JAQUELYN McCANDLESS, M.D. Certified by American Board of Psychiatry & Neurology HI Address: P.O. Box 1868, Honokaa, HI 96727, Phone 808-775-8142, Fax: 818-337-7338 JMcCandless@prodigy.net, www.starvingbrains.com www.LDNAfricaAIDS.org
SYNOPSIS: THE USE OF LOW-DOSE NALTREXONE IN TREATING AUTISM AND OTHER ILLNESSES June 2010 Introduction: Naltrexone is an opioid antagonist used for narcotic addiction treatment. At its full dose of 50mg or more per day, Naltrexone was approved by the US FDA in 1985 and made generic in 1997. In the US, once a drug has been tested and FDA approved for any use, physicians may work with compounding pharmacists to create different formulations and dosing of this drug as deemed appropriate for other disorders not formally studied, called “off label” use. This is why naltrexone at low doses has been increasingly used in the US (and elsewhere) over the past ten years. The following summary of the use of Low Dose Naltrexone (LDN) in the treatment of Autism Spectrum Disorder was prepared by Dr. Jaquelyn McCandless, a licensed physician certified by the American Board of Psychiatry & Neurology. Dr. McCandless has been treating ASD (Autism Spectrum Disorder) children since 1999 and is the author of a well-received book on the bio-medical treatment of autism, “Children with Starving Brains, A Medical Treatment Guide for Autism Spectrum Disorder” (First Edition 2002, Fourth Edition 2009 by Bramble Books). Autistic children are immuno-compromised, as demonstrated by multiple studies showing their inability to detoxify along with low glutathione levels (1-7). Glutathione is among the body’s endogenous detoxification agents (8). Dr. McCandless conducted private clinical studies in 2005 using LDN to assess its efficacy in improving the immune status in children with autism. History: A New York physician, Bernard Bahari MD, in working with hospitalized HIV+AIDS patients in 1985, was giving patients naltrexone to help addiction craving issues while being treated for the newly arising AIDS infectious disease (at that time, 50% of known AIDS patients in the US were addicted to narcotics from sharing contaminated needles). Addiction drug cravings were helped but blood tests showed immune systems responding negatively. He learned from a researcher at Penn State, Ian Zagon PhD, that in research work with animals naltrexone actually helped the immune system as the dose was lowered. Dr. Bahari did lower the dose and through serial blood tests of hospitalized patients determined that endorphin output increased and the ideal dose showing benefit to immunity was between 1.75-4.5mg of naltrexone compared to usual dosing of 50mg (9). Dr. Bahari started using LDN on HIV+AIDS patients, all of whom were expected to die; many of them are still alive today, 25 years later, using just LDN. For those who did proceed to full-blown AIDS, the combination of LDN and HAART medications worked quite successfully; most of those have also survived. Many hundreds of studies starting in
the 1970’s have shown the high level of safety of full-dose naltrexone (reviewed in 10-11). Dr. McCandless’ use of naltrexone to treat autistic children and adults with auto-immune illness has been and continues to be with an ultra-low dose of pure naltrexone powder, compounded with an immediate-acting carrier such as Avicel for capsules or Emu Oil for transdermal use, usually 3mg or less for children and 4.5mg or less for adults. LDN dosage is always less than one/tenth of the recommended dose of 50mg or more used for narcotic addiction. Mechanism of LDN: Studies have shown that naltrexone acts differently in the body at low doses than at regular dosing schedules (12-14). The tiny short-term blockage of opioid receptors provided by LDN activates the pituitary to respond with a high output of endorphins and enkephalins, known now to be among the primary activators of the immune system (15-18). This low dose formulation, made into capsules or in more recent years transdermal cream for adults with gut-absorption issues or autistic children (who often cannot swallow capsules), has been the form that Dr. McCandless has used in her “off label” studies. Findings: In her 2005 private LDN clinical studies with autistic children (written up and available but not published) Dr. McCandless discovered that 16 out of 20 children (80%) increased their CD4+ count in 16 weeks of LDN usage, and 20 out of 28 (70%) of their parents--an appreciable number of whom have autoimmune disorders--raised their CD4+ count. These results authenticated Dr. Bihari’s findings that LDN is safe and is an effective immune enhancer. The safety of LDN for children, as well as adults, is further inferred from the many studies with autistic children using naltrexone at much larger doses than 4.5mg (11, 13, 19-20). In this earlier published research naltrexone was shown to be safe, non-toxic and non-addicting at full dosage in clinical trials with children with autism. Since naltrexone