A Double-Blind, Placebo-Controlled, Crossover Pilot Trial of Low Dose Dimethylglycine in Patients with Autistic Disorder

Journal of Autism and Developmental Disorders, Vol. 29, No. 3, 1999

William M. Bolman1 and John A. Richmond2

As the treatability of the syndrome of autism becomes more possible there is a great deal more interest in the effectiveness of various therapies. Although the very influential nonmedical literature cited in the Autism Research Review International Newsletter finds that dimethylglycine (DMG) is regarded as more effective than the usual psychopharmacologic drugs, there have been no studies of DMG using the currently accepted research methodology. We report a double- blind, placebo-controlled, crossover pilot study of low dose DMG and placebo in a sample of eight autistic males ranging in age from 4 years 5 months to 30 years 8 months, who completed the full 3 1/2-month study consisting of drug-free baseline periods at the beginning, end, and in-between two, 1-month double-blind trials in which DMG or placebo was given. Measures in- cluded the Campbell-NIMH rating scale, an experimental rating scale, and an individualized scale created for each child. Analysis of all three scales revealed no statistically significant differences, and parent reports were equally distributed. The major methodologic weaknesses of the study are thought to be the low dosage of DMG and the small sample size.

KEY WORDS: Autism; dimethylglycine.

INTRODUCTION most recent edition of the Handbook of Autism and Per- vasive Developmental Disorders (Cohen & Volkmar, Prior to 20 or 25 years ago, autism was widely re- 1997). In the Preface, the editors state, "An index of garded as a developmental disability of unknown eti- the progress in the field is that more than 70% of the ology for which there was no consistently effective material in this Handbook is new" (p. xix). treatment. Today, the situation has changed dramati- Although the primary needs for autistic children cally, due to a combination of neurobiological knowl- involve rehabilitative efforts such as special education edge, a changed climate in child development about the and social/communication training, parents and pro- value of early intervention with handicapped children fessionals have been finding that a number of medi- (Dawson & Osterling, 1997), and the efforts of parent's cations may be useful in the management of disruptive advocacy groups. It has been recognized that autism is symptoms that interfere with learning. These include a broad syndrome and the prognosis of autism has methylphenidate and clonidine for hyperactivity and changed from complete pessimism to the recognition distractibility, the new antidepressant/anxiolytics (flu- there is a range of outcomes (Gillberg, 1991). An ex- oxetine, sertraline, paroxetine, fluvoxamine, and cellent overview of this transition to an increasingly clomipramine) for anxiety/environmental sensitivity defined neurobiological condition may be found in the and obsessive-compulsive symptoms, and most re- cently risperidone for improved sociability. However, it is important to note that some of these reports are 1 Formerly School of Medicine at the University of Hawaii. Now in private practice, 1600 Kapiolani Boulevard, #620, Honolulu, Hawaii based upon open-label trials and small case series 96814-3806. rather than double-blind, placebo-controlled studies. 2 Formerly at Tripler U.S. Army Medical Center, Honolulu, Hawaii. A good review of the psychopharmacology of autism

191 0162-3257/99/0600-0191$16.00/0 c 1999 Plenum Publishing Corporation 192 Bolman and Richmond

