Medical Management of
Attentional and Behavioral Difficulties of Childhood:
Stimulant and Non-stimulant Strategies
A Brief Literature Review by Robert Sinaiko, M.D.
Over the past six years, amid reports of an explosion of new cases of
attention deficit disorder (ADD), production of methylphenidate (Ritalin®)
and amphetamines has increased almost sixfold. While advocates see the
expanded use of these stimulants as an appropriate response to a legitimate
medical condition, critics allege that they are prescribed inappropriately to
children whose behaviors fail to satisfy adult expectations, but do not
conform to strict diagnostic criteria.
Professionals who treat children with ADD, hyperactivity, and related
disorders should of course be aware of the advantages of stimulant
medicines. It is incumbent upon them also to understand the limitations
and risks of these controlled substances, even when given to children
accurately diagnosed with ADD, and to maintain familiarity with the
considerable scientific literature supporting a range of effective
non-stimulant medical strategies, including, for example, diet restriction and
II. Effects of Stimulant Treatment in ADD
Swanson and his co-authors, in a comprehensive literature review,
that the proven advantages of stimulant medications (Ritalin® and the
amphetamines) for patients with ADD are modest. Accumulated evidence
reveals that, when they work, stimulants produce only temporary
improvement in overactivity, inattention, impulsivity, deportment,
aggression, social interactions, and academic productivity. Adverse drug
effects, such as increasing tics and problems with eating, sleeping,
cognition, and mood, must be weighed against these limited benefits. In
most cases, stimulant treatment is stopped within two years. Stimulants do
not improve reading or other skills, and ameliorate neither long term
academic achievement nor eventual social functioning.
III. Non-stimulant Medical Strategies
A. Elimination Diets
Recent years have seen the publication of a body of scientific research
supporting the effectiveness of elimination diets, most commonly targeting
artificial food colors and preservatives, cow's milk, wheat, and soy, for
ADD and hyperactivity. Experimental neurotoxic effects of synthetic food
colors have been demonstrated in both invertebrate
and vertebrate 
animal systems. Controlled human experiments investigating the
consequences of ingestion of food dyes by hyperactive children have
yielded evidence of adverse effects on learning
and behavior. A number
of well-designed double-blind, placebo controlled trials have demonstrated
the effectiveness of dietary elimination for the control of behavioral
symptoms in hyperactivity and ADD.
 The percentage of ADD or
hyperactive children who improve on an open elimination diet varies
among these reports from 58% to 82%.
 The percentage of subjects
whose food-induced behavioral symptoms are confirmed by double-blind
placebo-controlled food challenges ranges from 60%
It is possible that selection bias factitiously elevates the percentage of diet
responders in some or all of these reports, since parents who consent to
participation in diet studies may include a disproportionate number who
believe they have observed food-induced problems in their children. As
Carter et al. have shown, controlled food challenge usually validates
parental suspicions of food-induction of behavioral
On the other hand, lower percentages of subjects with food sensitivities
confirmed on double-blind food challenges, compared to percentages
responding in open diet trials, are due in part to the failure of some
subjects who complete the preliminary open phase of the study to
participate in the final double-blind phase; food sensitivities of those
subjects who complete the open trial but do not participate in double-blind
food challenge are counted (with non-responders) as non-confirmed by
These reports demonstrate that there is no single dietary regimen that is
best for all children with hyperactivity and/or ADD. Each subject
underwent a period of dietary elimination followed by oral challenges with
specific foods, to determine his or her "ideal" diet. Many children in these
studies reacted not only to one food, but to several.
B. Allergy Desensitization Treatment
To determine whether food-induced hyperactivity would respond to allergy
desensitization treatment, Egger, Stolla, and McEwen carried out a double-
blind trial of enzyme potentiated desensitization (EPD) treatment in a
group of children diagnosed with this
condition. Open food challenges
were conducted before and after a series of EPD injections. All 16
children who completed three active EPD injections at intervals of 2
months became tolerant of provoking foods, compared with only 4 of the
20 children who completed the same number of placebo injections
(p<0.001). Adverse effects of EPD injections were limited to transient
local discomfort at injection sites. In those actively treated subjects whose
food sensitivity returned after completion of the trial, desensitization was
restored by additional EPD injections.
