Complementary and Alternative Medicine for Autism – A Systematic Review

Autism spectrum conditions (hereafter, autism) are characterized by challenges in social communication, interaction and flexibility, and the presence of repetitive behaviours or restricted interests (Bargiela et al., 2016). The ability to hyperfocus, attention to detail, a good memory, creativity and differences in sensory processing are also frequently described autistic traits (Russel et al., 2019). Data from the Centre for Disease Control (CDC) in the US detail autism prevalence rates of 1 in every 36 children, while reported prevalence rates in adults differ, with only 2.2% of adults formally diagnosed as autistic (Maenner et al., 2023). Historically, autism has been perceived as being more prevalent in males, however recent research has evolved to suggest that there may be differing phenotypic presentations of autism that do not align with previous conceptualisations, including a Female Autism Phenotype (Holtman et al., 2007). Male-to-female ratios for autism prevalence range in research from 10:1 to 2:1, with sex differences more pronounced when the reported autism is not associated with an intellectual disability (Loomes et al., 2017). Ratios also change markedly with age, and as females are stated to be able to articulate their inner experience more as they get older, with internalizing behaviours such as depression, anxiety and eating disorders more prevalent in autistic females (Hull et al., 2017).

At present, a diagnosis of autism is based on clinical observation and subjective measurement against internationally validated diagnostic tools, such as the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013) using criteria based on significant deficits in social communication and interaction, together with at least two types of restricted and repetitive interests and behaviours (RRBs). Identification of autism in adults and pathways to diagnosis in adulthood remain poorly understood (Happe et al., 2016). Currently, there are no definitive, diagnostic biomarkers available for autism, with initial studies in the 1990’s focusing on the identification of genetic variants associated with autism, however more recent research efforts have focused on investigating potential neurodevelopmental markers (Chaboun et al., 2022). Despite ongoing research efforts, the ‘cause’ of autism remains unknown, however several genetic and non-genetic risk factors have been identified that, alone or in combination, may be implicated in the development and subsequent diagnosis of autism for an individual, with the causation of autism remaining widely misunderstood (Sauer et al., 2021). Whilst there continues to be advances in relation to research on diagnosis, effective supports and treatment approaches for autistic people, most of this research remains based on autistic children (Howlin et al., 2012). The body of research on the experience of autistic adults remains limited, including research into the use of Complementary and Alternative Medicine (CAM) by autistic adults (Hofer et al., 2017). Pharmacologic interventions for the core presentations of autism remain limited, with Risperidone and Aripiprazole two medications approved for use in autism, with most prescribing continuing to be off label (Hellings, 2023). Several such medications that have shown efficacy for autistic people include anti-depressants and attention deficit hyperactivity disorder (ADHD) medications (Birch et al., 2017). Similar to calls for further research into CAM use for autistic people, there is also a demand for further controlled studies in the use of pharmacological interventions (Aishworiya et al., 2022).

In addition to what are described as the core presentations of autism, there are also commonly co-occurring conditions that are experienced by autistic people that can be both psychological and physiological in nature (Khachadourian et al., 2023). Epilepsy and co-occurring psychiatric conditions such as anxiety and mood disorders are more frequently experienced in autistic people than their neurotypical peers (Khachadourian et al., 2023). Autistic children and adults are at risk of having gastrointestinal issues such as constipation, diarrhea, and abdominal pain, with suggestions that the associated pathways in the gut–brain axis contribute to alterations in both behaviour and cognition (Wasilewskal & Klukowski, 2015). Sleep disorders are also commonly experienced by autistic people, which can have an impact on social interaction, day to day life and academic achievement, with evidence suggesting that increased oxidative stress may play a major role in the pathogenesis of these symptoms (Devnani & Hedge, 2015).

