Using Evidence-Based

Medicine to Choose Effective

Biomedical Treatments for
Autism and ADHD
Dan Rossignol, MD FAAFP
International Child Development Resource Center
321-259-7111 www.icdrc.org
Autism One Conference 2009
May 24, 2009
 Autism Spectrum

ADHD Asperger PDD-NOS Autism

Syndrome

Psychologically / Behaviorally defined

Communication Stereotypical Social

behaviors interaction

Underlying pathophysiology ???

 Toxins Inflammation:
GI, Brain

Oxidative Impaired
Stress / Mito Glutathione /
Dysfunction Sulphation
 Active
Treatment Maintenance

IV Chelation
IVIG

Chelation
Anti-inflammatories
HBOT
Supplements
GFCF diet
Methyl B12
Antioxidants
Modified CGI – Parental
Autism Research Institute
 Levels of Evidence
 Level I: Evidence obtained from at least one properly
designed randomized controlled trial.
 Level II-1: Evidence obtained from well-designed
controlled trials without randomization.
 Level II-2: Evidence obtained from well-designed
cohort or case-control analytic studies, preferably
from more than one center or research group.
 Level II-3: Evidence obtained from multiple time
series with or without the intervention. Dramatic
results in uncontrolled trials might also be regarded
as this type of evidence.
 Level III: Opinions of respected authorities, based on
clinical experience, descriptive studies, or reports of
expert committees
This study presents the results of a 30-week
double-blind, placebo-controlled trial exploring
the effectiveness of ascorbic acid (8g/70kg/day)
as a supplemental pharmacological treatment
for autistic children in residential treatment.
Significant group by phase interactions were
found for total scores and also sensory motor
scores indicating a reduction in symptom
severity associated with the ascorbic acid
treatment.

Dolske et al., 1993 Prh Neuro-Psychopharmacol 17:765-74

Objective: Determine the effect of a moderate dose
multivitamin/mineral supplement on children with
autistic spectrum disorder. Design: Randomized,
double-blind, placebo-controlled 3-month study.
Twenty (20) children with autistic spectrum
disorder, ages 3-8 years. RESULTS: A Global
Impressions parental questionnaire found that the
supplement group reported statistically significant
improvements in sleep and gastrointestinal
problems compared to the placebo group.
Adams and Holloway, 2004 J Alt Comp Med 10(6): 1033-9
In an open-label trial, 40 autistic children were
treated with 75 mcg/kg methylcobalamin (2
times/wk) and 400 mcg folinic acid (bid) for 3 mo.
The 3-mo intervention resulted in significant
increases in cysteine, cysteinylglycine, and
glutathione concentrations (P < 0.001). Measures
of autistic behavior were assessed by a trained
study nurse before and after treatment using the
Vineland Adaptive Behavior Scales. Although
significant improvement was observed after
treatment, the scores remained significantly below
standard normal scores.
James et al., 2009 Am J Clin Nutr 89(1):425-30
Reduced folate transport to the CNS was
identified in two autism spectrum disorders, i.e.,
Rett syndrome and infantile low-functioning
autism with neurological abnormalities. Twenty-
five patients with early-onset low-functioning
autism with or without neurological deficits. Oral
folinic acid supplements led to normal CSF
5MTHF and partial or complete clinical recovery
after 12 months.

Ramaekers et al., 2007 Neuropediatrics 38(6): 276-81

Serum zinc correlated at r = -0.45 (p = 0.004) with
parent-teacher-rated inattention, even after
controlling for gender, age, income, and
diagnostic subtype. These findings add to
accumulating evidence for a possible role of zinc
in ADHD, even for middle-class Americans, and,
for the first time, suggest a special relationship
to inattentive symptoms. They do not establish
either that zinc deficiency causes ADHD nor that
ADHD should be treated with zinc.

