This systematic review (2021) examines whether MDMA can treat social impairments of autism, and draws supporting evidence from animal models which indicate MDMA-induced prosocial behaviors.
Abstract
“Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, no gold-standard treatments exist to alleviate the core socio-behavioural impairments of ASD. Meanwhile, the prosocial empathogen/entactogen 3,4- methylene-dioxy-methamphetamine (MDMA) is known to enhance sociability and empathy in both humans and animal models of psychological disorders.
Objective: We review the evidence obtained from behavioural tests across the current literature, showing how MDMA can induce prosocial effects in animals and humans, where controlled experiments were able to be performed.
Methods: Six electronic databases were consulted. The search strategy was tailored to each database. Only English language papers were reviewed. Behaviours not screened in this review may have affected the core ASD behaviours studied. Molecular analogues of MDMA have not been investigated.
Results: We find that the social impairments may potentially be alleviated by postnatal administration of MDMA producing prosocial behaviours in mostly the animal model.
Conclusion: MDMA and/or MDMA-like molecules appear to be an effective pharmacological treatment for the social impairments of autism, at least in animal models. Notably, clinical trials based on MDMA use are now in progress. Nevertheless, larger and more extended clinical studies are warranted to prove the assumption that MDMA and MDMA-like molecules have a role in the management of the social impairments of autism.”
Authors: Devahuti Chaliha, John C. Mamo, Matthew Albrecht, Virginie Lam, Ryu Takechi & Mauro Vaccarezza
Summary
- INTRODUCTION
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting in early childhood. It involves both genetic and environmental risk factors, affecting synaptogenesis and axon motility downstream.
ASD symptoms result in variable impacts on functioning across all domains of life, and the prevalence rates of ASD are rising worldwide, implicating an impending increase in disease burden. More effective interventions and treatments are needed to support this population.
There are no FDA-approved pharmacological treatments for the core impairments that define ASD. However, several off-label medications have been used to treat accessory symptoms of ASD, such as irritability and aggressiveness.
ASD is a developmental disorder with no approved drugs to treat the core impairments. However, several drugs have shown early-stage evidence for the treatment of these core behaviours, and many non-pharmacological treatments for ASD exist.
Animal models are used to examine the potential impact of pharmacological treatments on traits of autism, and are a more ethically accepted way of exploring neurological aberrational mechanisms and drug treatments, where those drugs have not been approved for human use.
This systematic review of animal and human studies on MDMA concludes that it may counteract social impairments in autism.
1.1. 3,4-Methylenedioxymethamphetamine (MDMA)
MDMA is known to have prosocial effects in humans and animal models. It may be used to treat the pathological lack of sociability featured in some individuals on the autism spectrum.
MDMA is a substrate for serotonin, norepinephrine, and dopamine monoamine transporters, which reverses their transport, thereby saturating their respective synapses and causing prosocial effects. MDMA is also a direct agonist at some serotonin receptors. MDMA activates oxytocinergic neurons in the hypothalamus, which releases oxytocin, which decreases amygdala activation and coupling, thereby providing a mechanism for reduced social anxiety. This mechanism may vary between individuals, and may be related to the hypothesis that autism is dependent on synaptic plasticity.
1.2. Aims/rationale
MDMA could be able to manage a core impairment constituting ASD, and could also be used to manage stereotypy and cognitive rigidity. This could shed light on the dose adjustments required to optimally reduce these other impairments in future human clinical studies.
2.1. Study Design
A systematic review of the literature was conducted on the influence of MDMA on ASD-like characteristics in animals and humans.
2.2. Search Strategy
Six electronic databases were consulted for this study. Only English-language studies were included.
This systematic review identifies literature examining the effects of postnatal MDMA administrations on the core behaviours affected in ASD, in rats and mice, other animals and humans. The included criteria were behaviours core to ASD, behavioural experiments on animals, the use of MDMA to affect the behavioural results, and placebo-controlled studies.
2.4.1. Rodent and Non-rodent Animals
MDMA increases intra-species sociable behaviours in rodents. The dosage routes have been categorised as singular (only one dose for the subject) and chronic (multiple doses for the subject).
2.4.2. Humans
MDMA generally increases social behaviour and altruistic feelings in humans. It also increases the time between MDMA intake and the first core-ASD-relevant measurement made.
2.4.3. Interspecies Focus
We investigated the behavioural effects of MDMA in laboratory animals and humans using a systematic literature review.
- RESULTS
MDMA has been shown to have a behavioural effect on both animals and humans in the laboratory (placebo-controlled experiments). The act of repetitive grooming is considered a possible sign of cognitive rigidity.