C. Ritalin® vs. Vitamin B6
Coleman et al. have published a report comparing methylphenidate
(Ritalin®) with pyridoxine (vitamin B6), for the treatment of
hyperactivity. Only 6 subjects participated,
and these children were
selected on the basis of their low blood serotonin levels and their previous
positive responses to methylphenidate. All subjects received a 3-week trial
each of placebo, low dose pyridoxine, high dose pyridoxine, low dose
methylphenidate, and high dose methylphenidate. In this group, behavioral
improvement on pyridoxine exceeded that on methylphenidate, both in
magnitude and in persistence of improvement after cessation of treatment;
both active treatments were superior to placebo. Blood serotonin, while
not consistently affected by methylphenidate or placebo, rose with
pyridoxine treatment, and remained increased during the post-pyridoxine
persistence of behavioral improvement. The intriguing results of this
study, which has yet to be repeated with a larger sample, have remained
unchallenged since publication in 1979.
D. Prevention of Hyperactivity
A positive correlation between recurrent middle ear infections (otitis
media) in infancy and the later diagnosis of hyperactivity has been
demonstrated by Hagerman and Falkenstein, who postulate that effective
strategies to reduce the incidence of otitis media might actually serve to
prevent cases of hyperactivity.
The authors' suggestion that, in order to
reduce the prevalence of hyperactivity, antibiotics should be given
vigorously to prevent otitis media (page 256) assumes not only that otitis
media is a cause of hyperactivity and not merely an associated condition,
but also that aggressive antibiotic treatment can reduce the incidence of
otitis media. The former assumption is untested; the latter is almost
A number of workers, failing to find any statistically verifiable advantage
of antibiotics for otitis media, have recommended their use only after 3 to
4 days of observation with analgesics and nose drops alone, and only in
those cases in which there is convincing evidence of focal bacterial
infection, the course of otitis is irregular, or there are complications such
as mastoiditis or ear discharge persisting beyond 14
Cantekin used a double-blind, placebo-controlled randomized trial
specifically to assess the efficacy of amoxicillin for otitis media with
effusion (OME). No benefit
was found, and unexpectedly, amoxicillin
significantly increased the recurrence rate of OME. Theoretical discussions
of possible mechanisms by which antibiotics might increase the incidence of
otitis media have focused on their tendency to cause microbes which do not
normally colonize the bowel to replace normal antibiotic-sensitive intestinal
flora. This might allow absorption of toxic microbial products and/or alter
host immunity. As an example, broad spectrum antibiotics, by destroying
normal bacteria, allow intestinal proliferation of Candida
fungus known to induce measurable changes in immune function.
The Developmental Delay Registry, a network of parents of children
suffering from a wide spectrum of developmental disorders encompassing
hyperactivity and ADD, has reported a survey directly correlating these
disorders with antibiotic use. The average number of courses of antibiotic
was 12.84 among 449 children diagnosed with developmental delays,
compared with 9.71 for 247 normally developing controls.
antibiotic use may simply reflect the higher incidence of infections in
children with hyperactivity, as reported by Hagerman and Falkenstein. On
the other hand, a role for antibiotics in causing hyperactivity would be
expected if Cantekin's observation that antibiotics increase recurrence of
otitis media, and the assumption that recurrent otitis media causes
hyperactivity, are both correct.
While antibiotics may have distanced us from the goal of preventing middle
ear infections, yet another clinical strategy is likely to bring us closer; a
recent report by Nsouli confirms that elimination diets for food allergy can
effectively treat and prevent recurrent otitis media.
significantly ameliorated OME in 81 of 104 children (86%) entered in this
study, and rechallenge with suspected offending foods provoked a
recurrence of OME in 66 out of 70 (94%). As with hyperactivity, the
demonstrated benefits of elimination diets for OME are contingent on
positive diagnostic oral food challenges, after a successful exclusion diet.
In otitis media, cow's milk, wheat, soy, egg white, peanut, and corn are the
most frequent provoking foods.
Given the state of this research, further scientific investigation, to
determine whether better diagnosis and treatment of food allergies and
restraint in the use of antibiotics will reduce the incidence of otitis media
and the prevalence of hyperactivity, would be welcome.
The burgeoning number of children receiving medical treatment for ADD
and related conditions is the focus of much public and scientific concern.
