Autism

Biomedical Complementary Treatment Approaches

Robert L. Hendren, DO

KEYWORDS
 Autism  Complementary and alternative treatment  Integrative treatment
 Biomedical treatment

KEY POINTS
 Families commonly seek alternative and complementary biomedical treatments with chil-
dren with autistic spectrum disorders (ASD).
 Although there are many biomedical CAM treatments in use, there is little evidence from
well-conducted randomized controlled trials (RCT) to support claims of efficacy or safety.
 A potential rationale for biomedical CAM treatments in autism is their potential beneficial
effect on epigenetic processes, which are increasingly shown to play a role in the gene-
environment interactions underlying the development of ASD.
 Three agents with a rationale for use with ASD, at least one RCT showing efficacy, and
safety data include melatonin, omega-3, and micronutrients.
 Additional agents with promise include N-acetylcysteine and methylcobalamin (methyl
B12), digestive enzymes, and memantine.
 Care providers should be prepared to thoughtfully discuss biomedical CAM treatments
with families to help them make informed decisions regarding the best options for their
child and for their family’s values.

INTRODUCTION

This article provides an overview of the biomedical subgroup of complementary and

alternative medicine (CAM) treatments for autism spectrum disorders (ASD). These
biomedical treatments include a variety of natural products, such as vitamins and min-
erals, melatonin, and digestive enzymes; procedures, such as neurofeedback and

Disclosures: Within the past year, the author has received research grants from Forest
Pharmaceuticals, Inc; Bristol Meyer Squibb; Otsuka America Pharmaceutical, Inc; Curemark;
BioMarin; Autism Speaks; the Vitamin D Council; and NIMH. The author is on an advisory
board for BioMarin, Forest, Janssen Pharmaceutical, and the Autism Speaks Treatment Advisory
Board. The author is not on any speakers bureaus.
Child and Adolescent Psychiatry, Department of Psychiatry, University of California, San
Francisco, 401 Parnassus Avenue, LP-360, San Francisco, CA 94143-0984, USA
E-mail address: Robert.Hendren@ucsf.edu

Child Adolesc Psychiatric Clin N Am 22 (2013) 443–456

http://dx.doi.org/10.1016/j.chc.2013.03.002 childpsych.theclinics.com
1056-4993/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
444 Hendren

chelation; some conventional medications that are being examined for new applica-
tions in treating autism, such as antifungals and memantine; diets; and nutraceuticals.
Nutraceutical agents are foods or food products that purportedly provide health and
medical benefits, including the prevention and treatment of disease. Biomedical
CAM treatments are integrative in nature, and most of them can be used in combina-
tion with conventional treatments for autism.
The author does not review the large number of CAM treatments that are less
biomedical in nature, such as mind/body approaches; body-based practices, such
as physical manipulation; or alternative medical systems, such as Ayurvedic or tradi-
tional Chinese medicine, despite the promising suggestive findings for some of these
treatments.
This article begins with a description of the evolving understanding of the cause of
ASD and how the recent shift in the etiologic paradigm is leading to increasing assess-
ment of treatment targets and the use of biomedical and CAM treatments. Many of the
potential biomedical CAM treatments are listed, and the ones with the most evidence
or most focus of public interest are reviewed briefly, along with a discussion of the
research models necessary to identify which children will be most likely to respond
to which treatments. Finally, a model is discussed for working with families who
have a member with an ASD when considering biomedical/CAM treatments. When
the term autism is used alone, it refers to autistic disorder as defined in the Diagnostic
and Statistical Manual of Mental Disorders (Fourth Edition). When ASD is used, it refers
to the spectrum of autism disorders from mild to severe.
Complementary and alternative treatments are commonly used. Although 12% of
children and adolescents in the United States use CAM treatments,1 up to 70% of chil-
dren with ASD are reported to use some form of biologic treatment (either CAM or
conventional),2 and an even higher percentage (up to 74%) of children with recently
diagnosed autism use only CAM and not conventional psychopharmacologic agents.3
The main reasons for families’ choice of CAM were related to concerns with the safety
and side effects of prescribed medications.3 Families are reported to expect their
primary care physicians to have knowledge about CAM treatments,4 yet many physi-
cians do not feel knowledgeable about them.