3.1.1. Rodents
There are 4 major tests for social and communication behaviour among mice and rats of different strains, and the MDMA-induced alterations on the respective induced social impairments in rodents are summarised below.
The studies used singular dosing and different modes of injection, and tested different ages, temperatures, and results in the treated rodents.
Table 3 shows the social-novelty preferences of postnatally MDMA-treated rodents, compared with control rodents. The studies were conducted using singular or chronic (multiple) dosing, and the timing of the doses was specified.
3.1.1.1. Ultrasonic-vocalisation Tests
The ultrasonic-vocalisation test is performed prior to weaning of the pup, and measures the pup’s ultrasonic vocalisation (USV) ability in response to being separated from its mother. Teratogenic agents administered in utero may result in deviations from this pattern.
We found one study where MDMA was given postnatally to pups. The study shows that the pups’ call frequency decreased initially, then increased later within a day.
3.1.1.2. Social-preference Tests
The social-preference test assesses a rodent’s preference to spend time with a conspecific vs. an inanimate object. MDMA increases social preference in rodents when given intra-peritoneally on PD 56-84.
The social-novelty-preference test assesses a rodent’s preference to spend time with an unfamiliar conspecific over a familiar conspecific. MDMA, given chronically intraperitoneally on PD 28-52, increased mouse social-novelty preference when tested later on PD 120.
The novel-object-recognition test assesses novelty preference and memory for a new object replacing an existing familiar object. Control rodents spend more time with the unfamiliar than the familiar object.
MDMA exacerbates the loss in the rodent’s exploratory discrimination between the two objects, in contrast to our expected effect on social impairment. This may indicate cognitive rigidity as opposed to social impairment.
3.1.1.5. Social-interaction Tests
MDMA increases prosocial behaviour and decreases asocial behaviour in rodents when given singularly or chronically postnatally. However, chronic dosing of MDMA has the opposite effect: decreasing prosocial behaviour and increasing asocial behaviour.
MDMA increased timidity in both types of mice, but increased social behaviour in aggressive mice and decreased social behaviour in timid mice. However, timid rats were more likely to become aggressive when given MDMA chronically at 6 mg/kg.
Table 5 shows the studies that were performed on rodents and includes the species, sex, sample size, dosing, route, age, temperature, and results obtained from the experiment in the treated rodents.
Each study shows the species, sex, sample size and mode of injection used, the ages of the rodents treated and tested, the temperature of the testing environment, and the duration of social restriction enforced before testing.
There have been studies that have found that MDMA increases social interaction more at higher temperatures, and decreases it at lower temperatures. Group-housed mice become more physically active and have longer social interactions than single-housed mice. One study found that the acute effects of MDMA were different from the chronic effects, and that the singular 8 mg/kg dose caused decreased social exploration, while the singular 5 mg/kg dose increased asocial behaviours. Some studies gave surprising results: decreased prosocial behaviour and increased asocial behavior when MDMA was given at a singular 5-10 mg/kg.
MDMA-treated rodents show increased USV calls, preferential spending time with conspecifics over objects, and mixed social behavioural results when given 5-10 mg/kg MDMA singularly or chronically postnatally.
3.1.2. Other Animals
Most studies on non-rodent animals focused on social behaviour after MDMA treatment. They found that chronic administration of 1.5 mg/kg s.c. or singular dose of 0.03-3 mg/kg i.m. increased prosocial behaviour, but also increased vigilance, indicating perhaps decreased social trust.
Four studies examined ASD-specific behaviour in MDMA-treated fish. They found that asocial behaviour decreased and prosocial behaviour increased when 1 or 5 mg/kg MDMA was singularly intramuscularly injected into electric fish.
Fish become anxious near the water’s surface and shoaling behaviour is caused by alarm pheromones dissipated among the fish. MDMA increases social preference and voluntary body contact between the animals.
In human studies, MDMA was given to non-autistic subjects at doses ranging from 1.5 mg/kg to 100 mg. Social outcomes were measured using a variety of instruments, and the results are summarized in the tables below.
MDMA increased prosocial behaviour at all doses, including self-perceptions of extroversion, openness, sociability, talkativeness, thoughtfulness or caring, sensitivity, friendliness, insightfulness of others, gregariousness or desire to be with others, empathy, lovingness, playfulness, closeness to others. MDMA impaired emotion recognition at higher doses.
The effects of MDMA found in young adults in their 20s-30s are difficult to attribute a certain cause to, although the common theme of increased empathic utterances continues at this dose.
Sex effects were apparent in some studies. Lower chronic doses of MDMA seemed to have prosocial effects in females exclusively, whereas higher chronic doses were required for men to attain the same empathy levels as women.