may be found in the chapter by McDougle (1997) in & Mayer, 1994), and maintenance of mood (Paul, Cohen and Volkmar (1997). Nowak, Layer, Popik, & Skolnick, 1994). This work is In addition to these drugs of known biologic ac- still so new and the possible relevance of DMG un- tion, there is an extensive nonmedical literature found known, it is not appropriate to speculate further, but it in the parent's advocacy literature, [e.g., the Advocate does suggest that there is a theoretical potential for DMG. and the Autism Research Review International (ARRI)]. Thus, given the potential of DMG as a neuro- In particular, Rimland (1990) has been interested in di- transmitter, the still unknown etiology(ies) of autism, methylglycine (DMG) for many years, and reports his the enthusiastic parental reports, and concern over conviction that it is helpful to "a substantial proportion adverse effects of psychoactive drugs, we thought that of autistic children and adults." Indeed, a sizable num- DMG deserved serious therapeutic trials. Due to the ber of parents of autistic children and adults claim that methodological problems of prior drug studies in autism, DMG is useful (Balliet, 1992; Doerfel, 1995; Dunn, we undertook a double-blind, placebo-controlled study, 1990; Gibbs, 1996; Hart, 1992; Jelen, 1991; Joss, 1991; to our knowledge the first such study of DMG ever Kutzin, 1992; Los Angeles attorney, 1993; Monihan, reported. 1990; New York mother, 1992; O'Reilly, 1991; Price, 1996; Reznek, 1993; Schultz, 1992; Stittgen, 1990; Turuba, 1994; Valentine, 1993; Venables & Venables METHOD 1994; Zhivago, 1993). Rimland has gathered parents reports on useful therapies, which has been published To get suitable subjects for the study, we ap- in the ARRI. According to this compilation, Vitamin proached our local Autism Society. Since this was our B6/Magnesium and DMG come out as considerably first trial, we chose a sample with a broad age range con- more effective than any of the known psychoactive med- sisting of 10 autistic males ranging from 4 years 5 months ications used by physicians, Rimland stated that DMG to 30 years 8 months. Seven were under 10 years and the often produces results within 1 to 2 weeks, and due to others were 13, 21, and 30 years, the mean age being its very low side-effect profile, he recommended that 10.74 years. Diagnoses were made using DSM-III-R cri- parents of autistic children do their own informal trials teria, with both authors concurring on the diagnosis. We without waiting for the medical community, given the did not evaluate the level of intelligence, but there were general climate of disinterest and the assumption that no "high-level" or Asperger syndrome patients in the DMG is ineffective. Additionally, he points out that since study. No patients were taking other medication either DMG is a generically available substance available in in the month before or during the study. Informed con- health food stores, no pharmaceutical company would sent was obtained from both the subject and from a par- be interested in funding studies. ent or guardian following university human subject There is little in the medical literature regarding guidelines. Rimland supplied DMG tablets and look-alike DMG. There was a single report on the use on N, N, placebos. We followed his intentionally conservative rec- -dimethylglycine in the treatment of epilepsy (Gascon, ommendations regarding DMG doses, which were var- Patterson, Yearwood, & Slotnick, 1989) but there were ied according to weight. Under 70 pounds received one no subsequent studies. However, since DMG is closely 125-mg tablet per day, 70 to 120 pounds received two related to the inhibitory neurotransmitter glycine, is less 125-mg tablets per day, and the single subject over polar than glycine, and potentially able to cross the 120 pounds got three 125-mg tablets daily. In his writ- blood-brain barrier, it would be expected to exert in- ings since 1995, Rimland suggested considerably higher fluence on the overall balance of inhibitory versus ex- dose levels. Of the 10 patients, 8 completed the full test- citatory neurotransmission. With the recent explosion of ing. One parent withdrew and a second was unable to molecular biological understanding of the central nerv- meet the data collection requirements and was dropped. ous system, neurotransmitter systems and their recep- The schedule of the study consisted of (a) a 2-week tors are now capable of being studied in detail. One of baseline; (b) 4 weeks of double-blind administration these is the N-methyl-d-aspartate (NMDA) receptor, a of DMG or placebo; (c) a 2-week washout period; subtype of glutamate receptor that mediates excitatory (d) 4 weeks of placebo or DMG; and (e) a 2-week base- amino acid transmission. This NMDA receptor contains line. Rimland held the key to the DMG/placebo, which a recognition site for glycine. Functioning of the NMDA was not released until data collection was completed. receptor is important in a variety of major physiologi- We used three clinical rating scales, (a) First was cal functions including neuronal development in the em- the Campbell-NIMH 14-point Autism Rating Scale bryonic nervous system, formation of memory (McBain taken from the larger Children's Psychiatric Rating Scale Pilot Trial of Low Dose Dimethylglycine in Autism 193