Arnold et al., 2005 J Child Adolesc Psychopharmacol 15(4):628-36

Yorbik et al., 2004 J Trace Elem Exp Med 17(2):101-107
Bilici et al., 2004 Prog Neuropsychopharmacol Biol Psychiatry 28(1):181-90
The Mg-B6 regimen improved PDD symptoms in
23/33 children (p < 0.0001) with no adverse effects:
social interactions (23/33), communication (24/33),
stereotyped restricted behavior (18/33), and
abnormal/delayed functioning (17/33); 15/33
children were improved in the first three groups of
symptoms. When the Mg-B6 treatment was
stopped, PDD symptoms reappeared in a few
weeks.
Mousain-Bosc et al., 2006 Magnes Res 19(1):53-62
Pyridoxine treatment was associated with a
significant increase in verbal IQ scores. Net gain
in verbal IQ scores in the pyridoxine group as
relative to the placebo group showed a signif-
icant difference (5.2, 95% CI 0.2 to 10.3). After
controlling for sex, age, body weight, interval
between IQ tests, and baseline verbal IQ scores
using ANCOVA, the adjusted net gain in verbal IQ
scores in the pyridoxine group compared with the
placebo group still showed a significant
difference (6.8, 95% CI 5.0 to 8.5; p=0.01).
Kuriyama et al., 2002 Dev Med Child Neurol 44(4):284-6
Konofal et al., 2004 Arch Pediatr Adolesc Med 158(12):1113-5
Infants are at high risk for iron deficiency and
iron-deficiency anemia. This review summarizes
evidence of long-term effects of iron deficiency in
infancy. Follow-up studies from preschool age to
adolescence report poorer cognitive, motor, and
social-emotional function, as well as persisting
neurophysiologic differences. Research in animal
models points to mechanisms for such long-
lasting effects. Potential mechanisms relate to
effects of iron deficiency during brain
development on neurometabolism, myelination,
and neurotransmitter function.
Lozoff et al., 2006 Nutr Rev 64(5 Pt 2):S34-43
Twenty-three nonanemic children (aged 5-8
years) with serum ferritin levels <30 ng/mL who
met DSM-IV criteria for ADHD were randomized
(3:1 ratio) to either oral iron (ferrous sulfate, 80
mg/day, n = 18) or placebo (n = 5) for 12 weeks.
Iron supplementation (80 mg/day) appeared to
improve ADHD symptoms in children with low
serum ferritin levels. Iron therapy was well
tolerated and effectiveness is comparable to
stimulants.
Konofal et al., 2008 Pediatr Neurol 38(1):20-6
Seventy-seven percent had restless sleep at
baseline, which improved significantly with iron
therapy, suggesting a relationship between
sleep disturbance and iron deficiency in
children with autism spectrum disorder. 69% of
preschoolers and 35% of school-aged children
had insufficient dietary iron intake. Children
with autism spectrum disorder require ongoing
screening for iron deficiency.

Dosman et al., 2007 Pediatr Neurol 36(3):152-8

The aim of this randomized, double-blind,
placebo-controlled trial was to investigate the
influence of administered Pycnogenol or placebo
on the level of reduced (GSH) and oxidized
(GSSG) glutathione in children suffering from
ADHD. One month of Pycnogenol administration
(1 mg/kg/day) caused a significant decrease in
GSSG and a highly significant increase in GSH
levels as well as improvement of GSH/GSSG ratio
in comparison to a group of patients taking a
placebo.
Dvorakova et al., 2006 Redox Rep 11(4):163-72
We have found significantly increased damage to
DNA in ADHD children when compared to
controls. 8-oxoG was significantly lower after 1
month of Pyc administration in comparison to the
beginning state and to placebo group.
Improvement of DNA damage and TAS after Pyc
administration is associated with the
improvement of attention in ADHD children. In
conclusion, Pycnogenol administration reduces
oxidative damage to DNA, normalizes TAS and
improves attention of ADHD children.

Chovanova et al., 2006 Free Radic Res 40(9):1003-10

Sixty-one children were supplemented with 1
mg/kg/day Pycnogenol or placebo over a period
of 4 weeks in a randomised, placebo-controlled,
double-blind study. Results show that 1-month
Pycnogenol administration caused a significant
reduction of hyperactivity, improves attention
and visual-motoric coordination and
concentration of children with ADHD. In the
placebo group no positive effects were found.
One month after termination of Pycnogenol
administration a relapse of symptoms was noted.

