (De Gregorio et al., 2016a;Holze et al., 2021b;Inserra et al., 2021a). These include lysergic acid diethylamide (LSD), psilocybin, N,Ndimethyltryptamine (DMT), and their derivatives (which will be hereafter referred to as "psychedelics"). Other nonserotonergic psychedelics, such as the empathogen 3,4-Methylenedioxymethamphetamine (MDMA), have also been shown to increase social behaviour and empathy (Bedi et al., 2010;Hysek et al., 2014;Heifets and Malenka, 2016), and to reduce social anxiety in individuals with ASD (Danforth et al., 2018). However, due to MDMA's vastly different pharmacological properties from serotonergic psychedelics, it will not be discussed in the present review.
Recent clinical and preclinical research demonstrates that psychedelics may hold therapeutic value in the treatment of some of ASD's core features. Despite the emergence of compelling research, early clinical trials carried out in the 1960s and 70s revealed a variety of side effects after psychedelics were administered experimentally to children with ASD. Thus, the risks associated with the use of these compounds must be carefully examined when considering their potential use in neuroatypical individuals.

CORE BEHAVIOURAL ATYPICALITIES AND CO-OCCURING CONDITIONS
ASD diagnoses are contingent on atypicalities in social behaviour. Clinical manifestations include a preference for non-social stimuli (Gale et al., 2019), aberrant non-verbal social behaviours (Osterling et al., 2002), and decreased attention to social stimuli (Sasson and Touchstone, 2014). Despite this diagnostic criterion, no selective treatments for ASD target these core traits. Instead, antipsychotics, antidepressants, mood stabilizers, and stimulants are used to target ASD-associated features, such as irritability, anxiety, and depression (DeFilippis and Wagner, 2016).
It is increasingly apparent that psychedelics enhance social behaviour and elicit empathogenic effects in healthy individuals (see Table 1 for a summarized list of recent clinical trials assessing the use of psychedelics in individuals without ASD). For instance, two psilocybin therapy sessions increased extraversion and openness for up to 3 months in individuals with treatmentresistant depression . Similarly, a single administration of LSD enhanced sociability and the desire to be with others, while also increasing feelings of trust, closeness, and empathy (Dolder et al., 2016). Another recent study demonstrated that LSD acutely increases emotional empathy and blood levels of oxytocin, a neuropeptide implicated in social behaviour (Churchland and Winkielman, 2012;Holze et al., 2021a). These results have also been corroborated by preclinical evidence, which demonstrate that both acute (Vesuna et al., 2020) and repeated LSD (De Gregorio et al., 2021) enhanced social behaviour in mice.
ASD is often accompanied by depression, generalized anxiety, and social anxiety in particular (Spain et al., 2018;Hollocks et al., 2019;Kirsch et al., 2020). These co-occurring diagnoses may also be potential targets of psychedelics. For instance, LSD (Gasser et al., 2014) and psilocybin (Griffiths et al., 2016) have been shown to reduce symptoms of anxiety and depression in patients with life-threatening conditions. Importantly, the anxiolytic effect produced by LSD was appreciable after only two psychedelicassisted therapy sessions and lasted for up to 12 months without any serious adverse effects; while the attenuative effects of psilocybin occurred after only one dose and were still present 6-months post-administration. Likewise, psilocybin has been shown to reduce depressive symptoms in those with treatment-resistant depression for up to 6 months Davis et al., 2021). The antidepressant and anxiolytic properties of DMT and ayahuasca have been observed similarly both clinically (Osório Fde et al., 2015;Palhano-Fontes et al., 2019) and pre-clinically (Cameron et al., 2019). It cannot be ruled out that the prosocial effects of psychedelics may reflect their anxiolytic effects, notably with regard to social anxiety.
Further, a recent double-blind randomized trial found that the antidepressant effects of psilocybin were not significantly different than those of the selective serotonin reuptake inhibitor (SSRI) escitalpram (Carhart-Harris et al., 2021). This result, in addition to the lack of a placebo-controlled group, limits support for the efficacy of psilocybin and highlights the importance of assessing whether or not the relative benefits of psychedelics (compared to established medications) warrant their potential side effects.