The current state of knowledge leaves many critical questions unanswered.
Clinicians, researchers, medical educators, teachers, parents and those
shaping public policy must stay abreast of emerging research, to insure that
the course they chart will optimize the healthy development of millions of
- Swanson JM, et al. (1993). Effect of Stimulant Medication on Children with
Attention Deficit Disorder.
A "Review of Reviews." Exceptional Children, 60, 154-162.
- Levitan H (1977). Food, drug, and cosmetic dyes: Biological effects related to
Proceedings of the National Academy of Sciences, U.S.A., 74, 2914-2918.
MEDLINE LINK and Full Text
- Logan WJ, Swanson JM (1979). Erythrosin B Inhibition of Neurotransmitter
Accumulation by Rat Brain Homogenate. Science, 206, 363-364.
- Augustine GJ, Levitan H (1980). Neurotransmitter Release from a
Vertebrate Neuromuscular Synapse Affected by a Food Dye. Science,
- Swanson JM, Kinsbourne M (1980). Food Dyes Impair Performance of Hyperactive
Children on a
laboratory Learning Test. Science, 207, 1485-1487.
- Rowe KS, Rowe KJ (1994). Synthetic food coloring and behavior: A
dose response effect in a double-blind, placebo-controlled,
repeated-measures study. The Journal of Pediatrics, 125, 691-698.
- Egger J, et al. (1985). Controlled Trial of Oligoantigenic Treatment in
the Hyperkinetic Syndrome.
Lancet, i, 540-545.
- Kaplan BJ, et al. (1989). Dietary Replacement in Preschool-Aged Hyperactive
Boys. Pediatrics, 83, 7-17.
- Carter CM, et al. (1993). Effects of a few food diet in attention deficit disorder.
Archives of Disease in Childhood, 69, 564-568.
- Boris MD, Mandel FS (1994). Foods and additives are common causes of the
hyperactive disorder in children. Annals of Allergy, 72, 462-468.
- Egger J, Stolla A, and McEwen LM (1992). Controlled trial of
hyposensitisation in children with food-induced hyperkinetic syndrome.
Lancet, 339, 1150-1153.
- Coleman M et al. (1979). A Preliminary Study of the effect of
Pyridoxine Administration in a Subgroup of Hyperkinetic Children: A
Double-Blind Crossover Comparison with Methylphenidate.
Biological Psychiatry), 14, 741-751.
- Hagerman RJ, Falkenstein AR (1987). An Association Between Recurrent
Otitis Media in Infancy and Later Hyperactivity. Clinical Pediatrics, 26, 253-257.
- Van Buchem FL, Dunk JHM, Van't Hof NIA (1981). Therapy of acute otitis media:
myringotomy, antibiotics, or neither? Lancet, ii, 883-887.
BACK MEDLINE LINK
- Van Buchem FL, Peeters MF, Van't Hof MA (1985). Acute otitis media: a new treatment strategy.
British Medical Journal, 290, 1033-1037.
- Froom J et al. (1990). Diagnosis and antibiotic treatment of acute otitis
media. Report from
International Primary Care Network. British Medical Journal, 300, 582-586.
- Cantekin EI (1990). Antibiotics for secretory otitis
media. Archives of Otolaryngology Head and Neck
Surgery, 116, 626-628.
- Bollag U, Bollag-Albrecht E (1991). Recommendations derived from practice
audit for the treatment of
acute otitis media. Lancet, 338, 96-99.
- Cantekin EI (1991). Antimicrobial Therapy for Otitis Media With Effusion
('Secretory' Otitis Media).
Journal of the American Medical Association, 266, 3309-3317.
- Stone HH (1973). Alimentary Tract Colonization by Candida Albicans.
Journal of Surgical Research,
BACK || MEDLINE LINK
- Domer JE and Garner RE (1989). In: The Immunology of Fungal Diseases,
Kurstak E (ed.). Marcel
Dekker, Inc., New York and Basel, 293-317.
- Dorfman K, Lemer P, Nadler J (1995). What puts a child at risk for
developmental delays? Results of
the Developmental Delay Registry Survey (Unpublished). Full version
reproduced in appendix.
- Nsouli TM, et al. (1994). Role of food allergy in serous otitis media.
Annals of Allergy, 73, 215-219.