Trebaticka et al., 2006 Eur Child Adolesc Psychiatry 15(6):329-35

Values of free and total carnitine (p < 0.001), and
pyruvate (p = 0.006) were significantly reduced
while ammonia and alanine levels were
considerably elevated (p < 0.001) in our autistic
subjects. The relative carnitine deficiency in
these patients, accompanied by slight elevations
in lactate and significant elevations in alanine and
ammonia levels, is suggestive of mild
mitochondrial dysfunction. It is hypothesized that
a mitochondrial defect may be the origin of the
carnitine deficiency in these autistic children.
Filipek et al., 2004 J Autism Dev Disord 34(6):615-23
Compared with the Rett syndrome controls,
treatment with L-carnitine led to significant
improvements in sleep efficiency (P=0.027),
especially in the subjects with a baseline sleep
efficiency less than 90%, energy level (P<0.005)
and communication skills (P=0.004). In addition,
before and after comparisons of the treatment
group showed improvements in expressive
speech (P=0.011).

Ellaway et al., 2001 Brain and Develop 23:S85-89

To determine safety and the efficacy of carnitine
treatment in children with attention-deficit
hyperactivity disorder (ADHD). In 13/24 boys
receiving carnitine, home behavior improved as
assessed with the CBCL total score (P < 0.02). In
13/24 boys, school behavior improved as
assessed with the Conners teacher-rating score (P
< 0.05). In the majority of boys no side effects
were seen. Treatment with carnitine significantly
decreased the attention problems and aggressive
behavior in boys with ADHD.
Van Oudhesden et al., 2002 Prostaglandins Leukot Essent Fatty Acids 67(1):33-8
We observed a stronger reduction of hyperactivity
and improvement of social behavior in patients
treated with LAC, compared with the placebo
group, as determined by the Conners' Global
Index Parents and the Vineland Adaptive Behavior
Scale. Our results show that LAC (20-50
mg/kg/day) represents a safe alternative to the
use of stimulant drugs for the treatment of ADHD
in FXS children.

Torrioli et al., 2008 Am J Med Genet A 146(7):803-12

We investigated 31 children with autistic
spectrum disorders in an 8-week, double-blinded
study to determine if 800 mg L-carnosine daily
would result in observable changes versus
placebo. After 8 weeks on L-carnosine, children
showed statistically significant improvements on
the Gilliam Autism Rating Scale (total score and
the Behavior, Socialization, and Communication
subscales) and the Receptive One-Word Picture
Vocabulary test (all P < .05).
Chez et al., 2002 J Child Neurol 17(11):833-7
Wu et al., 2006 Neuroscience Letters 400:146-9
Stevens et al., 1996 Physiol Behav 59(4-5):915-20
Absence of breastfeeding when compared to
breastfeeding for more than six months was
significantly associated with an increase in the
odds of having autistic disorder when all cases
were considered (OR 2.48, 95% CI 1.42, 4.35). The
results of this preliminary study indicate that
children who were not breastfed or were fed
infant formula without docosahexaenoic
acid/arachidonic acid supplementation were
significantly more likely to have autistic disorder.

Schultz et al., 2006 Int Breastfeed J 1:16

A randomized, controlled trial of dietary
supplementation with omega-3 and omega-6 fatty
acids, compared with placebo, was conducted with
117 children with DCD (5-12 years of age).
Significant improvements for active treatment
versus placebo were found in reading, spelling,
and behavior over 3 months of treatment in parallel
groups. After the crossover, similar changes were
seen in the placebo-active group.

Richardson, et al., 2005 Pediatrics 115(5):1360-6

 After 15 weeks there were improvements
in a test of the ability to switch and control
attention (Creature Counting) in the PUFA
groups compared to placebo (N=129,
p=0.002). This improvement was also
observed in the placebo group after taking
PUFA from weeks 16 to 30 (N=104). Total
of 167 children in study.

