D. LOW-DOSE NALTREXONE (LDN) FOR
IMMUNE ENHANCEMENT AND MOOD IN
AUTISM, CANCER & AUTOIMMUNITY
(Excerpt from “Children With Starving Brains,” 4TH Edition, Chap. 10)
By JAQUELYN McCANDLESS, M.D.
What is naltrexone? And what is the difference between
naltrexone and low-dose naltrexone (LDN)?
Naltrexone is a medication used for exogenous opiate antagonism for treating opiate drug and alcohol addiction since the 1970s. It has been FDA-approved since 1984 and has been available since 1998 in generic form as well as in the brand name ReVia, both only in 50mg tablets. At regular dosing to treat addiction, usually 50 to 150mg a day, this drug blocks the euphoric response to opiates such as heroin or morphine as well as alcohol. Low-dose naltrexone (LDN) usually ranges between 1.5 and 4.5mg, less than 1/10th of regularly manufactured naltrexone, (standard is 50mg tablets) and must be compounded in capsules or a transdermal cream to get the tiny doses.
Endogenous opioids operating as cytokines create immunomodulatory effects through opioid receptors on all immune cells. A popular immune
classification method is referred to as the Th1/Th2 balance: Th1 cells promote cell-mediated or innate immunity, while Th2 cells induce humoral
or acquired immunity. Simplistically, the inability to respond adequately with a Th1 response can result in chronic infection and cancer; an
overactive Th2 response can contribute to allergies and various syndromes and play a role in autoimmune disease, which most autism spectrum
children show on immune testing. The November 13, 2003 issue of the New England Journal of Medicine (1a) notes: “Preclinical evidence indicates
Overwhelmingly that opioids alter the development, differentiation, and function of immune cells and that both innate and adaptive systems
Since the 1970’s, studies have consistently shown a variety of immune system disorders in autistic children.(1b) Infectious agents, toxic chemicals
(such as adjuvants in vaccines) and dietary peptides have been shown to be triggers for immune dysregulation and autoimmunity.(2) Hypersensitivity reactions to the large peptides found in casein and gluten (and often soy) products by autistic children inspired research into the opioid antagonist naltrexone in hopes of avoiding restrictive diets to prevent caseo-opioid and gluteo-opioid compounds in the brain from creating deleterious effects cognitively and behaviorally.(3a,b,c) An Italian study done in 1996 with varying naltrexone dosing showed significant reduction of autistic behaviors in 7 out of 12 children.(4) Behavioral improvement was accompanied by alterations in the distribution of the major lymphocyte subsets with increase in normalization of the CD4/CD8 (T/1) ratio.(5) No similar immune studies have since been reported on the use of naltrexone in autism, while a large body of research has pointed repeatedly to endogenous opioid secretions as playing the central role in the beneficial orchestration of the immune system.(6) Opioids are endorphins and operate as cytokines, the principal communication signalers or neurotransmitters of the immune system.(7) Studies at UC Davis Mind Institute show that cytokine responses elicited by the T-cells, B-cells, and macrophage cell populations following their activation differ markedly in children with autism compared to age-matched neurotypical children in the general population.(8)
History of LDN
Bernard Bihari, MD, a New York physician studying the immune responses in HIV+ AIDs patients in 1985,(9a,b) discovered that an ultra-low dose of naltrexone, approximately one-tenth or less than the usual dosage, boosts the immune system and helps fight diseases characterized by inadequate immune function. These diseases include autism, cancer, and autoimmune disorders. The temporary inhibition of brain endorphins when patients are given a very tiny dose of naltrexone apparently results in a reactive increase in the production of endorphins, tending to normalize/optimize the immune system with this elevation, accomplishing its results with virtually no side effects or toxicity. Naltrexone is considered very safe and has never been reported as being addicting. When LDN is given between 9 p.m. and 2 a.m., the pituitary is alerted and the body attempts to overcome the opioid block with an endorphin elevation, staying elevated throughout the next 18 hours. Studies in human cancer patients show that LDN acts to increase natural killer cells and other healthy immune defenses, and many hundreds of multiple sclerosis patients have totally halted progression of their disease for up to 8-10 years or more so far with regular use of this medication. Restoration of the body’s normal production of endorphins in those with cancer or autoimmune diseases is the major therapeutic action of LDN, which needs to be given only once a day between 9pm and 1-2am.
LDN In Autism
The use of LDN for children with autism spectrum disorders was previously studied in the 1990s, with researchers using from 5 to 50mg daily or every other day. In these early trials, researchers were looking for opioid antagonism because of these childrenis hypersensitivity reactions to the large peptides found in casein and gluten products. The enzyme needed to break down these peptides (DPPIV) is defective in most autistic children, and they are believed to form caseo-opioid and gluteo-opioid compounds in the brain creating deleterious effects cognitively and behaviorally. Researchers werehoping to counteract these opioid effects with the opioid antagonism offered by naltrexone rather than subjecting the children to dietary restriction (GF/CF) for these very common foods. Panksepp, Shattock and other early researchers noted variably better results with low doses; studies on higher doses were more equivocal in children, and non-compliance due to bitterness of the drug posed a problem for autistic children most of whom could not swallow capsules.