The use of Complementary and Alternative Medicine (CAM) in Australia remains high, with recent figures indicating that approximately 70% of the population are utilizing some form of CAM as part of their health care (Complementary Medicines Association Australia, 2021). Females have been found more likely than males to seek CAM support (Steel et al., 2018). CAM has also been found to be widely used by autistic people, with up to 95% reported to have utilized some form of CAM (Alwhabi & Sambamoorthi, 2016). CAM therapies are generally divided into five domains, including biologically based therapies, mind–body therapies, manipulative and body-based therapies, energy therapies and whole medical systems/alternative medical systems (Koithan, 2009). CAM treatments offer a variety of supportive actions for some of the physiological pathways related to autism, which may explain the consistent uptake of biologically based CAM therapies (Bent & Hedren, 2015). Despite their popularity however, the research is still lacking as to how CAM can effectively and safely support autistic people (Trudeau et al., 2019).

Brondino et al (2015) conducted a review into the use of CAM therapies for autism over the period of 2003–2013, with the aim of their systematic review being to provide a comprehensive overlook at the efficacy of CAM use in autism. The aim of this systematic review is to provide a comprehensive review of original research over the last 10 years (2013–2023) on the efficacy of CAM use in autism, conducted in the context of a rapidly evolving landscape of personalised CAM interventions and an increasing understanding of autistic phenotypical presentations and lived experience. The high usage of CAM in the autistic population indicates that evidence-based, effective, and safe CAM interventions for autistic children and adults demand urgent investigation (Castejon et al., 2021).

This systematic review was registered with Prospero, prior to commencement, registration no: 459294. Research was conducted following the PRISMA guidelines.

The following databases were used for the search: PubMed, CINAHL Plus full text, EBSCO – Medline, Proquest and Cochrane. The search terms were as follows: Complementary medicine OR Naturopathy OR Nutrition OR Herbal Medicine OR Complementary and alternative medicine OR Alternative medicine OR Diet OR Lifestyle OR Supplements OR Nutraceutical OR Botanicals OR Plant OR Vitamins OR Dietary Intervention AND Autis* OR Autism OR ASD OR Autism Spectrum Disorder OR Autistic AND Randomised control trial OR Clinical trial or Trial AND (y_10[Filter])) Filters: in the last 10 years.

The search strategy was defined for research that was published between 2013 and 2023, was not limited to any specific country but was limited to articles only in English. The articles reviewed had no age limits and were not gender specific. All publications were reviewed for further relevant references. One researcher in the field was reached out to with a query on accessing a paper that there was difficulty in accessing. Two researchers (MD and JS) independently reviewed all information about the articles provided by the databases. Any discrepancies were solved by consensus.

The inclusion criteria were Randomized Controlled Trials (RCTs) and Clinical Trials from only original research, providing results on the effects of variety of biologically based CAM treatments for autistic people of all ages, including dietary interventions, vitamins and herbal medicines. Autism was defined according to internationally valid diagnostic criteria such as the DSM. Case reports and case series, commentaries, editorials, non-RCTs, retrospective studies, reviews, meta-analyses, or thesis, and on animals were excluded. Pharmaceutical medicines and non-biological CAM therapies including mind–body medicine, manipulative/body-based therapies, and energy therapies were not included in this review. All biologically based CAM treatments included in this review would fall under the SEC classification of a precursor safety event, which result in no detectable harm, based upon the relevant evidence (Throop & Stockmeier, 2011). The Johanna Briggs Institute Critical Evaluation tool for Systematic Reviews was applied to all selected articles.

This research was reviewed by a member of the autistic community prior to submission, and led by an adult who self-identifies as autistic and is a parent to a formally diagnosed autistic child.

Our literature search identified 1,826 clinical publications with 694 duplicates removed. After the title/abstract screening, 102 publications were obtained for full text review. After detailed evaluation 39 studies were included, with no studies from a hand search of references retrieved. It is noted that no studies on the use of herbal medicines for autism were included because of the search, screening and evaluation process. Supplementary Tables 1, 2, 3, 4, 5, included as supplementary material, detail the results of all studies included in this systematic review. Supplementary Figure 1 (Appendix 1) further explains the process of selecting articles (Page et al., 2021).