EPA 93 mg, DHA 29 mg, GLA 10 mg

Sinn et al., 2008 Prostaglandins Leukot Essent Fatty Acids 78(4-5):311-26

30 autistic children (18 males and 12 females)
aged 3-11 years and 30 healthy children as control
group were included in this study. After taking
Efalex, 66% of autistic children showed clinical
and biochemical improvement, linolenic acid and
docosahexaenoic acid showed the highest levels
after Efalex supplementation. CONCLUSION:
PUFA supplementation may play an important role
in ameliorating the autistic behavior.
Increased eye contact, language, concentration,
and motor skills in 2/3.
Meguid et al., 2008 Clin Biochem 41(13):1044-8
We observed an advantage of omega-3 fatty
acids compared with placebo for hyperactivity
and stereotypy, each with a large effect size.
Repeated-measures ANOVA indicated a trend
toward superiority of omega-3 fatty acids over
placebo for hyperactivity. No clinically relevant
adverse effects were elicited in either group.

840 mg/day EPA

700 mg/day DHA

Amminger et al., 2008 Biol Psychiatry 61(4):551-3

Results suggested that fewer hours of sleep per
night predicted overall autism scores and social
skills deficits. Similarly, stereotypic behavior was
predicted by fewer hours of sleep per night and
screaming during the night. Increased sensitivity
to environmental stimuli in the bedroom and
screaming at night predicted communication
problems. Finally, sensitivity to environmental
stimuli in the bedroom also predicted fewer
developmental sequence disturbances.
Schreck et al., 2004 Res Dev Disabil 25(1):57-66
Melke et al., 2008 Molecular Psych 13:90-98
107 children (2-18 years of age) with a confirmed
diagnosis of autism spectrum disorders who
received melatonin were identified. After initiation
of melatonin, parents of 27 children (25%) no
longer reported sleep concerns at follow-up visits.
Parents of 64 children (60%) reported improved
sleep, although continued to have concerns
regarding sleep. Parents of 14 children (13%)
continued to report sleep problems as a major
concern.

Andersen et al., 2007 J Child Neurol 23(5):482-5

Garstang and Wallis, 2006 Child Care Health Dev 32(5):585-9
 200 mg/day

After the intervention, (1) AD/HD symptoms were

significantly improved (p<0.01). Significant
improvement was observed both in the inattention
and hyperactivity and impulsiveness (p<0.01 and
p<0.05 respectively) (3) visual perception was also
significantly improved (p<0.001). A tendency
towards an improvement was observed in (2) LD
and (5) CPT (9 only error) (p<0.10). However, no
significant difference was observed with regard to
visual and auditory short-term memory (4).
Hirayama et al., 2006 AgroFood industry hi-tech 17(5):16-19
 800
mg/day

p < 0.001

Akhondzadeh et al., 2008 Child Psychiatry Hum Dev 39(3):237-45

Twelve children, all boys, aged 4 to 7 years, with a
diagnosis of autistic disorder and low
concentrations of spinal tetrahydrobiopterin. The
children received a daily dose of 3 mg
tetrahydrobiopterin per kilogram during 6 months
alternating with placebo. Post hoc analysis looking
at the 3 core symptoms of autism, that is, social
interaction, communication, and stereotyped
behaviors, revealed a significant improvement of
the social interaction score after 6 months of
active treatment.
Danfors et al., 2005 J Clin Psychopharmacol 25(5):485-9
Study was short-term tryptophan depletion in a
double-blind, placebo-controlled, randomized
crossover design. Tryptophan depletion led to a
significant increase in behaviors such as
whirling, flapping, pacing, banging and hitting
self, rocking, and toe walking (p < 0.05). In
addition, patients were significantly less calm
and happy and more anxious.

McDougle et al., 1996 Arch Gen Psychiatry 53(11):993-1000

 TP 5-HTP Stay
Asleep
Low Serotonin
OCD Anxiety

Self-
stimulatory Frustration
Behavior
Melatonin
The diets were supplemented with a novel dietary
enzyme formulation, ENZYMAID, for a period of 12
weeks. Progress was tracked according to the
Symptom Outcome Survey (SOS) (1) form method
of symptom charting and presented in a table for
further analysis. The novel enzyme formula,
ENZYMAID, beneficially and safely affected all 13
of the parameters measured. Improvements
ranged from 50-90%, depending on the parameter
measured.
Brudnak et al., 2002 Med Hypotheses 58(5):422-8
http://news.scotsman.com/ViewArticle.aspx?articleid=2807937
Children receiving cholesterol treatment
display fewer autistic behaviours, infections,
and symptoms of irritability and
hyperactivity, with improvements in physical
growth, sleep and social interactions. Other
behaviours shown to improve with
cholesterol supplementation include
aggressive behaviours, self-injury, temper
outbursts and trichotillomania.