3.2.1.1. Open-field Tests
In the open-field test, investigators observe solitary behaviours of rodents and find that repetitive stereotypies are increased at 5-20 mg/kg, and fewer varied holepokes at chronic 10 mg/kg. However, perseverative locomotor patterns are decreased at 1-20 mg/kg in other studies.
Thigmotaxis decreased when rodents were singularly given 1-20 mg/kg, and even chronically 5-10 mg/kg, but increased at 15-20 mg/kg with higher sustained hyperlocomotion (possibly indicating anxiety). At lower doses, hyper-locomotion appeared early on, followed by hypo-locomotion, and then rearings increased. At higher doses, hyper-locomotion continued, but under red light, there was increasing hyperlocomotion at 12.5 mg/kg, whereas the same dose under white light had no effect.
Tests for repetitive/compulsive behaviours can be undertaken via the marble-burying test in rodents.
When 2.5 mg/kg MDMA is given intraperitoneally thrice, 3 hours apart, fewer marbles are buried, possibly providing a means of decreasing compulsion/stereotypy.
3.2.3. Humans
There are no studies specifically investigating the effect of MDMA on repetitive behaviours in human subjects. However, MDMA may increase stereotyped behaviour in humans.
3.3.1.1. T/Y-maze Tests
This test is confounded by working spatial memory, which is independent of ASD, and can also be used to monitor frustrated responses to going towards the previous/wrong arm.
We found 21 studies where MDMA was given mostly chronically postnatally, and the rodents’ inclinations to spontaneously alternate arms were assessed. 10-20 mg/kg MDMA seemed to have less influence on cognitive rigidity than doses either side of this range.
3.3.2. Other Animals
Studies using non-rodent animals found that when given MDMA orally, cynomolgus monkeys tended to have more reversal-learning errors, predominated by persevering at the same option.
There are only two placebo-controlled studies showing how MDMA affects cognitive rigidity in humans, and one showed some effect. The studies compare the effects of chronic 1.1 mg/kg and singular 1.5 mg/kg MDMA in humans, and the second study shows an inflexibility-exacerbating effect at 1.5 mg/kg. In the latter study, subjects predicted where a stimulus would be presented on a computer screen, based on previous outcomes or responses. The predictability of subject responses was measured.
- DISCUSSION
Table 8 shows the results of the studies using T- or Y-shaped mazes, chronic dosing, the dose and route of injection, the age of the rodents treated and tested at, the temperature of the testing environment, and the food used.
Table 9 shows non-rodent animal studies testing core ASD behaviours. The studies are grouped by species, sex and sample size, dosing, route of administration, ages, and temperature of the testing environment.
4.1.1. Rodent Studies
This systematic review shows that 5-10 mg/kg MDMA given singularly or chronically postnatally has mixed effects on social-impairment experiments relating to autism. However, sustained long-term effects are also present in people with ASD who are treated with MDMA.
Limitations of this study include small sample size, wide range of results, potentially confounding comorbidities unaccounted for, uncertain autism diagnostic methods, and recruitment challenges.
Chronic/high dosing or late testing had the opposite effects in rodents, with decreased prosocial and increased asocial behaviour. This was attributed to increased anxiety, or to a change in serotonin-receptor function or a reorganisation of developing serotonergic innervation.
MDMA was anxiogenic at both low and high doses, but low doses increased social interaction and high doses decreased social interaction. The decreased social interaction was attributed to neurotoxicity.
A chronic dose of 5-20 mg/kg MDMA given twice daily over 3 days increased mouse social novelty preference, but a singular 5-10 mg/kg dose caused decreased social and prosocial behaviours and decreased sensitivity to subsequent MDMA-increased social behaviours.
Anxiogenic effects have been found in several studies with chronic dosing of MDMA, accompanied by a modest serotonin depletion. These effects may be due to long-term amygdalar/hippocampal hyperinnervation, which is significant because these areas modulate serotonin receptor function and/or response to negative stimuli. One study found no significant serotonin depletion with moderate chronic doses of MDMA, but more prefrontal-cortical serotonin depletion still occurs than single-dose. It is unclear whether this is due to neurotoxicity or natural neuroplasticity over time.
Adjacent lying is a social passive behaviour involving 5-HT1A receptors. Previous MDMA dosing reduces the sensitivity to future acute MDMA doses by eliciting serotonin release less, and may also result in persistent desensitisation of the oxytocinergic network. Homberg et al. (2007) found that playful social behaviours were affected by a novel bright environment, whereas a dark familiar environment was not. This may be due to increased anxiety, but it is also possible that social interaction can be used as a measure of social anxiety. A study found that oxytocin improved social cognition in autistic adults, but did not improve social behavior in autistic pre-teens and teenagers. It was also found that oxytocin decreased copulating behaviour in rats, and that females were more affected with investigation (sniffing) behaviours whereas males were more affected with other social-interaction behaviours.