Despite ongoing research, there is still a lack of systematic, double-blind, placebo-controlled clinical trials assessing the specific therapeutic and adverse effects of psychedelics in neurotypical individuals and in those with ASD. Thus, further research is needed to identify an optimal dose that both minimizes the risk of adverse effects, and importantly, to elucidate whether or not the therapeutic effects of psychedelics observed in neurotypical individuals can be clinically observed in those with ASD. Further research is also needed to better understand how the effects and mechanisms of action associated with psychedelics differ when administered acutely or chronically, and to what extent such interventions provide therapeutic effects for people with ASD.

NEUROBIOLOGY
Due to the heterogeneity of ASD, the neurobiological underpinnings of its behavioural phenotypes remain difficult to characterize. ASD is diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, including individuals with genetic and non-genetic etiologies across the spectrum. This presents an inherent challenge in hypothesizing how individuals with ASD might respond to psychedelic administration, given that ASD diagnoses cover a large spectrum of neurobiological and genetic profiles.
It is important to note that due to the lack of recent studies assessing the use of psychedelics in ASD, the following discussion reflects neurobiological processes that represent potential targets Frontiers in Pharmacology | www.frontiersin.org January 2022 | Volume 12 | Article 749068 of psychedelics in ASD, not phenomena which have been proven to be associated with their effects in this population.

Synaptic Function
Many genes associated with ASD play integral roles in synaptic function (Guang et al., 2018), suggesting a critical involvement of synaptic dysfunction in ASD pathogenesis. Mutations in the SH3 and Multiple Ankyrin Repeat Domains (SHANK3) gene-encoding a synaptic scaffolding protein-can cause ASD (Durand et al., 2007). In a transgenic mouse model, this mutation produced a lengthening of dendritic spines and long-term potentiation deficits in the hippocampus (Wang et al., 2011). Mutations in the Contactin-Associated Protein-Like 2 (CNTNAP2) gene can also result in ASD (Penagarikano and Geschwind, 2012). CNTNAP2 encodes a synaptic cell-adhesion protein, and its deletion leads to altered dendritic arborization, spine development, and global synaptic transmission in mice (Anderson et al., 2012;Lazaro et al., 2019). Hyper-methylation of the Fragile X Mental Retardation 1 (FMR1) gene-which encodes an important regulatory protein for dendritic mRNA-is an epigenetic modification that can cause ASD (Bassell and Warren, 2008). FMR1 knockout rats display decreased hippocampal long-term potentiation and long-term depression, in addition to impaired α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor-mediated synaptic strength (Tian et al., 2017). Recently, ASD-induced synaptic impairments have also been identified in human-derived samples. Induced pluripotent stem cell-derived neurons from individuals with ASD exhibited reduced miniature excitatory post-synaptic current frequency and impaired N-Methyl-Daspartic acid (NMDA) receptor function (Ross et al., 2020). Given that alterations in synaptic properties are consistently found in different mouse models of ASD and recently in humans, the ability of psychedelics to modulate synaptic events might play an important role in their potential therapeutic effects in ASD. Recently, a single administration of psilocybin in mice was shown to produce AMPA receptor-mediated synaptic strengthening in hippocampal brain slices (Hesselgrave et al., 2021); an effect which may normalize the synaptic dysfunction of FMR1 knockout rats (Tian et al., 2017). Additionally, LSD and DMT were shown to promote structural and functional neural plasticity in rodent neuronal cultures and in Drosophila larvae (Ly et al., 2018). This study demonstrated that the increased dendritic arbor complexity, dendritic spine growth, and synapse formation caused by psychedelics were mediated by the mammalian target of rapamycin (mTOR)-and 5-HT 2A -signaling. Accordingly, our study revealed that LSD requires intact mTOR signaling in excitatory neurons and intact 5-HT 2A neurotransmission in the mPFC to enhance social behaviour (De Gregorio et al., 2021). Given that mTOR (Hoeffer and Klann, 2010;Li et al., 2010) and the 5-HT 2A receptor (Barre et al., 2016;Berthoux et al., 2019) play important roles in mediating neuroplastic events, LSD's ability to increase social behaviour might be contingent on its ability to modulate neuroplasticity.