Aneja and Tierney, 2008 Int Rev Psychiatry 20(2):165-70

 Doses: Antioxidants
 Vitamin C: 100 mg/kg/day
 CoEnzyme Q 10: 5-10 mg/kg/day
 Acetyl-L-Carnitine: 50-100 mg/kg/day
 L-Carnosine: 200-400 mg twice a day
 Pycnogenol: 1 mg/kg/day (often higher)
 MB12 injections: 75 mcg/kg every 1-3 days
 Folinic acid 400 mcg twice a day
 Omega-3’s: DHA and EPA ~800 mg/day each
 Zinc 20-150 mg/day
 Melatonin: 1-6 mg 30 mins before bedtime
We undertook a randomised, double-blinded,
placebo-controlled, crossover trial to test
whether intake of artificial food colour and
additives (AFCA) affected childhood behaviour.
Artificial colours or a sodium benzoate
preservative (or both) in the diet result in
increased hyperactivity in 3-year-old and 8/9-
year-old children in the general population.
McCann et al., 2007 Lancet 370(9598):1560-7
The aim of the present study has been to verify
the efficacy of a cow's milk free diet (or other
foods which gave a positive result after a skin
test) in 36 autistic patients. We noticed a marked
improvement in the behavioural symptoms of
patients after a period of 8 weeks on an
elimination diet. Our results lead us to
hypothesise a relationship between food allergy
and infantile autism as has already been
suggested for other disturbances of the central
nervous system.
Lucarelli, 1995 Panminerva Med 37(3):137-41
Hadjivassiliou et al., 2002 J Neurol Neurosurg Psychiatry 72(5):560-3
Sun et al., 1999 Autism 3(1):67-83
The effect of particular foods on levels of hyperactivity,
uncontrolled laughter, and disruptive behaviors was
studied in an 8-year-old autistic boy. The floor of the child's
room was taped off into 6 equal-sized rectangles to
measure general activity level. Frequency data were
recorded on screaming, biting, scratching, and object
throwing. During an initial 4-day period the child was fed a
normal American diet. A 6-day fasting period followed,
during which time only spring water was allowed. The third
phase lasted 18 days and involved the presentation of
individual foods. During the final phase the child was given
only foods that had not provoked a reaction in the third
phase. Results showed that foods such as wheat, corn,
tomatoes, sugar, mushrooms, and dairy products were
instrumental in producing behavioral disorders with this
child.
O’Banion et al., 1978 J Autism Child Schizophr 8(3):325-37
The introduction of a gluten-free diet to children
with autism and associated spectrum disorders
(n 5 22) was monitored over a 5 month period
using a battery of parental and teacher
interview/questionnaire sessions, observation
reports, psychometric tests and urinary profiling.
Results suggested that participants on a gluten-
free diet showed an improvement on a number of
behavioural measures.

Whiteley at al., 1999 Autism 3(1):45-65

The aim of this single blind study was to evaluate
effect of gluten and casein-free diet for children
with autistic syndromes and urinary peptide
abnormalities. A randomly selected diet and
control group with 10 children in each group
participated. Observations and tests were done
before and after a period of 1 year. The
development for the group of children on diet was
significantly better than for the controls.