CAM is a common therapeutic option utilized by autistic people globally (Alam et al., 2022). Whilst historically CAM interventions for autism have had an erroneous focus on ‘curing’ autism, because of continued research, significant advocacy efforts and an increased understanding of the presentation and lived experience of being autistic, a shift in such narratives is required (Bent & Hedren, 2019). It is also noted in this systematic review, and potentially reflective of other research into CAM use by autistic people, that the research focus is on outcome measures based on the level/severity of autistic traits, and to a lesser extent, physiological and biochemical measures. What is clearly lacking in the studies included in this systematic review, is the prioritisation of Quality of Life as a primary outcome measure. How CAM support may serve to improve the quality of life of autistic people is an important consideration in the utilization of this modality. Such detail on quality of life may aid in providing important direction on which interventions, taken at what dosage, frequency and duration may make a meaningful difference to an autistic person’s experience of their life.

Whilst CAM offers the potential for meaningful improvements to the quality and experience of life for all autistic children and adults, the focus of both interventions and their associated research continues to be on ‘minimising’ or ‘eliminating’ the autism and it’s ‘symptoms’, rather than offering support in areas of significance that are identified by autistic people. More focused research on how CAM may support quality of life in autistic children and adults is urgently needed. An autism diagnosis is lifelong and research into safe and effective supports for autistic adults continues to be lacking, for both pharmacologic and CAM options (Christon et al., 2010). A focus on quality of life may be lacking in CAM research for autistic people because the research has historically been focused on children, with the presumption historically that autism is a condition of childhood (Alam et al., 2022). It is important to recognise that the support needs for any given autistic person will no doubt change and evolve over a life span (Onal et al., 2023).Focused research into CAM use by autistic adults who may be able to articulate their experience of a given CAM intervention and it’s impact on their quality of life would make a meaningful and significant contribution to the literature on CAM options for autistic people. Autistic adults may also be more likely to have agency in the CAM supports they choose to implement, as compared to children, and in participating in such research can play an important role in guiding future prescribing and research direction (Hofer et al., 2017).

There has been a noticeable shift over the last 10 years from CAM interventions that are particularly based on exclusion, such as the exclusion of certain foods, to an evolution to less invasive, more supportive treatments that are focused on the inclusion of functional foods and nutraceutical supplements as discussed in the results of this systematic review. This review has highlighted studies in which nutraceuticals that target some of the key physiological pathways and presentations that are associated with autism, such as oxidative stress, which are an increasingly key focus of research. An increasing shift to the use of nutraceuticals such as sulforaphane, coenzyme Q10, prebiotics and strain specific probiotics is noted, with no studies included in this review on previous ‘first line’ CAM supports for autism such as zinc, magnesium and Vitamin B6. This may reflect an evolution of CAM research shifting from general one size fits all ‘protocols’ for autistic people, to more targeted, personalised interventions (Onal et al., 2023).

There were no studies included in this review on Dimethylglycine (DMG), N-Acetyl Cysteine (NAC) or Palmitoylethanolamide (PEA), all novel nutraceutical approaches that currently have limited research to support their use by autistic people but warrant further review as potentially valid and safe CAM supports (Bent & Hedren, 2015; Colizzi et al., 2021; Dhanjal et al., 2022). The limited existing research on use of DMG by autistic people demonstrates improvements in verbal communication, social interaction, affection and minimisation of repetitive behaviours (Dhanjal et al., 2022). The action of DMG is said to have a protective effect from physical, environmental and metabolic stress, however further research is required to understand the mechanisms of action of DMG in the human body and its interaction with the pathways implicated in autism (Dhanjal et al., 2022). Initial research into the use of NAC by autistic children indicates that NAC may be an option to reduce irritability in autistic children, hypothesised due to its antioxidant action, without the observed side effects of the existing pharmaceutical medications (Bent & Hedren, 2015). PEA supplementation may modulate immune response, neuroinflammation, mitochondrial function, and microbiota activity, and may improve quality of life, including the experience of common co-occurring conditions experienced by autistic people (Colizzi et al., 2021).

