Pharmacobiological t...

Pharmacobiological treatments for ASD


Autism spectrum disorders (ASD) in young children and adults are characterized by problems in socialization, communication, emotion processing, and stereotyped/repetitive behaviors, along with sensory processing dysfunction, speech and language impediments, seizures, gastrointestinal issues, irritability, aggression, hyperactivity, and sleep disorders [1, 2]. Numerous underlying causes for ASD have been indicated such as genetic mutations, neurotoxicity and inflammation, impaired immune response, dysbiosis, nutrient imbalance, and oxidative stress [2].

Several treatment strategies have been undertaken in patients with ASD including behavioral and physiological interventions. Here, we review some of the physiology- and pharmacology-based interventions for ASD along with recent-advances in ASD treatment and their effectiveness in treating ASD. These include selective serotonin receptor-uptake inhibitors (SSRIs), antidepressants, antipsychotic drugs, stimulants, dietary supplements, herbal medications, special diets, hyperbaric oxygen therapy, stem cell therapy, and transcranial magnetic stimulation. Very limited data are currently available regarding the long-term effectiveness and side-effects of these existing treatments for ASD. So far, no medication has shown a consistent positive effect on patients with ASD.


Selective serotonin-uptake inhibitors (SSRIs) and Tricyclic antidepressants

Serotonin (5-hydroxytryptamine) is a neurotransmitter derived from tryptophan, and mainly sourced from the raphe nuclei in the brain. The serotonergic system plays an important role in attention, arousal, and feeding. Studies have shown that children with autism have elevated levels of blood serotonin [3].

SSRIs used in the treatment of ASD in various randomized controlled trials (RCTs) include fluoxetine, fluvoxamine, fenfluramine, and citalopram. SSRIs block the re-uptake of serotonin at the synapse, thus increasing the availability of serotonin and the activation of serotonin receptors [4]. In children and adults, SSRIs have shown limited positive outcome, although all the studies have been with small sample sizes, with potential risk of bias. In addition, SSRIs such as olanzapine, and fluvoxamine, have been shown to have undesirable side effects including irritability and weight gain [5, 6]. On the other hand, prenatal exposure to SSRIs have been linked to ASD risk in epidemiological studies [7, 8]. However, two very recent studies have concluded that there is no significant relationship between prenatal exposure to SSRIs and ASD risk and suggest that the previously observed association may be due to other factors [9, 10].

Tricyclic antidepressants (TCAs) have the same effect as SSRIs in increasing the serotonin levels. A short-term treatment of tianeptine showed a modest effect on irritability in 12 children with ASD [11]. Low-dose amitriptyline has also shown promise in youth with ASD for hyperactivity and impulsivity [12]. However, no large randomized clinical trials have been conducted till date with TCAs for treatment of ASD.


Old antipsychotics or neuroleptics are D2 dopamine receptor antagonists, although they are also effective against acetylcholine receptors, serotonin receptors, and adrenergic receptors. The old antipsychotics are less preferable due to their tight, long-lasting binding with the receptors. On the other hand, the second generation or atypical antipsychotics such as risperidone and aripiprazole, dissociate more rapidly from the receptors due to hit-and-run binding properties. Risperidone and aripiprazole have shown positive effects in several different clinical trials especially for ASD-related irritability [13, 14]. However, the major drawback of atypical antipsychotics are side effects such as weight gain, metabolic changes, sleep disturbances, higher risk of sedation and tremor, drooling, increased appetite, fatigue, dizziness, and withdrawal dyskinesias. Another atypical antipsychotic drug, clozapine, has been shown to be effective against hyperactivity and aggression in children with ASD [15].   

Stimulants and Non-stimulants

Stimulants such as methylphenidate are shown to improve the hyperactivity-impulsive symptoms in children with ASD. However, some studies have shown severe adverse effects with methylphenidate including social withdrawal, irritability, insomnia, and anorexia in children with ASD [16].   

Among non-stimulants, atomoxetine has been commonly used for treating the hyperactivity-attention deficit symptoms of ASD. In a recent double-blind placebo-controlled trial in children with ASD, the atomoxetine group showed an improvement in hyperactivity symptoms, with side effects of only fatigue and reduced appetite [17].