Knivsberg et al., 2002 Nutr Neurosci 5(4):251-61

This study tested the efficacy of a gluten-free and
casein-free (GFCF) diet in treating autism using a
randomized, double blind repeated measures
crossover design. The sample included 15
children aged 2-16 years with autism spectrum
disorder. Data on autistic symptoms and urinary
peptide levels were collected in the subjects'
homes over the 12 weeks that they were on the
diet. Group data indicated no statistically
significant findings even though several parents
reported improvement in their children.
Elder et al., 2006 J Autism Dev Disord 36(3):413-20
MAIN RESULTS: Two small RCTs were identified
(n = 35). No meta-analysis was possible. There
were only three significant treatment effects in
favour of the diet intervention: overall autistic
traits, mean difference (MD) = -5.60 (95% CI -9.02
to -2.18), z = 3.21, p=0.001 (Knivsberg 2002) ;
social isolation, MD = -3.20 (95% CI -5.20 to 1.20),
z = 3.14, p = 0.002) and overall ability to
communicate and interact, MD = 1.70 (95% CI
0.50 to 2.90), z = 2.77, p = 0.006) (Knivsberg
2003).

Millward et al., 2008 Cochrane Database Syst Rev(2): CD003498

Bone development, casein-free diet use,
supplements, and medications were assessed
for 75 boys with autism or autism spectrum
disorder, ages 4-8 years. The 12% of the boys on
casein-free diets had an overall % deviation of
-18.9 +/- 3.7%, nearly twice that of boys on
minimally restricted or unrestricted diets (-10.5
+/- 1.3%, p < .04), although even for boys on
minimally restricted or unrestricted diets the %
deviation was highly significant (p < .001).
Hediger et al., 2008 J Autism Dev Disord 38(5):848-56
We assessed organophosphorus (OP) pesticide
exposure from diet. The median total dimethyl
metabolite concentration was approximately 6 times
higher for children with conventional diets than for
children with organic diets (0.17 and 0.03 micro
mol/L; p = 0.0003). The dose estimates suggest that
consumption of organic fruits, vegetables, and juice
can reduce children's exposure levels from above to
below the U.S. Environmental Protection Agency's
current guidelines.
Curl et al., 2003 Environ Health Perspect 111:377-82
Lu et al., 2006 Environ Health Perspect 114:260-3
A pilot prospective follow-up study of the role of
the ketogenic diet was carried out on 30 children
with autistic behavior. The diet was applied for 6
months, with continuous administration for 4
weeks, interrupted by 2-week diet-free intervals.
Seven patients could not tolerate the diet,
whereas five other patients adhered to the diet for
1 to 2 months and then discontinued it. Of the
remaining group who adhered to the diet, 18 of 30
children (60%), improvement was recorded in
several parameters and in accordance with the
Childhood Autism Rating Scale.
Evangeliou et al., 2003 J Child Neurol 18(2):113-8
 Attention / Hyperactivity
 Eliminate food coloring, additives, dyes
 Methyl B12 shots 75 mcg/kg every 2-3 days
 Pycnogenol 1 mg/kg/day
 Acetyl-L-Carnitine 50-100 mg/kg/day
 Zinc sulfate 150 mg/day (40 mg elemental zinc)
 Omega-3 fatty acids (~800 mg each DHA + EPA)
 Iron (if deficient)
 Phosphytidylserine 200 mg/day
 GABA: calming, 250-500 mg 3x/day, as needed
 Insomnia
 Melatonin
 5-HTP 25-50 mg 1 hr before bedtime
 GABA 250-750 mg 3x/day, as needed
 Omega-3 fatty acids
 Acetyl-L-Carnitine
 Clonidine
 Speech
• Omega-3 fatty acids
• MB12 injections
• L-Carnosine
• DMG 125 mg/year of life
• Acetyl-L-Carnitine
• Tetrahydrobiopterin (BH4) 1 mg/kg/day
• Piracetam 800 mg/day
 Social Interaction
• Acetyl-L-Carnitine
• Vitamin B6
• Oxytocin

Eye Contact
• Omega-3 fatty acids
• Vitamin A
• Galantamine
 Coordination
• Pycnogenol
• Omega-3’s

Toe-walking
• Tryptophan deficiency
• GI-related
 Self-stimulatory Behavior
Consider Treatment