The results of this systematic review confirm that for autistic people, vitamin and mineral supplements may only be of benefit if there is a deficiency. Moreover, the evidence does not support some of the most frequently utilised dietary interventions, such as a GFCF diet. The use of targeted nutraceutical supplements may be of benefit, however more conclusive research is still required to identify safe and effective treatments. The results of this systematic review also demonstrated the contradictory/inconsistent evidence regarding the effectiveness of CAM treatments for autism. For any given intervention, there may be reported variance in results, with the included study by Voigt et al. (2014) a given example, with no improvement reported in the primary outcome measure, yet differing/varying improvements in parent and teacher outcome measures. Whilst there continues to be an increasing number of well-designed studies reviewing the safety and effectiveness of an increasing variety of dietary and nutraceutical interventions, more rigorous research is required. Such research is essential to review the potential benefits and harms, safety, cost considerations and efficacy on reported core characteristics and co-occurring conditions offered to autistic adults via CAM support, with a goal to inform individual decision-making and future clinical guidelines.

Serious side effects or adverse events were found to be rare in the studies included in this review, with some mild, transient side effects, such as nausea, abdominal pain and skin rashes reported, sometimes contributing to discontinuation/dropout by participants. Families of autistic children are often worried about the potential side effects of pharmaceutical medications, which may include adverse metabolic and cardiovascular effects and sedation (Stoner, 2017). CAM therapies, which are more likely to be associated with milder side effects than pharmaceutical medications, are becoming an increasingly popular alternative, with safety considerations and side effect severity potentially having an important influence on CAM uptake and use (Akins et al., 2010). If there is a CAM option available that may offer appropriate support to an autistic person, with fewer side effects and less risk of serious adverse events, these too should also be deemed as valid options, with appropriate research available to support their use. It is important that future research into CAM use by autistic people prioritises not only the efficacy, but the safety and financial accessibility of CAM therapies (Shuai et al., 2020).

Limitations consistent in most of the studies reviewed included small sample size, limited study length/duration, issues with compliance, consistent dropout rates and heterogeneity of the age of participants (with a focus on children under age 12 particularly). Also noted as a limitation is that the literature search is over a year old before publication. Such limitations must be considered in the interpretation of whether results of a given study are significant and meaningful. Compliance is an important consideration to note in discussing the results of the included studies, as it is a potential barrier common to the implementation of dietary interventions, particularly dietary interventions over a long duration, and the effectiveness of an intervention will be directly influenced by the compliance and consistent uptake of an intervention (Semple et al., 2011). It is also important when analysing the efficacy and use of dietary interventions for autistic people, particularly those of dietary exclusion, to consider the potential risks associated with such interventions (Yu et al., 2022). Given that restricted eating/feeding is more frequently experienced by autistic people, and the increased incidence of disordered eating and eating disorders, further increasing restrictions to dietary intake could prove to be problematic (Kerr-Gaffrey et al., 2020).

Finally, it is of the upmost importance that CAM support for autistic children and adults reflect the needs and wants of the autistic community, including a prioritisation of the consideration of the influence of social determinants, cultural factors and intersectionality, particularly in relation to gender identity (Zuckerman et al., 2015). Such considerations are critical as they may have a significant impact on the perceptions, understanding of and beliefs around autism, engagement in the diagnosis process, and which supports and/or interventions are chosen, if at all (Davenport et al., 2018). The de-stigmatisation of the autistic neurotype, an understanding of the breadth and depth of the varying autistic phenotypical presentations and the understanding that narratives around the autistic experience should be led by autistic people, are key factors in the shifts that have occurred over the last decade in CAM treatment approaches. Best practice CAM supports autistic people and ensures that as a priority any treatment recommendations accommodate the varied experiences and preferences of autistic people and their families, who are increasingly being empowered to articulate and validate their experiences of both their inner and outer worlds (Manzini et al., 2021).

The best evidence of CAM treatments for autism based on the current literature in this systematic review are those that target specific vitamin or mineral deficiencies, such as Vitamin D, Omega 3 and Vitamin B12. In addition, nutraceutical interventions that support biochemical and physiological pathways and functions in the aetiology of autism including strain specific probiotics/prebiotics, digestive enzymes, sulforaphane, CoQ10 and camel milk may be beneficial. Whilst lacking in the included reviews, it is suggested that quality of life measures be prioritised in future studies on CAM use by autistic people, and that any research conducted with and on the autistic population should be led by and reflect the identified needs and wants of the autistic community.