Autisme

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,N-dimethyltryptamine (DMT), and their derivatives (which will be hereafter referred to as “psychedelics”). Other non-serotonergic 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 treatment-resistant depression (Erritzoe et al., 2018). 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 psychedelic-assisted 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 (Carhart-Harris et al., 2018; 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 of psychedelics in ASD, not phenomena which have been proven to be associated with their effects in this population.

Clinical Trials of Psychedelics in Children With ASD (1961–1970)

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 “autistic-schizophrenic” (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.

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 “autistic-schizophrenic” girl receiving LSD and psilocybin, the emergence of internal conflict led to acute anxious, aggressive, and self-harming 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 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.

Acknowledgments

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