• Low Serotonin • 5-HTP or TP

• PANDAS • Omega-3 fatty
• Clostridia acids
• Vitamin C (~100
mg/kg/day)
• Azithromycin or
PCN
 Seizures
 Taurine
 Vitamin B6
 Magnesium
 Omega-3 fatty acids
 GABA
 DMG
 L-Carnosine
 Summary: Where to start?
 Sleep / Melatonin / 5-HTP
 Multivitamin
 Omega-3 fatty acids
 Anti-oxidants
 Methyl B12 (SC injections)
 Diet, at least organic and eliminate food
colorings and preservatives, GFCF
 Digestive enzymes / probiotics
CONCLUSION: Children with autism who
received hyperbaric treatment at 1.3 atm and 24%
oxygen for 40 hourly sessions had significant
improvements in overall functioning, receptive
language, social interaction, eye contact, and
sensory/cognitive awareness compared to
children who received slightly pressurized room
air.

Rossignol et al., 2009 BMC Pediatr 9:21

The authors describe a child whose language
and behavior regressed at 22 months and in
whom pervasive developmental disorder was
later diagnosed. At 6 years, he displayed a
profound receptive-expressive aphasia
accompanied by behavioral disturbances
characterized by hyperactivity, impaired social
interactions, tantrums, gestural stereotypies,
and echolalia. Corticosteroid treatment
resulted in amelioration of language abilities
and behavior.
Stefanatos et al., 1995 J Am Acad Child Adolesc Psychiatry 34(8):1107-11
Bradstreet et al., 2007 Med Hypotheses 68(5):979-87
A total of 25 children (average age 7.9 +/- 0.7 year
old) were enrolled. Safety was assessed by
measurements of metabolic profiles and blood
pressure. There were no adverse effects noted and
behavioral measurements revealed a significant
decrease in 4 out of 5 subcategories (irritability,
lethargy, stereotypy, and hyperactivity). Improved
behaviors were inversely correlated with patient
age, indicating stronger effects on the younger
patients.
Boris et al., 2007 J Neuroinflammation 4:3
Acute nicotine treatment has been found to
reduce symptoms of attention deficit/hyperactivity
disorder in adults. Acute and chronic nicotine
treatment significantly attenuated the rise in hit
reaction time standard error over session blocks
on the Conners Continuous Performance Test.
Acute nicotine significantly reduced severity of
clinical symptoms on the Clinical Global
Impressions scale. Nicotine caused a significant
decrease in self-report of depressive mood as
measured by the Profile of Mood States test.

Levin et al., 2001 Exp Clin Psychopharmacol 9(1):83-90

Forty-three patients (35 males, 8 females, average
age 6.8 yrs., range 2.1-10.3 yrs), with diagnoses of
Autistic Spectrum Disorders enrolled in a
randomized six-week, double blind, placebo-
controlled trial of donepezil hydrochloride, with an
additional six weeks of open-label treatment.
Expressive and receptive speech gains, as well as
decreases in severity of overall autistic behavior,
were documented after 6-weeks for the treatment
group. These improvements were statistically
significant when compared to placebo, and were
clinically meaningful as assessed over time.
Chez et al., 2003 Journal of Pediatric Neurology 1(2):83-88
When parent and teacher scores were combined,
mean scores were slightly lower during treatment
with galantamine than during treatment with
placebo for irritability classified by ratings of the
aberrant behaviour checklist (galantamine 11.5
(7.6) v placebo 15.1 (5.4), P=0.039), hyperactivity
(17.2 (12.8) v 21.7 (15.4), P=0.038), inadequate eye
contact (placebo 7.6 (3.2) v 8.4 (5.2), P=0.049), and
inappropriate speech 4.7 (3.1) v 6.2 (2.4), P=0.045).

Niederhofer et al., 2002 BMJ 325:1422

OBJECTIVE: To review the efficacy and safety of
naltrexone in pediatric patients with autistic
disorder (AD). Naltrexone has been used most
commonly at doses ranging from 0.5 to 2
mg/kg/day and found to be predominantly effective
in decreasing self-injurious behavior. Naltrexone
may also attenuate hyperactivity, agitation,
irritability, temper tantrums, social withdrawal, and
stereotyped behaviors. Patients may also exhibit
improved attention and eye contact. Transient
sedation was the most commonly reported
adverse event.
Elchaar et al., 2006 Ann Pharmacother 40(6):1086-95
Subjects were included in the study if they had
inattention, impulsivity, and hyperactivity that was
excessive for their developmental level. Subjects
had not tolerated or responded to other
psychopharmacologic treatments (neuroleptics,
methylphenidate, or desipramine). Teacher ratings
on the Aberrant Behavior Checklist irritability,
stereotypy, hyperactivity, and inappropriate speech
factors were lower during treatment with clonidine
than during treatment with placebo.