Despite the pronounced neurotrophic effects of psychedelics, the dysregulation of mTOR and 5-HT 2A signaling in individuals with ASD may be a limiting factor for the therapeutic action of psychedelics on synaptic structure and function. For instance, hyperactive mTOR signaling was found in T cells isolated from children with ASD (Onore et al., 2017) and in post-mortem ASD brain samples (Tang et al., 2014). Positron emission tomography (PET) imaging studies have also revealed that individuals with ASD have reduced 5-HT 2A -binding affinity in various brain regions compared to neurotypical individuals, suggesting a reduced expression of this receptor (Murphy et al., 2006;Oblak et al., 2013;Brandenburg and Blatt, 2019). In agreement, a significant overrepresentation of the G allele in the -1438 A/G polymorphism in the 5-HT 2A gene was found in individuals with ASD (Hranilovic et al., 2010) and this has been associated with decreased receptor expression (Parsons et al., 2004;Myers et al., 2007). Given that mTOR and 5-HT 2A mediate psychedelics' synaptic effects, their dysregulation in ASD might limit or alter the therapeutic effects in these populations.

Serotonin Signaling
Serotonin (5-HT) is a neurotransmitter and hormone implicated in a variety of physiological phenomena and psychiatric conditions including neuronal development (Brummelte et al., 2017), synaptic plasticity (Kirkwood, 2000), depression (Cowen and Browning, 2015), and ASD (Chugani, 2002). Several lines of evidence suggest a dysregulation of the serotonergic system in ASD. Elevated blood serotonin levels was identified as one of the first putative biomarkers of ASD (Schain and Freedman, 1961), a finding that has been corroborated using meta-analysis, revealing that 28.3% of individuals with ASD have elevated 5-HT levels (Gabriele et al., 2014). Differences in 5-HT production have also been found in the brains of individuals with ASD. For instance, the development of brain serotonin synthesis capacity during childhood is robustly different in children with ASD (Chugani et al., 1999). Human studies generally point to lower levels of brain serotonin in ASD (Adamsen et al., 2014;D'Eufemia et al., 1995;McDougle et al., 1996;Nakamura et al., 2010). However, these studies have used proxy markers of serotonin levels such as PET binding of serotonin transporters and receptors, and cerebrospinal fluid serotonin metabolites. Thus, more direct studies are needed before low brain serotonin can be characterized as a biomarker of ASD. However, in support of this hypothesis are preclinical studies demonstrating that the depletion of brain serotonin in neonatal mice produces ASD-like behaviours such as altered social and stereotypical behaviours and increased anxiety Hohmann et al., 2007).
Interestingly, the 5-HT 1A and 5-HT 2A receptors may be key mediators of the role that serotonin signaling plays in the pathogenesis of ASD. Neuroimaging studies have found reduced binding affinity of these receptors in limbic and neocortical brain regions of individuals with ASD (Murphy et al., 2006;Oblak et al., 2013;Brandenburg and Blatt, 2019). Accordingly, mice with impaired 5-HT 1A or 5-HT 2A receptor expression or function display increased anxiety-like behaviour which is rescued with the selective genetic restoration of the respective receptor (Ramboz et al., 1998;Gross et al., 2002;Weisstaub et al., 2006;Piszczek et al., 2015). LSD administration increases brain serotonin levels (Freedman, 1961) and potentiates the excitatory response of 5-HT 2A receptor agonism (De Gregorio et al., 2021). Given that psychedelics are agonists of the 5-HT 1A and 5-HT 2A receptors (De Gregorio et al., 2016a;Inserra et al., 2021a), their pharmacological effects may help restore the altered serotonergic signaling observed in ASD.