Cause of Autism and the Biomedical Concept

The cause of autism is widely accepted to be strongly genetic in origin, but the
increasing prevalence and recent studies of the genetics of autism5,6 suggest that the
cause of autism is also related to gene-by-environment interactions expressed through
or manifest in epigenetic processes. Epigenetics refers to the reversible regulation
of various genomic functions, independent of DNA sequence, mediated principally
through DNA methylation, chromatin sequence, and RNA-mediated gene expression.7
The related endophenotypes (measurable components along the epigenetic pathway
between the genotype and the distal symptom, personal characteristic, or phenotype)
are simple biologic aspects of a disease that can be observed in unaffected relatives
with a similar endophenotype at a higher rate than in the general population8 and that
are potentially reversible through nutrition, social factors, behavioral interventions,
and drugs.9 Executive and frontal lobe functions shared by family members may be
examples.
In autism, this process of gene-environment interaction and the resulting endo-
phenotypes might be viewed schematically as a model in which the layers of the
earth represent the expression of the genotype into various types of the phenotype
(Fig. 1). The surface of the earth represents the personal expression and symptoms
we see (phenotype), and the core of the earth represents the genes of that person
 Biomedical Complementary Treatment Approaches 445

Fig. 1. Surface (phenotype) to core (genotype) model of endophenotype.

(genotype). In between is the complex and interactive layering of developmental

processes that represent the endophenotype. Interventions targeting the surface
level 4 might include behavioral interventions, such as applied behavior analysis
and the external provision of structure. Levels 3 to 4 can be targeted with occupa-
tional therapy, physical therapy, speech and language therapy, and cognitive behav-
ioral therapy; levels 3 to 2 with pharmacotherapy; deeper into levels 3 and 2 with
biomedical and CAM therapies; and level 1 with treatments that result in gene
modification.
This middle earth of levels 2 and 3 is the target of biomedical therapy in autism and
other neurodevelopmental disorders and entails various active biochemical or physi-
ologic processes such as the following:
 Immune abnormalities/inflammation10
 Oxidative stress11
 Disturbed methylation11
 Mitochondrial dysfunction12
 Free fatty acid metabolism13
 Excitatory/inhibitory imbalance14
 Hormonal effects15
Such abnormal epigenetic processes are not found in all people with ASD or may
be active only during particular periods of time (Fig. 2). Therefore, treatment
research should recruit subjects for trials based on the state of their previously vali-
dated endophenotypic biomarkers16 to know if an intervention is targeting an active
biomedical process in the subject at that time. For instance, identifying an inflamma-
tory process through a biomarker such as a cytokine abnormality could be entry
criteria to a study of an antiinflammatory agent for the treatment of autism. Other
biomarkers of the active epigenetic process might be such measures as glutathione
(GSH) metabolites, glutamate and g-aminobutyric acid, magnetic resonance imag-
ing, genomic arrays, and others based on the current gene-by-environment interac-
tion altering the epigenetic process17 and are discussed further in studies presented
later in this article.
446 Hendren

Various biochemical and physiologic processes operate at levels 2 and 3; various

biomedical CAM therapies can target these processes, including CAM therapies
described by Levy and Hyman18–20:
 Neurotransmitter production or release (dimethylglycine, vitamin B6 with magne-
sium, vitamin C, omega-3 fatty acids, St. John’s wort)
 Food sensitivities and gastrointestinal function (gluten-free casein-free [GFCF]
diets, secretin, digestive enzymes, famotidine [Pepcid], antibiotics)
 Putative immune mechanism or modulators (antifungals, intravenous immuno-
globulin [IVIG], vitamin A/cod liver oil)
 Potential heavy metal toxin removal (chelation)
 Methylation (methylcobalamin, folinic acid)
 Nonbiologic (craniosacral manipulation, transcranial magnetic stimulation,
acupuncture)

Biomedical Treatments
Biomedical treatments include both conventional treatments, such as psychopharma-
cological agents, and less studied and less medically accepted treatments, such as
nutraceuticals, as well as other types of treatments, including devices like transcranial
magnetic stimulation.
Risperidone and aripiprazole are the only medications that the Food and Drug
Administration (FDA) has given approval for marketing for the indication of irritability

Fig. 2. Endophenotype stress cycle.