For private clinical studies in response to my request for a suitable transdermal form of LDN, molecular pharmacologist Dr. Tyrus Smith then
(2005) at Coastal Compounding Pharmacy in Savannah GA created a very effective transdermal cream compounded with emu oil. This allowed easy adjustment of dosing (some of the smaller kids did better with only 1.5mg), the bitter taste was no problem, and the cream could be put on children’s bodies while they slept. The cream is put into syringes, with 0.5 ml providing 3mg for children or 4.5mg for adults; most adults prefer capsules; both are equally effective. Many Crohn’s patients are now coming to prefer the transdermal form where absorption does not have to depend on a well-functioning gut mucosa.
I completed a preliminary eight-week informal study on 15 of my autism patients May-June 2005 applying 3mg of LDN transdermally between 9 and 12 p.m. Several adults participated also, one with Crohnis disease (CD) and one with chronic fatigue syndrome (CFS) using 4.5mg nightly. Parents and participating adults reported weekly on the results of the treatment. Eight of the 15 children in this study had positive responses, with five of these eight having results considered quite phenomenal according to their parents. The primary positive responses are in the area of mood regulation, cognition, language, and socialization. Two small children responded better when changed to 1.5mg dosing. No allergic reactions were noted, and the primary negative side effect was insomnia and earlier awakening, usually fairly short-lived. The two adults in the study had very positive responses, with the Crohn’s participant still reporting that she has been in remission since starting LDN (over several years at this writing).
All of the children in my study were on well-controlled dietary restriction, a standard part of the bio-medical treatment of children with autism as
practiced and taught by the (Defeat Autism Now!) Defeat Autism Now! branch of the Autism Reseach Institute. I have received reports from the
LDN-Autism e-list I monitor (over 2500 participants now) of about 5-10% of other children (not my patients) having side effects such as irritability, agitation, and restlessness, subsiding as soon as the drug is withdrawn. I queried parents about gluten/casein/soy in the children’s diets, as this response is likely indicative of withdrawal symptoms of opioid block even though brief. I suspect that children on a strict GF/CF/SF diet are less apt to show this response, and I personally see this negative reaction as a diagnostic clue that the child would benefit from dietary restriction; this has yet to be tested. The immediate positive mood/cognitive/social effects seen in many children starting this intervention is unlikely to be from immune enhancement showing up so quickly, sometimes within a few days. For other autoimmune studies on adults using LDN, the evidence is that the optimum immune response can take up to four – six months. In private correspondence with earlier autism researchers Drs. Panksepp and Shattock, they postulated that the LDN therapeutic effect with the rebound of endogenous opioids in the brain “loosens up” the opioid social-reward systems so children who were not connecting to the many known opioid based social rewards in the environment begin to respond to those rewards. (Endorphins are considered a source of our sense of well-being). Even traumatized animals (canines and primates) show new socialization behavior on LDN that had been previously missing. Both these researchers emphasized the importance of positive social reactions being reinforced and enhanced substantially by social support and encouragement, helping the new behavior become part of positive behavior modification. A certain proportion (estimate 15%) of children upon starting LDN show not only some increased hyperactivity and sleep changes, but a bout of what seems like “infection activation” in the form of a cold, fever blister, yeast flare-up and other reactions. These do not seem to be contagious and are usually short-lived, often followed by a burst of improved language,cognition, and socially seeking behavior. More recent input about this transition effect indicates that it is probably a “perturbation” of the immune status to another level of functioning, and some pathogen levels previously immuno-suppressed may be disturbed while immune elements are changing. Those children whose parents state “they never get sick” may now be moving from their reactive hyperimmune state to one where they are responding as most neurotypical children do to exposure to a new pathogen, giving the immune system an opportunity to develop antigens which will be in place to fight this organism when it reappears in their environment. Now, instead of immediately lowering the dose, I ask parents to use the full dosage quite soon, which seems to cut down this time of adjustment for most of the children, not all. Some need to go down in dosage, but I urge parents to try to stay the course if possible as I suspect the maximum immune benefits occur with full dose, whereas immediate social-reward and cheerfulness effects occur on ultra-tiny doses perhaps without maximizing immune benefits for long-term healing.
LDN For HIV+AIDS
My second clinical study in 2006 with 20 ASD children and 38 adults, mostly parents of ASD children, showed that 80% of the children had an increase in their CD4+ cell count on 16 weeks of LDN and 70% of the adults studied showed an increase. We (the author and her husband Jack Zimmerman PhD) are working with a health team in Mali Africa conducting a study for HIV+ adults to formally determine whether this medication can enhance/modulate the immune system to prevent progression to full-blown AIDS (See www.LDNAfricaAIDS.org). As opposed to the current standard AIDS medications which aim at disabling or killing the HIV virus, LDN is directly used to enhance oneis own endogenous immune system so it can ably fight the loss of cells essential to proper immune functioning and oppose any pathogen invasion or immune dysregulation.