Based on the Pauling theory that suggests that deficiencies of vitamins and minerals may lead to mental disorders, many doctors have recommended the use of supplements in children with ASD, including omega-3-fatty acids, various vitamins, magnesium, iron, zinc and copper. In ASD studies, although omega-3-fatty acid supplementation had no significant beneficial effects in adult patients [18], another study on children have shown significant improvements in social and communication responses [19]. Among vitamins, vitamin B6 and magnesium [20], and vitamin D [21], have shown beneficial effects in few studies. Minerals such as magnesium [20], iron [22], and zinc [23], have also been recommended for nutritional therapies in ASD. However, large-scale high-quality randomized-controlled studies are required to conclusively determine if nutritional supplements are an effective therapeutic approach for ASD.

Special diets

Although special diets such as  gluten-free casein-free (GFCF) diet have been reported to have beneficial outcomes in children with ASD, most of these reports are anecdotal and do not have sufficient clinical evidence. The hypothesis behind the proposal of GFCF diet for ASD treatment is that the overload of high peptides such as gluten and casein may produce an opioid-like effect that could manifest as common behavioral symptoms of ASD. In addition, inflammation of the gastro-intestinal tract as well as unbalanced gut microbial, both of which are implicated in ASD, could get aggravated with casein and gluten, causing discomfort and pain in children with ASD leading to behavioral issues. However, intervention studies with GFCF diet show mixed results. Two of the most recent reviews on this topic suggest that there is very little evidence to suggest any beneficial outcome with GFCF diet on ASD symptoms [24, 25]. GFCF diet may be beneficial for ASD individuals with specific gut-related issues, or as a short-term relief.

The ketogenic diet, which is usually used for treating children with refractive epilepsy, is a high-fat, low-protein, low-carbohydrate diet. One study that investigated the effect of ketogenic diet on 30 children with ASD showed significant improvements in social and communication functions [26].

A low-oxalate diet has been recommended for children with ASD (40-50 mg per day) based on one study in patients with ASD showing higher plasma oxalate and urine oxalate levels [27].

Herbal medicines

A preliminary study using Panax ginseng, a commonly used herbal medicine, showed improvements of ASD symptoms, suggesting that it could be used as an add-on therapy for treating ASD [28].

Hyperbaric oxygen therapy

In hyperbaric oxygen therapy (HBOT), the patient is exposed to multiple sessions of pure oxygen in a sealed chamber, where the pressure is 1.5 to 3 times the normal atmospheric pressure. It is hypothesized that HBOT increases tissue oxygenation, decreased inflammation, and may have an anti-oxidation effect.  However, a randomized controlled trial with 60 children with ASD showed no improvements in any ASD symptoms compared to sham treatment, and more children in the hyperbaric oxygen group experienced adverse events compared to those in the sham treatment group [29].

Stem cell therapy

Since ASD has been linked to immune alterations and inflammatory cytokine overproduction, stem cells have been proposed as a treatment option due to their paracrine and immunomodulatory properties. A very recent study using human embryonic stem cell treatment in three pediatric patients showed improvements in various ASD symptoms including speech, cognition, eye coordination, and balance, and showed reduced hypersensitivity [30]. Another short study on bone marrow aspirate concentrate cell therapy in 10 patients with ASD also showed improvements in scores in autism scales after the therapy [31]. Combined transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in 37 subjects with ASD showed significantly improved scores in standard scales for ASD, with no safety issues and adverse events [32]. Similar improvements in scores were also observed in a pilot study using fetal stem cells in children with ASD [33]. However, given the controversial nature of using certain stem cells, and lack of solid evidence from a large-scale study, stem cell therapy for ASD should be considered with caution.

Transcranial magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive procedure for altering the excitability of the brain. Alterations in the cortical excitatory/inhibitory balance and abnormal event-related potentials (ERPs) have been implicated in ASD (34). It has been hypothesized that low-frequency rTMS over dorsolateral prefrontal cortex (DLPFC) would help modulate this imbalance and help in the treatment of ASD symptoms, and preliminary study results have been obtained to this effect [35, 36]. Although promising, carefully designed controlled clinical trials are required to evaluate the use of rTMS as a therapeutic approach for ASD.