 Biomedical Complementary Treatment Approaches 447

associated with autism. Irritability is not a core symptom of autism, and no drug has the
FDA’s marketing approval for the indication of autism itself or for any core symptom of
autism.
Conventional pharmacologic treatments for symptoms associated with ASD include
stimulants, antidepressants, antipsychotics, anticonvulsants, and anxiolytics. Each of
these agents has been examined for autism-related symptoms in published studies,
and comprehensive critical reviews of this literature are available in 2 excellent recent
articles.21,22
Pharmacologic agents that are not traditionally considered as treatments of ASD or
associated symptoms but that have one or more published studies for the treatment
of symptoms associated with autism include propranolol,23 amantadine,24 D-cyclo-
serine,25 cholinesterase inhibitors,26 nicotinic agonist,27 memantine,28 naltrexone,29
and buspirone.30
The list of potential biomedical CAM treatments is long and most have inadequate
evidence to judge potential efficacy. See Box 1 for a list of most of the biomedical
CAM treatments of ASD. Two comprehensive reviews of those treatments with
reasonable efficacy data have been recently published.31,32
For this short article, the biomedical CAM treatments that have the most published
evidence, that have generated the greatest interest or controversy, and/or that none-
theless have significant promise for treating autism or autism-associated symptoms
are briefly discussed. These treatments include melatonin, omega-3, injectable meth-
ylcobalamin (methyl B12), N-acetylcysteine (NAC), memantine, pancreatic digestive
enzymes, micronutrients, immune therapies, and chelation.

Melatonin
Melatonin is an endogenous neurohormone released by the pineal gland in response to
decreasing levels of light. It causes drowsiness and sets the body’s sleep clock. ASD is
associated with a high frequency of sleep problems, and melatonin is increasingly used
to help children with ASD fall asleep.33,34 Rossignol and Frye35 published a review and
meta-analysis of 35 studies. They described reports of abnormalities in melatonin
levels in patients with ASD (9 studies: 7 low, 2 high, 4 circadian); significant correlations
between melatonin levels and ASD symptoms (4 studies); and gene abnormalities
associated with decreased melatonin production (5 studies). Of 18 treatment studies
of melatonin, there were 5 randomized controlled trials (RCTs) involving a total of 61 pa-
tients treated with nightly doses of 2 to 10 mg. These RCTs showed positive effects on
sleep in that sleep duration was increased (44 minutes, Effect Size [ES] 5 0.93) and
sleep onset latency was decreased (39 minutes, ES 5 1.28), but nighttime awakenings
were unchanged. The duration of the studies varied between 4 weeks and 4 years. One
study suggested a loss of benefit at 4 weeks, whereas the study of 4 years reported
continued benefits. The side effects were minimal to none.
Melatonin is one of the best-studied biomedical CAM treatments of ASD. Although
small sample sizes, variability in sleep assessments, and lack of follow-up limit the value
of these studies in supporting its use, treatment with melatonin has a clear physiologic
rationale; and it is sensible, easy, cheap, and safe.

Omega-3 Fatty Acids

Omega-3 long-chain fatty acid supplementation is reasonable to consider because
omega-3 fatty acids are essential to brain function and development.36 They are a
critical component of neuronal membranes, they are essential for their optimal func-
tioning, and they serve as substrates for the production of the eicosanoids, such as
prostaglandins, which are necessary for cell communication and immune regulation.
448 Hendren