Fenfluramine, a serotonin-releasing agent, enhances serotonin signaling in the brain. While few small-sample, placebocontrolled studies found moderate efficacy in fenfluramine's ability to increase IQ in individuals with ASD (Geller et al., 1982;Ritvo et al., 1984), far more have found that this treatment is only effective in mildy reducing some of the motor and attentional atypicalities in people with ASD. This data suggests that increasing brain serotonin levels (and consequently serotonin signaling) is generally ineffective in improving the behavioural condition of individuals with ASD. Thus, the mechanisms of action of psychedelics must be better characterized in order to assess how they may interact with the altered serotonin signaling observed in ASD.

Prefrontal Cortex
The prefrontal cortex (PFC), and especially the medial PFC (mPFC), mediates social behaviours and cognition (Grossmann, 2013). Indeed, lesion of the PFC, which is clinically referred to as "frontal lobe syndrome," induces profound deficits in social interaction (Anderson et al., 1999;Eslinger et al., 2004;Kim et al., 2015;Kirsch et al., 2020). Accordingly, reduced PFC activity is observed in various preclinical models of ASD (Krueger et al., 2011;Duffney et al., 2015;Brumback et al., 2018). Aberrant mPFC activity is also observed in human neuroimaging studies, which report altered mPFC recruitment and connectivity in individuals with ASD compared to neurotypical individuals (Kennedy and Courchesne, 2008;Lombardo et al., 2010;Li et al., 2020). Human post-mortem studies have also found that the PFC of children with ASD have greater neuronal disorganization and differences in neuronal composition compared to neurotypical children (Stoner et al., 2014;Hashemi et al., 2017).
Due to its high 5-HT 2A receptor expression, the PFC is highly modulated by the effects of serotonergic psychedelics (De Gregorio et al., 2021;Inserra et al., 2021b;Jakab and Goldman-Rakic, 1998). Indeed, psychedelics activate unique 5-HT 2A -mediated transcriptional responses in the mouse mPFC (Martin and Nichols, 2016). Corroborating a crucial role of the mPFC in social behaviour, we demonstrated that the photoinhibition of mPFC excitatory neurons decreases sociability and blocks LSD's prosocial effects (De Gregorio et al., 2021). Accordingly, in humans, mPFC activation was associated with LSD's ability to enhance social adaptation to others whose opinions are similar to one's own (Duerler et al., 2020). Another neuroimaging study revealed that psilocybin dampens mPFC neural activity, an effect correlated with the intensity of the subjective effects (Carhart-Harris et al., 2012). Similarly, LSD reduced the activity of the right mPFC in individuals presented with fearful faces (Mueller et al., 2017).
Although it is not clear which specific biological processes in the PFC may be targeted in ASD by psychedelics, signaling in this brain region plays an important role in the mechanism through which these compounds modulate social behaviour.

Thalamocortical Circuit
The thalamus plays a significant role in the integration of external and internal stimuli, and its projections to the cerebral cortex are believed to play a vital role in consciousness (Llinas et al., 1998;Redinbaugh et al., 2020). Thus, thalamocortical dysfunction can interfere with complex human behaviours, such as social functioning. Recent studies have employed large, multi-site neuroimaging datasets to assess thalamocortical functional connectivity in ASD.
Given the vast heterogeneity of the ASD spectrum and that some of these studies considered the thalamus with other brain regions as a single subcortical structure in their analysis (Cerliani et al., 2015;Maximo and Kana, 2019), there are some inconsistencies in the literature. Nevertheless, two main connectivity trends are appreciable in individuals with ASD: 1) hyperconnectivity between the thalamus and sensorimotor cortex (Di Martino et al., 2014;Cerliani et al., 2015;Woodward et al., 2017;Maximo and Kana, 2019;Tomasi and Volkow, 2019;Ayub et al., 2021), suggesting an anomalous filtering of sensory information; and 2) hypoconnectivity between the thalamus and multimodal association cortices (Nair et al., 2013;Chen et al., 2016;Maximo and Kana, 2019), suggesting an aberrant integration of sensory information.
