Key messages
At present, it is unclear whether acetylcholinesterase inhibitors are effective in treating the core features of autism. This is because very few studies have been carried out. The two we found were small, and did not report the outcomes very well. However, there are a number of ongoing studies in this area.
What is autism spectrum disorder?
Autism spectrum disorder (autism) is a condition that affects the way a person thinks, feels, interacts with others, and experiences their environment. The core behaviours of autism include reduced sharing of interests, difficulties with nonverbal communication (for example, little eye contact), difficulties forming and maintaining relationships and restricted, or repetitive behaviours or interests. These behaviours can vary in severity, but they still interfere with the person's daily functioning and participation in activities. Medicines, called acetylcholinesterase inhibitors (chemicals that block the normal breakdown of nerve transmitters), have been used to treat Alzheimer's disease (for example, donepezil and galantamine). Recently, it has been suggested that they may also decrease some of the difficulties seen in people with autism.
What did we want to find out?
Do acetylcholinesterase inhibitors, alone or with other medicines, reduce the core features of autism (social communication and interaction, restrictive and repetitive behaviours) compared with a placebo (a dummy pill). We also wanted to find out if acetylcholinesterase inhibitors were associated with any unwanted side effects.
What did we do?
We searched for studies that explored whether there were any differences in autistic people's behaviours after they had taken acetylcholinesterase inhibitors compared to people who had taken placebo pills. We compared and summarised the results of the studies, and rated our confidence in the evidence, based on things, such how big and well carried out the studies were.
What did we find?
We found two relevant studies. One study looked at whether an acetylcholinesterase inhibitor called galantamine, combined with a drug called risperidone (traditionally used to treat psychosis), was better than a placebo combined with risperidone. The study included 40 children, aged between 4 and 12 years, with a diagnosis of autism. it took place over 10 weeks in Iran. A second study compared an acetylcholinesterase inhibitor called donepezil with placebo. It included 34 children, aged between 8 and 17 years, with a diagnosis of autism. It was carried out in the USA. All studies involved children attending outpatient clinics.
What are the main results of the review?
It is unclear if acetylcholinesterase inhibitors make any difference to the core features of autism in children or adults.
Galantamine may cause little to no difference in social interaction and communication skills and irritability levels in children with autism after 10 weeks of treatment. There is no evidence that galantamine reduces difficulties associated with restricted or repetitive behaviours or hyperactivity. Galantamine may also cause some side effects, including nervousness, drowsiness, increased appetite, and tremor.
There is no evidence that donepezil reduces difficulties associated with the core features of autism or associated secondary problems. We were unable to find out whether it causes unwanted side effects in children with autism, because the study did not report the results completely.
What are the limitations of the evidence?
We have little confidence in the evidence for using this medicine to treat problems associated with autism, because the evidence comes from only two small studies that were not very well carried out or reported. Each study looked at a different type of acetylcholinesterase inhibitor and delivered the medicine differently. They did not provide information about all the issues we were interested in, and they measured the side effects differently.
If more studies are included in future reviews, these results may change.
How up-to-date is this review?
The evidence in this review is current to November 2022.
Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain.
There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.
Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features.
Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated.
To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism.
To assess the effects of acetylcholinesterase inhibitors on non-core features of autism.
In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies.
Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion.
We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence.
We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear.
Galantamine plus risperidone versus placebo plus risperidone
One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed.
Donepezil versus placebo
One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention.
Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group.