Box 1
Potential biomedical CAM treatments of ASD

Pioglitazone hydrochloride (Actos) Immune therapies

Acupuncture IVIG
Animal-assisted therapy L-carnosine

Antibiotics Magnesium
Antifungals (fluconazole [Diflucan], nystatin) Melatonin
Antiviral (valacyclovir hydrochloride [Valtrex]) Methylcobalamin (methyl B12)
Amino acids N-acetylcysteine
Auditory integration therapy (music therapy) Naltrexone
Chelation Neurofeedback
Chiropractic Oxalate (low) diet
Cholestyramine Oxytocin
Coenzyme Q10 Pyridoxal phosphate
Craniosacral therapy Probiotics
Curcumin Ribose and dehydroepiandrosterone
Cyproheptadine S-adenosyl-methionine
Dehydroepiandrosterone Secretin
Digestive enzymes Sensory integration therapy
Dimethylglycine, trimethylglycine Specific carbohydrate diet
Fatty acids (omega-3) St. John’s wort
5-hydroxytryptophan Steroids
Folic/folinic acid Transfer factor
GSH Vitamin A
GFCF diet Vitamin B3
Food-allergy treatment Vitamin B6 with magnesium
Hyperbaric oxygen treatment Vitamin C
Iron Zinc
Infliximab (Remicade)

The two omega-3 fatty acids of primary interest are eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA). Based on data from other disorders, they might be ex-
pected to improve mood, attention, and activity level as well as, conceivably, actual
symptoms of autism. Low levels of omega-3 fatty acids have been reported in chil-
dren with ASD.37–39
There have been 4 open trials35,38,40 and 2 double-blind, placebo-controlled, ran-
domized pilot trials in children with ASD.41,42 Amminger and colleagues42 randomized
13 children (aged 5–17 years) to EPA 840 mg and DHA 700 mg daily (n 5 7) or placebo
(n 5 6) for 6 weeks. There were no significant differences between groups on the Aber-
rant Behavior Checklist, possibly because of the small sample and insufficient power;
but omega-3 seemed nominally superior to placebo for stereotypy (Cohen’s d 5 0.72),
 Biomedical Complementary Treatment Approaches 449

hyperactivity (d 5 0.71), and inappropriate speech (d 5 0.39). In a study by Bent and

colleagues,43 27 children (aged 3–8 years) with ASD were randomly assigned to
12 weeks of omega-3 fatty acids (1.3 g/d) or an identical placebo. Hyperactivity
seemed to improve more in the omega-3 group than in the placebo group, although
not with statistical significance (2.7  4.8 vs 0.3  7.2, P 5 .40). Correlations were
found between decreases in the levels of 5 different fatty acids and decreases in
hyperactivity, with milder changes in other behaviors. There were no differences in
side effects. A larger Internet-based study of omega-3 fatty acid supplementation is
currently underway.
With only 2 small placebo-controlled RCTs totaling 38 children, and all 4 open
studies without statistically significant effects (possibly a power issue), the evidence
is small for omega-3 supplementation in ASD. This effect of omega-3 supplementation
on hyperactive behavior might mirror recent suggestions of a modest,44 though debat-
able,45 effect of omega-3 fatty acids in treating attention-deficit hyperactivity disorder
(ADHD). Despite the weak evidence and the modest effect, it has a rationale for its use;
and it is sensible, easy, inexpensive, and safe.

Methylcobalamin (Methyl B12)