The effect of psychedelics on functional thalamocortical connectivity in humans has recently been investigated. Some studies demonstrate a general 5-HT 2A -mediated increase in thalamocortical connectivity following LSD (Tagliazucchi et al., 2016;Müller et al., 2017), while others show that psychedelics increase or decrease thalamocortical connectivity depending on the cortical region observed (Preller et al., 2018;Preller et al., 2019). Specifically, Preller and others (2018) revealed that LSD increases thalamic connectivity to cortical sensory regions while decreasing its connectivity to associative areas. This specific finding suggests that LSD may potentially exacerbate the abnormal thalamocortical connectivity in individuals with ASD. Thus, more investigation is required to elucidate the link between thalamocortical connectivity and social behaviour in ASD, and the way that psychedelics mediate this link.
In addition to thalamocortical connectivity, the effects of psychedelics on social behaviour may involve the regulation of spontaneous firing of thalamic neurons. The mediodorsal nucleus of the thalamus (MDT) has extensive reciprocal projections to the mPFC and is implicated in various cognitive functions, including sociability (Ferguson and Gao, 2018;Parnaudeau et al., 2018). Individuals with ASD present with morphological thalamic alterations, such as decreased global thalamic volume (Tsatsanis et al., 2003;Waiter et al., 2004), and increased surface area of the MDT specifically (Schuetze et al., 2016). Interestingly, the pharmacogenetic inhibition of MDT projections has been shown to reduce social preference in rats (Ferguson and Gao, 2018), further supporting this nucleus's role in mediating social behaviour. We recently discovered that LSD increases neuronal firing in the MDT (Inserra et al., 2021b), suggesting that LSD's effects may partly be mediated by its modulation of MDT projections.
Year Modification of autistic behaviour with LSD-25 "Autistic" twin males (4 years 9 months old at study start, 5 years 2 months at study end)   (1961)(1962)(1963)(1964)(1965)(1966)(1967)(1968)(1969)(1970) assessing the use of psychedelics in "autistic schizophrenic" children. The terms "autistic" and "schizophrenic" do not reflect the currently approved terminology of the DSM-V, but rather the terminology that was used at the time of these early studies. Altogether, we suggest that psychedelics may target the dysregulated thalamocortical connectivity and thalamic neuronal firing in individuals with ASD. However, it is also true that the thalamocortical dysregulations in individuals with ASD may concurrently limit the behavioural effects of psychedelics (such as changes in social behaviour) that are mediated by thalamocortical signaling. For instance, mice with embryonic-stage deletions of the Tuberous Sclerosis Complex 1 (Tsc1) gene (a standard preclinical model of ASD) had an overabundance and greater diffusion of thalamic projections to the somatosensory cortex (Normand et al., 2013). Since structural thalamocortical connectivity is profoundly altered in this ASD model, the response of this circuit to the administration of psychedelics may also be altered. Thus, any cognitive effects of psychedelics mediated by their ability to modulate thalamocortical signaling may be significantly different in people with ASD, potentially limiting their therapeutic effects. (1961)(1962)(1963)(1964)(1965)(1966)(1967)(1968)(1969)(1970) Prior to the classification of psychedelics as Schedule 1 Controlled Substances in 1970, these substances were tested in the treatment of children with ASD in order to assess their efficacy in relieving treatment-refractory ASD-like behaviours. Importantly, these individuals were classified as "autisticschizophrenic" (Bender et al., 1961;Freedman et al., 1962;Bender et al., 1966;Fisher, 1970), and "severely emotionally disturbed" (Fisher and Castile, 1963). Thus, they may not have necessarily been diagnosed with ASD using contemporary diagnostic criteria, imposing a significant limitation on these findings (reviewed and summarized in Table 2). Although significant methodological and ethical shortcomings are evident through the lens of modern clinical and ethical research standards, this early work is being re-scrutinized to extrapolate potentially meaningful data which could inform contemporary research.