Apart from the various treatments reviewed here, other approaches such as acupuncture, music therapy, various early behavior interventions, and social skill groups have been implemented for treatment of ASD with varying results. The review of recent literature shows us that there are no large-scale, high-quality studies for any ASD treatments that have looked at their long-term effectiveness and/or side effects. Moreover, the evidence is contradictory between studies for several treatments. For treatments that show promise, for example, atypical antipsychotic drugs, the side effects are significant. Hence, well-designed long-term RCTs with sufficient sample size are required to conclusively link the potential efficacy and/or the side effects of these treatments with ASD.


  1. Ivanov HY, Stoyanova VK, Popov NT, Vachev TI. Autism Spectrum Disorder - A Complex Genetic Disorder. Folia Med (Plovdiv). 2015;57:19-28.
  2. Bhat S, Acharya UR, Adeli H, Bairy GM, Adeli A. Autism: cause factors, early diagnosis and therapies. Rev Neurosci. 2014;25:841-50.
  3. Gabriele S, Sacco R, Persico AM. Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Eur Neuropsychopharmacol. 2014;24:919-29.
  4. Williams K, Brignell A, Randall M, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2013;(8):CD004677.
  5. Hollander E, Wasserman S, Swanson EN, Chaplin W, Schapiro ML, Zagursky K, et al. A double-blind placebo-controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder. J Child Adolesc Psychopharmacol. 2006;16:541-8.
  6. Maina G, Albert U, Salvi V, Bogetto F. Weight gain during long-term treatment of obsessive-compulsive disorder: a prospective comparison between serotonin reuptake inhibitors. J Clin Psychiatry. 2004;65:1365-71.
  7. Man KK, Tong HH, Wong LY, Chan EW, Simonoff E, Wong IC. Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: a systematic review and meta-analysis of observational studies. Neurosci Biobehav Rev. 2015;49:82-9.
  8. Boukhris T, Sheehy O, Mottron L, Bérard A. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr. 2016;170:117-24.
  9. Sujan AC, Rickert ME, Öberg AS, Quinn PD, Hernández-Díaz S, Almqvist C, et al. Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring. JAMA. 2017;317:1553-62.
  10. Brown HK, Ray JG, Wilton AS, Lunsky Y, Gomes T, Vigod SN. Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children. JAMA. 2017;317:1544-52.
  11. Niederhofer H, Staffen W, Mair A. Tianeptine: a novel strategy of psychopharmacological treatment of children with autistic disorder. Hum Psychopharmacol. 2003;18:389-93.
  12. Bhatti I, Thome A, Smith PO, Cook-Wiens G, Yeh HW, Gaffney GR, et al. A retrospective study of amitriptyline in youth with autism spectrum disorders.J Autism Dev Disord. 2013;43:1017-27.
  13. Dinnissen M, Dietrich A, van den Hoofdakker BJ, Hoekstra PJ. Clinical and pharmacokinetic evaluation of risperidone for the management of autism spectrum disorder. Expert Opin Drug Metab Toxicol. 2015;11:111-24.
  14. Ghanizadeh A, Tordjman S, Jaafari N. Aripiprazole for treating irritability in children and adolescents with autism: A systematic review. Indian J Med Res. 2015;142:269-75.
  15. Frogley C, Taylor D, Dickens G, Picchioni M. A systematic review of the evidence of clozapine's anti-aggressive effects. Int J Neuropsychopharmacol. 2012;15:1351-71.
  16. Simonoff E, Taylor E, Baird G, Bernard S, Chadwick O, Liang H, et al. Randomized controlled double-blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability. J Child Psychol Psychiatry. 2013;54:527-35.