Methyl B12 is a vital cofactor for the regeneration of methionine from homocysteine,
by providing methyl groups for metabolic pathways involving transmethylation and
transsulfuration. Reduced activity in the transsulfuration pathway can lead to reduced
levels of cysteine and GSH, which are crucial antioxidants responsible for minimizing
macromolecular damage produced by oxidative stress.
James and colleagues11 showed that many children with ASD exhibit low levels of
GSH and a decreased GSH/GSSG redox ratio. In an open-label trial in 40 children with
autism, administration of methyl B12 for 1 month resulted in a significant increase in
plasma GSH concentrations, although behavioral assessments were not done in
this study.11 Improvements were noted in social relatedness, language, and behavior
problems.
In a recent study, 30 patients completed a 12-week, double-blind RCT of subcuta-
neously injected methyl B12 at a dosage of 64.5 mcg/kg every 3 days; 22 patients
completed the 6-month extension study.46 The supplement was well tolerated. No sta-
tistically significant differences in behavior tests or in GSH status were identified be-
tween active and placebo groups. However, 9 (30%) patients demonstrated clinically
significant improvement on the Clinical Global Impression–Improvement Scale and
at least 2 behavioral and language measures. Improvements in social interaction and
language were most consistently reported. Notably, this subgroup of responders
exhibited significantly increased concentrations of GSH and GSH/GSSG compared
with the nonresponders. This study is the only published RCT, but a new RCT from
the same group will be completed in early 2013. Additional research is needed to delin-
eate a subgroup of responders and ascertain a biomarker of response to methyl B12.
Methyl B12 is typically administered at dosages of 64.5 to 75.0 mcg/kg with subcu-
taneous injections every 2 to 3 days. There are no studies in ASD of oral or nasal
methyl B12, which do not maintain consistently high levels and are thought to be
less effective. Subcutaneous injectable methyl B12 does seem to be safe. Although
initial studies are promising for a subgroup of children with ASD, and subcutaneous
injectable methyl B12 supplementation seems to be safe and well tolerated, additional
study is needed to determine whether this will become a recommended treatment of
ASD. However, despite reasonable cost, with repeated frequent injections, this treat-
ment is not easy to use.
450 Hendren

NAC
NAC is a glutamatergic modulator and an antioxidant. There is one published report of
a 12-week, double-blind, randomized, placebo-controlled study of NAC in children
with autism.47 Patients (31 boys, 2 girls; aged 3–10 years) were randomized, and
NAC was initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks,
and 900 mg 3 times daily for 4 weeks. Compared with placebo, oral NAC resulted in
significant improvements on the Aberrant Behavior Checklist (ABC) irritability subscale
(P<.001; d 5 0.96) and induced limited side effects. The results are promising, espe-
cially because the supplement is well tolerated; but this study will need to be repli-
cated before recommendations can be offered.

Memantine
There are biochemical studies suggesting that aberrant functioning of the N-methyl
D-aspartic acid (NMDA) receptor and/or altered glutamate metabolism may play a
role in autism. Memantine is a moderate-affinity antagonist of the NMDA glutamate re-
ceptor and is hypothesized to potentially modulate learning by blocking excessive
glutamate effects that can include neuroinflammatory activity. Its capacity to block
glutamate neurotoxicity and neuroinflammatory activity and to stimulate synapse
formation makes it an interesting candidate for treating autism. An open-label case se-
ries reported significant improvement in language and socialization in children with
autism.28 Memantine is well tolerated in children, and a multisite RCT is currently un-
derway. This treatment could be considered off-label use of a conventional medication
approved for the treatment of Alzheimer disorder rather than as a CAM treatment.

Pancreatic Digestive Enzymes

Enzyme deficiencies in children with autism result in a reduced ability to digest protein,
which affects the availability of amino acids essential for brain function. There is in-
creasing evidence for a gut-brain connection associated with ASD, at least in some
cases.48 This finding suggests a possible benefit from a comprehensive digestive
enzyme supplement with meals to aid digestion of all proteins and peptides, especially
for those children with ASD who have gastrointestinal disturbance.
Probiotics (consisting of microorganisms thought to improve digestive health by
repopulating the gastrointestinal tract with favorable flora) have also been proposed
to improve digestion and gut-brain activity in children with ASD. Some proponents
suggest these agents may also help remove toxins and improve immune function.
A double-blind placebo-controlled trial of digestive enzyme supplementation using
a 6-month crossover design in 43 children with ASD (aged 3–8 years) did not show any
clinically significant improvement of ASD symptoms.49 A possible effect on improve-
ment in the variety of foods eaten was suggested in the results. A commercially devel-
oped product (CM-AT by Curemark) has been specifically developed to target enzyme
deficiencies that affect the availability of amino acids in children with autism; fecal
chymotrypsin is used as a biomarker. Curemark (www.curemark.com) notes that it
has reached its targeted enrollment for a phase III study of a total 170 children with
autism at 18 sites. The unpublished Curemark study is interesting, and the FDA is
reviewing its findings; but further conclusions await the published results. There are
no reported trials of probiotics for ASD.