CLINICAL TRIALS OF PSYCHEDELICS IN CHILDREN WITH ASD
Most of these studies involved a regimen of LSD given at medium to high doses (25-400 µg), with schedules ranging from a single administration to daily administrations for up to 18 months. The most effective results were observed when daily or weekly LSD was given over relatively extended periods of time (Bender et al., 1961). Greater improvements were observed when the therapist was more actively involved with the children; when they were given the possibility to experience meaningful interpersonal psychotherapeutic interactions; and when the settings were free of artificial or experimental restrictions. When the children were taken off the drug, their behaviour regressed, but not to the extent observed previously (Bender et al., 1963).
Psychedelic-assisted therapy in children with ASD resulted in a variety of clinical improvements: enhanced mood, sociability, and affectionate behaviour; increased emotional closeness, relatedness, and responsiveness to others; increased desire to communicate and interest in the surrounding environment; relief of perceptual hypersensitivity; improved speech and vocabulary; increased playfulness, smiling, and laughing; increased eye and face-gazing behaviour; decreased aggressive and repetitive behaviours; and improved sleep patterns.
Although the aforementioned effects of psychedelics are desirable in the treatment of ASD, adverse effects of varying severity were also reported. Some of the children experienced rapid mood swings, ataxia, and moderate to severe anxiety, with at least one case of a "panic-like state" (Bender et al., 1961;Freedman et al., 1962). One girl experienced two episodes of seizures during LSD treatment (Fisher and Castile, 1963). Some of the children displayed increased biting and pinching behaviour, some engaged in aggressive behaviour even after the effects of the drug had worn off, and some had difficulty sleeping in the days following administration (Bender et al., 1961;Freedman et al., 1962;Bender et al., 1963;Fisher and Castile, 1963;Bender et al., 1966;Fisher, 1970). In one "autisticschizophrenic" girl receiving LSD and psilocybin, the emergence of internal conflict led to acute anxious, aggressive, and selfharming behaviour (Fisher, 1970).
Given that certain individuals with ASD present atypical behavioural characteristics such as increased aggression (Fitzpatrick et al., 2016) and epilepsy (Tuchman and Rapin, 2002), it is not entirely surprising that psychedelic treatment triggered aggressive behaviour (Bender et al., 1966) and seizures (Fisher and Castile, 1963) in some of the children. Consequently, serious precautions must be taken when using psychedelic treatments in these vulnerable populations.
Another potential risk is the potential for psychedelics to induce psychosis and/or schizophrenia. The prevalence of schizophrenia is significantly higher in people with ASD compared to neurotypical individuals (Zheng et al., 2018). Since psychedelic use is associated with the development of psychosis in people with genetic predispositions (Breakey et al., 1974;Vardy and Kay, 1983), the risk of psychosis and schizophrenia must be carefully considered when assessing the potential adverse effects of psychedelic administration in this population. Altogether, although some therapeutic effects of psychedelics in children with ASD have been reported, the extended list of reported adverse effects demands caution.

CONCLUSION
Due to the limited treatment options for ASD, the development of novel therapies is warranted. Clinical and preclinical trials suggest that psychedelics may improve social behaviour and decrease the burden of co-occurring diagnoses in ASD by targeting synaptic function, serotonin signaling, PFC activity, and thalamocortical signaling. Early clinical trials in childhood ASD suggest that psychedelics might hold therapeutic potential; however, the side effects encountered represent potential limitations to this treatment. It is possible that psychedelics may alleviate a few core social-behavioural features in individuals with ASD, such as social anxiety, but carefully performing a risk-to-benefit assessment is crucial due to the severity of their potential side effects.
Individuals with ASD represent a highly heterogeneous demographic; therefore, only certain subsets of individuals Frontiers in Pharmacology | www.frontiersin.org January 2022 | Volume 12 | Article 749068 with ASD may respond well to psychedelic treatment options. Clinical trials must proceed with caution because this population is also comprised of children and some individuals with intellectual disabilities, for which obtaining informed consent is a challenge. Future studies must make these considerations when determining if some of the positive findings obtained in the "first wave" of psychedelic research in ASD can be validated when employing contemporary scientific and ethical standards.