and LDN are generic since 1997, they are also inexpensive; the cost for a month’s supply of transdermal LDN cream or oral capsules is about $25 or less. Since 2005 many thousands of autistic children from ages 2 to 18 yrs of age (as well as adults) have been and are still using LDN with no serious or irreversible harm reported. Side effects are mild and short-lived (temporary hyperactivity). LDN is very easy to use, as one capsule or one transdermal application is needed only once daily at bedtime. For children, the transdermal cream is easily applied while they are sleeping, since the optimum time of application is after 9pm for maximum effectiveness in working with the circadian rhythm of the usual nightly endorphin output. By 2007 the pharmacologist who, under Dr. McCandless’ guidance created LDN cream using Emu Oil as transmission medium, had given his formula to over 50 compounding pharmacies in the US, as well as pharmacies in Israel, Hong Kong and the UK. (The latter are locations where Dr. McCandless has taught physicians about bio-medical treatments of autism). In 2007 a query of three of the pharmacies that had compounded LDN over the longest period showed records of an average of 5000 prescriptions annually of both capsules and cream. Since then many more pharmacies are compounding LDN in both forms. In 2007 75% of a 200 parent assay conducted by a physician trainee rated LDN “Overall Beneficial,” which is high for a disease as complex and challenging as Autism Spectrum Disorder. Though autistic children are most often prescribed LDN for immune
system benefits, what parents notice and appreciate most is an increase in socialization that occurs with LDN in the vast majority of cases. Parents have nicknamed it “the happy cream.” Socialization benefits show up often within several weeks, while immunity benefits can take up to 3-4 months or more to attain the maximum effect. Despite the positive effects of LDN with ASD children, it is not a stand-alone treatment for autism. Rather LDN is part of a broad spectrum bio-medical approach that deals with dietary, gut inflammatory and toxicity issues as well. The causes of autism are increasingly being seen as arising from a combination of genetic predisposition and environmental toxicities (21-23). Since the latter are in general increasing universally, it is not surprising that ASD is growing to epidemic proportions in many parts of the world (eg, 24-28). By 2007, LDN’s usefulness in treating ASD children in the US, UK, Israel and Hong Kong led Dr. McCandless to want to make the medication available in Africa, not only in the treatment of autism, but also for treating other autoimmune illnesses in both children and adults. This led her and others to reactivate a study in Mali of the efficacy of LDN in treating adults with HIV+AIDS that Dr. Bihari had proposed six years before but which was never funded. This study was initiated in Mali in the fall of 2007 at CNAM, Pt. G Hospital, the University of Bamako and subsequently at CESAC, under the direction of an international team of physicians and specialists from Mali and the US, with Abdel Kader Traore, MD as the principal investigator. This clinical study, scheduled to be completed in July, 2010, consists of three groups, one receiving LDN only, one receiving standard HAART medications and a placebo, and the third receiving both HAART and LDN. It is planned to have this study ready for presentation at the August 2010 Scientific Conference in Bamako. Apart from this Mali Project, a variety of studies conducted in recent years in the US show the effectiveness and safety of LDN. These include studies on cancer, fibromyalgia, Crohn’s disease in both adults and children, and multiple sclerosis (eg, 29-33). Other clinical studies are in the planning stages. It is important to initiate the approval process for the use of LDN in Mali for treating autism as soon as possible. It’s success and safety in this context in the US and elsewhere justifies such approval. With completion of the current HIV/AIDS study and clinical evaluation of LDN with children, further steps can be taken to bring LDN into the mainstream of Malian medical practice. Lack of funding for more expensive medications as well as the shortage of trained medical personnel generally in sub-Saharan Africa makes children a group often deprived of adequate medical care. It is quite likely that ASD is under-diagnosed in Mali as it is in many countries unfamiliar with the condition and the fact that it is a bio-medical and not a mental illness. With medication as simple, effective, non-toxic, easy to administer, inexpensive and non-addicting as well as requiring minimal medical supervision, LDN would be a highly useful addendum to medical care for ASD children and others with auto-immune illnesses in sub-Saharan Africa. We also envisage Mali as being a resource for providing LDN to other African countries. The pharmaceutical approval of LDN in Mali would be an apt tribute to Dr. Bernard Bihari, the courageous discoverer of the use of LDN in humans, who at age 78 very recently passed away after a prolonged illness. Jaquelyn McCandless MD