4.1.2. Human Studies
For social interaction, a virtual ball-throwing task, an ultimatum game, the Prisoner’s Dilemma, and a welfare trade-off task are worth mentioning. MDMA reduces the decreasing effect of rejection on mood and self-esteem. The ultimatum game and prisoner’s dilemma assess social decision-making (trust and cooperation). Chronic 1.5 mg/kg MDMA decreased the probability of rejecting unfair offers and increased prosocial interaction, but did not increase cooperation with an untrustworthy opponent or game server.
MDMA increases prosocial feelings towards another person. Chronic 0.75-1.5 mg/kg MDMA given orally to humans increased positive emotion words, whereas 1.5 mg/kg MDMA increased words describing another that were social and reflective of theory of mind.
At chronic 1.1 mg/kg MDMA, participants were equally aroused by positive and negative sounds, and showed increased explicit and implicit emotional empathy for positive emotional stimuli. They also showed increased concern and arousal for people depicting emotions, and increased prosociality via a resource-allocation task.
4.2. Repetitive Behaviours (Rodent and Human Studies)
The studies indicate that singular 10-5 mg/kg MDMA may reduce repetitive and compulsive behaviours in rodents, but more studies are needed to determine the effects on humans.
Rodent studies indicate that chronic 10-20 mg/kg MDMA seems to have the least aggravating effect on cognitive rigidity. Older rodents had more cognitive rigidity, but were less impaired compared to their placebo counterparts, as were younger rodents which showed more working-memory impairments.
Accessory ASD traits are also worth investigating, such as an empathy deficiency, motor coordination and anxiety. MDMA tests could also be extended to test for these traits, but for treatment purposes it would be essential to look at the core impairments first.
A randomised double-blind placebo-controlled clinical trial on 12 humans with autism found that MDMA treatment reduced social anxiety and that positive scores were maintained in the follow-up at 6 months.
MDMA’s well-established prosocial effects include decreased social anxiety, increased empathy/perception/response to positive emotions/touch, and decreased empathy/perception/response to negative emotions/touch.
MDMA causes structural and physiological changes in serotonin neurons, and can cause long-term neuropsychological and affective impairments. The most prominent toxicological finding in the literature arises from the excessive administration of MDMA, which can cause decreased brain serotonin in the forebrain in rats.
Recreational MDMA users also tend to use other drugs in addition to ecstasy, which could also be the reason for these adverse effects. However, clinical use of MDMA has not been shown to produce serious persistent adverse effects in any of the clinical trials reported to date. MDMA produces hyperthermic effects in both humans and rodents. Repeated MDMA doses decrease the hyperthermic effect, which may produce tolerance against serotonin depletion. MDMA is known to cause neurodegeneration in rodents, as well as cortical, hippocampal and striatal neurodegeneration. Its dose should be monitored.
4.7. Dosing Regimen
MDMA has a narrow range of doses testable, and it would be inadvisable on ethical grounds to test MDMA given within PD 1-5 to rodents. The effect of MDMA on humans is different to that of rats, and requires 4 times the dose given to humans.
4.8. Summary
In rodents, administering 5-10 mg/kg MDMA seems to ameliorate social impairments significantly, but not cognitive rigidity and motor stereotypies. Therefore, clinicians need to assess MDMA’s dose-response curve to find a way to reduce these core impairments in ASD.
In humans, 0.75 mg/kg taken orally and chronically alleviates social impairment and minimal emotion recognition impairment. At 1.5 mg/kg, repetitive stereotypy may increase.
Non-rodent animals have the same effect of social impairment alleviation and no effect on stereotypy as rodent animals, but chronic 1.5 mg/kg p.o. causes cognitive rigidity.
Our review has several limitations, including the fact that only English-language papers were reviewed, and that only six databases were screened. Additionally, molecular analogues of MDMA may be worth investigating to optimise treatment drugs to maximise alleviations to the ad- dressed impairments, and minimise the adverse effects and exacerbations of impairments. There are a wide variety of rodent strains, each of which may have different responses to MDMA, and there are also limitations in mapping healthy rodents to ASD humans.
We have surveyed the effects of MDMA on other core autism-related impairments in rodent studies, and we cannot apply MDMA to reverse these other core behavioural impairments. Further research is needed to establish MDMA as an effective medication for this impairment.
A list of abbreviations is given, including 5-HT, ASD, DSM, FDA, MAO, MBDB, MDA, MDE, OXTR, PRISMA, USV, and PD.