Micronutrients (Vitamins and Minerals)

Although multivitamin and mineral levels generally are not found to be abnormal in chil-
dren with autism, biomarkers of general nutritional status have been reported to be
 Biomedical Complementary Treatment Approaches 451

associated with autism severity.50 One open-label study of 44 individuals with autism,
aged 2 to 28 years, who were selected because they (or their parents) preferred a nat-
ural treatment, reported a benefit.51 There are only 2 RCT clinical trials of multivitamin/
multimineral supplements for children with autism, both from the same group. The first
randomized 20 children (aged 3–8 years) and reported the micronutrient supplement
yielded significantly better sleep and gastrointestinal symptoms than placebo.52
Another RCT of an oral vitamin/mineral supplement for 3 months with 141 children
and adults with ASD showed an improved nutritional and metabolic status of children
with autism, including improvements in methylation, GSH, oxidative stress, sulfation,
ATP, NADH, and NADPH.53 The micronutrient-treated group also had significantly
greater improvements on measures of global change (P 5 .008), hyperactivity (P 5
.003), and tantrums (P 5 .009).53
Despite limited evidence for the efficacy of vitamin and mineral supplements for
autism, there is widespread usage. The promising results from 2 RCTs suggest benefit
from a safe, easy to use, and relatively inexpensive agent.

Immune Therapies
Evidence is accumulating that there are subgroups of patients with ASD that have im-
mune deficiencies and signs of autoimmunity, such as atopy.10 Various approaches
have been tried to boost immune function or block autoimmunity. One of the most
obvious candidates has been IVIG treatment, and there are now 6 published open-
label trials of IVIG treatment with ASD.
In one open-label study, IVIG treatment improved eye contact, speech, behavior,
echolalia, and other autistic features.53 Others have claimed that IVIG treatment led
to improvements in gastrointestinal signs and symptoms as well as behavior. Subse-
quent studies have shown questionable benefits and mixed results for language and
behavior.
IVIG is a biomedical treatment whose overall results have been weak, and it carries
some significant risks. Other immune-boosting therapies may be of benefit but have
not been adequately studied. For future studies, it is unclear if an underlying immuno-
logic dysfunction is present in all individuals with ASD or if treatment trials should
target the patients with demonstrable inflammatory changes.

Chelation
Chelation, a process for removing heavy metals from the blood, has been used in
treating ASD based on the unproven theory that ASD is caused by heavy metal
toxicity; there is no convincing evidence of heavy metal toxicity from biochemical
studies in ASD. The hypothesized accumulation of heavy metals, particularly mercury,
would presumably be caused by the body’s inability to clear the heavy metals, by
increased exposure, or both.
Detoxification involves several intermittent courses of oral 2, 3-dimercaptosuccinic
acid (DMSA) or the intravenous chelator ethylenediaminetetraacetic acid, with periodic
elemental analysis of urine. According to proponents, successful detoxification treat-
ment requires clearing the gastrointestinal tract of harmful dysbiotic flora and bolstering
metabolism with essential nutrients, so that the individual can tolerate detoxification.
Two related studies have been published54,55 involving 65 children with ASD who
received one course of DMSA for 3 days. Selected for high urinary excretion of toxic
metals following the DMSA administration, 49 were randomly assigned in a double-
blind design to receive either 6 additional rounds of DMSA or placebo. DMSA was
reportedly well tolerated and resulted in high excretion of heavy metals, normalization
452 Hendren

of red blood cell GSH, and possibly improved ASD symptoms. Further studies are
needed to confirm these results.
Chelation is controversial because of its risks and because of its questionable
clinical findings, and the Institute of Medicine recently issued warnings. The most
common side effects are diarrhea and fatigue. Less common side effects include
abnormal complete blood count, liver function tests, and mineral levels. Renal and he-
patic toxicity is possible with oral agents, and seizures have been reported. Some pa-
tients may experience a sulfur smell, regression, gastrointestinal symptoms, or rash.