(CPRS; Campbell & Palij, 1985). These 14 items in- ject 8 was thought to be "calmer at times." Subject 8 volved social relatedness, speech characteristics, activ- was also thought to have "somewhat better" speech after ity, affect, and abnormal movements. Patients were the DMG trial, but the experimental checklist and re- videotaped weekly following a semistructured set of view of the videotape suggested a worsening of speech. guidelines in a playroom with standardized toys and rated This one family chose to continue DMG following the with this scale, (b) An experimental 10-item checklist termination of the study, while the remaining 9 chose developed by Rimland; this scale was intended to show not to continue. At the end of the trial we also asked the change in behavior in a wide variety of categories. These parents which time period they thought was associated were speech, eye contact, cooperation, understanding, with DMG and which with placebo. Three of the 8 sub- attention, sleep, bizarre behavior, anger/tantrums, activ- jects who completed the study were correct, slightly less ity level, and overall behavior, (c) Finally, given the than chance. varied and often unique and idiosyncratic behavior of The possible methodologic concerns for the study autistic children, we created an individualized scale, de- are (a) the dosage of DMG may have been too low; veloped with the help of the child's parents to rate be- (b) too small a sample of a syndromic condition raises haviors in the areas of attention, social relationships, the possibility that these patients were not representa- sensory-motor behaviors, language/communication, tive, and (c) insensitive clinical measures and inadequate self-help skills, and any unique symptoms the child had. methodology (i.e., failure to use single-case analyses on The ratings on the latter two scales were obtained dur- children who were responders). Given the range of autis- ing weekly clinic visits, and the videotaped records were tic symptomatology and presumed variable responsive- labeled and stored for later analysis. ness to DMG, it may be necessary to locate children who are responders and use a single-case study approach.

RESULTS CONCLUSION Individualized Scales. Analysis of variance of the individualized scales was examined child by child and Eight of 10 boys completed a 14-week double- for the group overall. From a total of 55 individualized blind, placebo-controlled, crossover study with 4 weeks scale items, 5 showed improvement with DMG versus on dimethylglycine and placebo. Although a few bene- placebo, 14 worsened, and 36 showed no difference. Fur- ficial and adverse effects were noted, there did not ap- ther, there was no evidence of clustering within the three pear to be significant, reproducible positive results with major symptom areas (social, communication, behavior). this sample. We hope to repeat the study at a future Experimental Checklist. Mean scores for each date and hope other investigators will look into DMG study period (baseline, drug/placebo, washout, drug/ with a larger sample. placebo and baseline) were pooled and a GLM (Gen- eral Linear Model) ANOVA was performed. There were REFERENCES no significant differences between any of the study periods for any of the 10 items, with p values ranging from The Advocate, Newsletter of the Autism Society of America. (1992). .280 to .896. Although not statistically significant, the Vol. 2, p. 27. Balliet, M. (1992). Letters to the Editor: B6, magnesium and DMG. Autism Research Review International, 6(2), 6. direction of change between placebo and DMG was Campbell M., & Palij, M. (1985). Behavioral and cognitive mesures slightly negative (i.e., worse on DMG) for all items ex- used in psychopharmacological studies of infantile autism. The cept eye contact and sleep. Children's Psychiatric Rating Scale (CPRS). Psychopharma- cology Bulletin, 21, 1047-1050. Videotaping. An initial review of the videotapes Cohen, D. J., & Volkmar, F. R. (Eds.). (1997). Handbook of autism at each study period by each researcher of the other and pervasive developmental disorders (2nd ed.). New York: researcher's patients indicated that here, too, there Wiley. Dawson G., & Osterling J. (1997). Early intervention in autism In were no significant results. Indeed, neither of us saw M. J. Guralnick (Ed.), The effectiveness of early intervention any significant change in behaviors using the CPRS. (pp. 307-326). Baltimore, Paul H Brookes. Therefore, a full review of all tapes by both re- Doerfel, K. S. (1995). Letters to the Editor: Vitamin B6/DMG. Autism Research Review International, 9(2), 7. searchers using the CPRS was not justified, and the Dunn, K. L. (1990). Letters to the Editor: DMG and vitamin B6. tapes were stored in the event of future need. Autism Research Review International, 4(4), 7. Parent Reports. At the conclusion of the study, Gascon, G., Patterson, B., Yearwood K., & Slotnick, H. (1989). N,N- dimethylglycine and epilepsy. Epilepsia, 30(1), 90-93. only 2 parents reported seeing any change. Subject 6 was Gibbs, L. (1996). Letters to the Editor: B6 safety fear; DMG. Autism reported as being more "edgy" during the trial, and Sub- Research Review International, 10(3), 7. 194 Bolman and Richmond

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