References: 1. The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels. Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr JM. J Toxicol. 2009;2009:532640 2. Oxidative stress in Egyptian children with autism: relation to autoimmunity. Mostafa GA, El-Hadidi ES, Hewedi DH, Abdou MM. J Neuroimmunol. 2010 Feb 26;219(1-2):114-8. 3. Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism. Pastural E, Ritchie S, Lu Y, Jin W, Kavianpour A, Khine Su-Myat K, Heath D, Wood PL, Fisk M, Goodenowe DB. Prostaglandins Leukot Essent Fatty Acids. 2009 Oct;81(4):253-64. 4. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O, Gaylor DW. FASEB J. 2009 Aug;23(8):2374-83. 5. Biomarkers of environmental toxicity and susceptibility in autism. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R, Geier MR. J Neurol Sci. 2009 May 15;280(1-2):101-8. 6. Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. James SJ, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW. J Autism Dev Disord. 2008 Nov;38(10):1966-75 7. Glutathione and immune function. DrĂśge W, Breitkreutz R. Proc Nutr Soc. 2000 Nov;59(4):595-600 8. The central role of glutathione in the pathophysiology of human diseases. Franco R, Schoneveld OJ, Pappa A, Panayiotidis MI. Arch Physiol Biochem. 2007 Oct-Dec;113(4-5):234-58. 9. Efficacy of low dose naltrexone as an immune stabilizing agent for the treatment of HIV/AIDS. Bihari B. AIDS Patient Care. 1995 Feb;9(1):3. 10. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Bouza C, Angeles M, MuĂąoz A, Amate JM. Addiction. 2004 Jul;99(7):811-28 11. Efficacy and Safety of Naltrexone Use in Pediatric Patients with Autistic Disorder Gladys M ElChaar et al. The Annals of Pharmacotherapy 2006 (40) 1086-1095
12. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a doubleblind, placebo-controlled study. Bouvard MP, Leboyer M, Launay JM, et al. Psychiatry Res. 1995;58:191-201. 13. Placebo-controlled acute dosage naltrexone study in young autistic children. Willemsen-Swinkels SH, Buitelaar JK, Weijnen FG, et al. Psychiatry Res. 1995;58:203-215. 14. Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation. Webster LR. Expert Opin Investig Drugs. 2007 Aug;16(8):1277-83. 15. Enkephalins, brain and immunity: modulation of immune responses by methionineenkephalin injected into the cerebral cavity. Janković BD, Radulović J. Int J Neurosci. 1992 16. Multiple endogenous opiate and non-opiate analgesia systems: evidence of their existence and clinical implications. Watkins LR, Mayer DJ. Ann N Y Acad Sci. 1986;467:273-99 17. Neuroendocrine-immune interactions: immunoregulatory signals mediated by neurohumoral agents. Cavagnaro J, Waterhouse GA, Lewis RM. Year Immunol. 1988;3:228-46. Review. 18. Endogenous opioid peptides and hypothalamo-pituitary function. Howlett TA, Rees LH. Annu Rev Physiol. 1986;48:527-36 19. Naltrexone in autistic children: a double-blind and placebo controlled study. Campbell M, Anderson LT, Small AM, et al. Psychopharmacol Bull. 1990;26:130-135. 20. Brief report: a double-blind study of naltrexone in infantile autism. Leboyer M, Bouvard MP, Launay JM, et al. J Autism Dev Disord. 1992;22:309-319. 21. Autism and environmental influences: review and commentary. Bello SC. Rev Environ Health. 2007 Apr-Jun;22(2):139-56 22. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Persico AM, Bourgeron T. Trends Neurosci. 2006 Jul;29(7):349-58. 23. Autism and environmental genomics. Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG, Cremer L, Hatchwell E.
Neurotoxicology. 2006 Sep;27(5):671-84. 24. What's going on? The question of time trends in autism. Blaxill MF. Public Health Rep. 2004 Nov-Dec;119(6):536-51 25. Trends in autism. Merrick J, Kandel I, Morad M. Int J Adolesc Med Health. 2004 26. The rise in autism and the role of age at diagnosis. Hertz-Picciotto I, Delwiche L. Epidemiology. 2009 Jan;20(1):84-90. 27. Epidemiological study of autism spectrum disorder in China. Wong VC, Hui SL. J Child Neurol. 2008 Jan;23(1):67-72. 28. The incidence and prevalence of pervasive developmental disorders: a Danish populationbased study. Lauritsen MB, Pedersen CB, Mortensen PB. Psychol Med. 2004 Oct;34(7):1339-46. 29. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Berkson BM, Rubin DM, Berkson AJ. Integr Cancer Ther. 2009 Dec;8(4):416-22. 30. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Younger J, Mackey S. Pain Med. 2009 May-Jun;10(4):663-72. 31. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G. Mult Scler. 2008 Sep;14(8):1076-83. 32. Low-dose naltrexone therapy improves active Crohn's disease. Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Am J Gastroenterol. 2007 Apr;102(4):820-8 33. Low-dose naltrexone for multiple sclerosis and autism: does its benefit reveal a common cause? Good P. Med Hypotheses. 2006;67(3):671-2.