  17. Tumuluru RV, Corbett-Dick P, Aman MG, Smith T, Arnold LE, Pan X, et al. Adverse Events of Atomoxetine in a Double-Blind Placebo-Controlled Study in Children with Autism. J Child Adolesc Psychopharmacol. 2017. doi: 10.1089/cap.2016.0187.
  18. Politi P, Cena H, Comelli M, Marrone G, Allegri C, Emanuele E, et al. Behavioral effects of omega-3 fatty acid supplementation in young adults with severe autism: an open label study. Arch Med Res. 2008;39:682-5.
  19. Amminger GP, Berger GE, Schäfer MR, Klier C, Friedrich MH, Feucht M. Omega-3 fatty acids supplementation in children with autism: a double-blind randomized, placebo-controlled pilot study. Biol Psychiatry. 2007;61:551-3.
  20. Murza KAPavelko SLMalani MDNye C. Vitamin B6-magnesium treatment for autism: the current status of the research. Magnes Res. 2010;23:115-7.
  21. Mazahery H, Camargo CA Jr, Conlon C, Beck KL, Kruger MC, von Hurst PR. Vitamin D and Autism Spectrum Disorder: A Literature Review. Nutrients. 2016;8:236.
  22. Dosman CFDrmic IEBrian JASenthilselvan AHarford MSmith R, et al. Ferritin as an indicator of suspected iron deficiency in children with autism spectrum disorder: prevalence of low serum ferritin concentration. Dev Med Child Neurol. 2006;48:1008-9
  23. Babaknejad N, Sayehmiri F, Sayehmiri K, Mohamadkhani A, Bahrami S. The Relationship between Zinc Levels and Autism: A Systematic Review and Meta-analysis. Iran J Child Neurol. 2016;10:1-9.
  24. Piwowarczyk AHorvath AŁukasik JPisula ESzajewska H. Gluten- and casein-free diet and autism spectrum disorders in children: a systematic review. Eur J Nutr. 2017. doi: 10.1007/s00394-017-1483-2.
  25. Elder JHKreider CMSchaefer NMde Laosa MB. A review of gluten- and casein-free diets for treatment of autism: 2005-2015. Nutr Diet Suppl. 2015;7:87-101.
  26. Evangeliou AVlachonikolis IMihailidou HSpilioti MSkarpalezou AMakaronas N, et al. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. 2003;18:113-8.
  27. Konstantynowicz J, Porowski T, Zoch-Zwierz W, Wasilewska J, Kadziela-Olech H, Kulak W, et al. A potential pathogenic role of oxalate in autism. Eur J Paediatr Neurol. 2012;16:485-91.
  28. Niederhofer H. First preliminary results of an observation of Panax ginseng treatment in patients with autistic disorder. J Diet Suppl. 2009;6:342-6.
  29. Xiong TChen HLuo RMu D. Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2016;10:CD010922.
  30. Shroff G. Human Embryonic Stem Cells in the Treatment of Autism: A Case Series. Innov Clin Neurosci. 2017;14:12-16.
  31. Bansal H, Verma P, Agrawal A, Leon J, Sundell IB, Koka PS. A Short Study Report on Bone Marrow Aspirate Concentrate Cell Therapy in Ten South Asian Indian Patients with Autism. J Stem Cells. 2016;11:25-36.
  32. Lv YT1, Zhang YLiu MQiuwaxi JNAshwood PCho SC, et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 2013;11:196.
  33. Bradstreet JJSych NAntonucci NKlunnik MIvankova OMatyashchuk I, et al. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant. 2014;23 Suppl 1:S105-12.
  34. Uzunova G, Pallanti S, Hollander E. Excitatory/inhibitory imbalance in autism spectrum disorders: Implications for interventions and therapeutics. World J Biol Psychiatry. 2016;17:174-86.
  35. Sokhadze EM, El-Baz AS, Tasman A, Sears LL, Wang Y, Lamina EV, et al. Neuromodulation integrating rTMS and neurofeedback for the treatment of autism spectrum disorder: an exploratory study. Appl Psychophysiol Biofeedback. 2014;39:237-57.
  36. Enticott PG, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB. A preliminary transcranial magnetic stimulation study of cortical inhibition and excitability in high-functioning autism and Asperger disorder. Dev Med Child Neurol. 2010;52:e179-83.