Jaselskis et al., 1992 J Clin Psychopharmacol12(5):322-7

Open-label add-on therapy was offered to 151
patients with prior diagnoses of autism or
Pervasive Developmental Disorder Not
Otherwise Specified over a 21-month period.
Results showed significant improvements in
open-label use for language function, social
behavior, and self-stimulatory behaviors,
although self-stimulatory behaviors
comparatively improved to a lesser degree.

Chez et al., 2007 J Child Neurol 22(5):574-9

METHODS: Oxytocin and placebo challenges
were administered to 15 adult subjects
diagnosed with autism or Asperger's
disorder, and comprehension of affective
speech (happy, indifferent, angry, and sad) in
neutral content sentences was tested.
RESULTS: All subjects showed
improvements in affective speech
comprehension from pre- to post-infusion.

Hollander et al., 2007 Biol Psychiatry 61(4):498-503

A double-blind crossover design was used to
assess the efficacy of wearing ambient lenses to
reduce the behavioral symptoms of autism.
Eighteen autistic individuals, ranging in age from
7 to 18 years, participated in the study. Behavior,
attention, and orientation were evaluated at 1 1/2
months, 2 months, 3 months, and 4 months.
Compared to the placebo condition, the results
showed a decrease in behavior problems at the 1
1/2 and 2 month assessment periods and a slight
loss of these benefits at the 3 and 4 month
assessment periods.
Kaplan et al., 1998 Child Psychiatry Hum Dev 29(1):65-76
According to parents' and teachers' ratings,
children of the neurofeedback training group
improved more than children who had participated
in a group therapy program, particularly in
attention and cognition related domains.
CONCLUSION: There is a specific training effect of
neurofeedback of slow cortical potentials due to
enhanced cortical control. However, non-specific
factors, such as parental support, may also
contribute to the positive behavioural effects
induced by the neurofeedback training.
Drechsler et al., 2007 Behav Brain Funct 3:35
A total of 326 articles were identified, 91 of which
were retrieved for detailed evaluation. Sixteen
trials that assessed 9 different conditions were
included in the study. With the exception of
attention-deficit/hyperactivity disorder and acute
childhood diarrhea (each tested in 3 trials), no
condition was assessed in more than 2 double-
blind randomized clinical trials. The evidence for
attention-deficit/hyperactivity disorder and acute
childhood diarrhea is mixed, showing both
positive and negative results for their respective
main outcome measures.
Altunc et al., 2007 Mayo Clin Proc 82(1):69-75
Three small studies were included (total n = 24).
These examined the short-term effect of brief
music therapy interventions (daily sessions over
one week) for autistic children. Music therapy was
superior to "placebo" therapy with respect to
verbal and gestural communicative skills (verbal:
2 RCTs, n = 20, SMD 0.36 CI 0.15 to 0.57; gestural:
2 RCTs, n = 20, SMD 0.50 CI 0.22 to 0.79). Effects
on behavioural problems were not significant. The
findings indicate that music therapy may help
children with autistic spectrum disorder to
improve their communicative skills.
Gold et al., 2006 Cochrane Database Syst Rev (2):CD004381
Twenty children with autism, ages 3 to 6 years,
were randomly assigned to massage therapy and
reading attention control groups. Parents in the
massage therapy group were trained by a massage
therapist to massage their children for 15 minutes
prior to bedtime every night for 1 month. Results
suggested that the children in the massage group
exhibited less stereotypic behavior and showed
more on-task and social relatedness behavior
during play observations at school, and they
experienced fewer sleep problems at home.

Escalona et al., 2001 J Autism Dev Disord 31(5):513-6