Summary of Biomedical Treatments for Autism and Future Directions

Research on CAM biomedical treatments for autism remains in its early stages, but
emerging data suggest several possible directions for current treatments (Tables 1
and 2) and future development. Melatonin for sleep induction is supported by 3 of
5 RCTs in children with ASD. Omega-3 fatty acids have 2 positive trending RCTs sug-
gesting the possibility of clinical value for treating hyperactivity associated with ASD,
but this might mirror recent findings of the putative efficacy of omega-3 fatty acids in
treating ADHD. Methylcobalamin may induce behavioral improvements, according to
a single RCT, but the treatment involves repeated injections several times weekly.
NAC has one RCT suggesting improvement in irritability. Memantine, which is an estab-
lished prescription drug treatment for Alzheimer disease, showed encouraging results
on language and socialization in one open-label series. Digestive enzyme supplemen-
tation is weakly supported by weak data, but a recent unpublished study suggests
possible benefit. Micronutrients (multivitamin and multimineral mixtures), based on
2 RCTs, may improve tantrums, hyperactivity, sleep, and gastrointestinal symptoms.
IVIGs have mixed findings in open-label trials (no controlled trials), entail medical risks,
and require repeated injections. Chelation showed trends toward improvements in so-
ciability, language, and cognition in a single RCT; but again medical risks are significant.

Table 1
Evaluations of biomedical CAM treatments for ASD: the evidence base

Strength of
Quality of Recommendations
Treatment Evidence Based on Data Evidence Base in Youth
Melatonin Good Recommend strongly 18 trials, 5 RCT
Omega-3 fatty acids Good Recommend 4 open trials, 2 RCT
Multivitamin/ Fair Recommend 2 RCTs
micronutrients
NAC Fair Neutral/recommend 1 RCT with group
significance
Memantine Fair Neutral/recommend 3 open trials, ongoing
multisite
Digestive enzymes Poor Neutral Anecdotal evidence
Methylcobalamin Fair Neutral 1 RCT w/o significance
(methyl B12)
Immune therapies Poor Insufficient data None
intravenous
Immunoglobulins Poor Insufficient data None
Chelation Poor Insufficient data None

Abbreviation: w/o, without.

 Biomedical Complementary Treatment Approaches 453

Table 2
Evaluation of biomedical CAM treatments for ASD: authors’ personal clinical opinion

Strength of
Recommendations Based Author’s Clinical
Treatment on Published Data Recommendations
Melatonin Reasonably good studies Very useful
Omega-3 fatty acids Improvement trends Suggest always
Multivitamin/micronutrients Possible benefit Routinely recommend
NAC Promising Suggest
Memantine Good open label Frequently consider
Methylcobalamin (methyl B12) Promising for subgroup Suggest cautiously
Digestive enzymes Not good evidence, yet Suggest for GI symptoms
Immune therapies No good data Discourage
IVIG No good evidence Discourage
Chelation Not good evidence Discourage

Abbreviation: GI, gastrointestinal.

Taken together, none of these treatments are ready for general usage; but some
families might elect to try such treatments. It is desirable for practitioners and families
to work together to review, evaluate, and perhaps select the treatments that offer the
most promise, have a rationale for use, fit with the families’ values, and have evidence
for safety and possible efficacy.
Multiple levels for intervention in the treatment of ASD are possible. Reviewing and
monitoring the levels for intervention assures an integrated approach to autism treat-
ment. A thorough medical assessment includes a review of symptoms, including a
possible genetic, neurologic, and gastrointestinal workup and consideration of other
medical symptoms when indicated. Applied behavioral analysis approaches, speech
and language assessment followed by therapies indicated by these evaluations, and
possible occupational therapy should be considered. Education, help in identifying
appropriate resources, and overall support is an essential part of the collaborative
relationship between the practitioner and the family.
Conventional psychopharmacology should be considered for severe symptoms
associated with autism, such as aggression, irritability, and anxiety. Integrated into
these interventions should be a thoughtful review and possible use of biomedical
CAM treatments, including melatonin for sleep, micronutrients, and omega-3 fatty
acids. Other interventions with promise and some safety data include NAC, digestive
enzymes, and methylcobalamin.

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