Recent and Proposed New Research
As of this writing (early 2009) two more studies by Dr. Jill Smith on Crohn’s disease have been approved at Penn State, one a Phase 2 study for adult Crohn’s disease, and her Phase I study for children with Crohn’s is seeking participants. A study has been approved for a behavioral/cognitive study in Israel on autistic children, and LDN studies on MS and fibromyalgia at first-rate universities are on-going. In recent correspondence with neuropharmocology researcher Richard Deth, PhD, he reports that a new connection between opiate receptors such as naltrexone and redox (reduction oxidation reactions) has emerged. This study shows that morphine treatment causes a sizable down-regulation of the transporter that brings cysteine into neurons. This transporter is known as EAAT3, named after its ability to also transport glutamate, and it is essentially
the sole source of cysteine to neurons.(10) As such, it regulates neuronal redox status, especially in human neurons where the supply of cysteine from homocysteine transulfuration is very limited. The finding that morphine down-regulates this transporter raises an intriguing possibility that low-dose naltrexone may serve to up regulate cysteine uptake, with beneficial redox (detoxification) consequences. Other studies have shown acute down-regulation of glutathione in cerebrospinal fluid after morphine.(11) Dr. Deth believes this finding deserves further investigation. He believes some of the effects of opiates can be considered as a decrease in the mechanism of attention caused by interference with dopamine-stimulated phospholipid methylation by lowering glutathione levels. This recent research pointing toward the possibility that LDN could play a role in brain redox by creating more cysteine and therefore more glutathione to neurons is exciting and can be tested. Dr. Deth says, “Redox is at the heart of all cells, so it’s not surprising to think that agents affecting redox will exert broad benefits.” Research along these lines is being considered by Dr. Deth and colleagues, and if successful and positive could markedly enlarge the understanding behind benefit being seen in so many people with so many different illnesses taking LDN for immune enhancement. (A common comment upon hearing about LDN is, “It sounds too good to be true.”)
As an effective, non-toxic, non-addicting, and inexpensive behavioral and immuno-enhancing/modulating intervention, LDN is joining our biomedical arsenal to help more and more children recover from autism as well as helping many persons both adult and children with autoimmune diseases including HIV+ AIDS, MS, Crohn’s, and cancer or any disease that is caused by immune/autoimmune impairment or endorphin deficiency. Currently used in these ultra small doses as an “off-label” FDA approved medication, it must be prescribed and also compounded for the tiny dosing required. The filler medium carrying the medication is very important – it should be hypoallergenic and immediate-release to get the “jumpstart” for the brain to send the message out to the adrenal and pituitary glands to tell them to make endorphins. As to the carrier, I personally prefer emu oil for transdermal, avicel for capsule preparations. For more information on LDN see www.lowdosenaltrexone.org,
join Autism_LDN@yahoogroups.com, and see www.LDNAfricaAIDS.org.
1a NEJM 349:1943-1953 Nov 13 2003 #20, Ballantyne J, Mao J,”Opioid Therapy for Chronic Pain”
1b Cohly HH, Panja A., Immunological findings in autism. Int Rev Neurobiol 2005;71:317-41
2 A Vojdani, JB Pangborn, E Vojdani, EL Cooper: Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism,” International Joural of Immunopathology and pharmacology, Vol. 16, #3, 189-199 (2003)
3a Paul Shattock, Alan Kennedy, Frederick Rowell, Thomas Berney, Role of Neuropeptides in Autism and Their Relationships with Classical Neurotransmitters,” Brain Dysfunct 1990;3:328-345
3b Jaak Panksepp, Patrick Lensing, Marion Leboyer, Manuel P. Bouvard, “Naltrexone and Other Potential New Pharmacological Treatments of Autism”, Brain Dysfunct 1991:4:281-300
3c Paul Shattock, Paul Whiteley, iBridging the Gap—Opioid Peptides and Executive Function,” Paper presented at the Durham Conf 1998, Univ of Sunderland, UK
4 Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C. Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti B, “Opioid-immune interactions in autism: Behavioral and immunological assessment during a double-blind treatment with naltrexone,” Ann 1st Super Sanita. 1996;32(3):351-9
5 MP Bouvard, Marion Leboyer, JM Launay, C Recasens, MH Plumet, D Waller-Perotte, F. Tabuteau, D Bondouz, M Dugas, P Lensing, J Panksepp, “Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study”, Psychiatry Research 58 (1995) 191-201
6 Lois McCarthy, Michele Wetzel, Judith Sliker, Toby Eisenstein, Thomas Rogers, Opioids, opioid receptors, and the immune response,” Drug and Alcohol Dependence 62 (2001) 111-123 (Review)
7a Jean M. Bidlack, (Minireview), Detection and Function of Opioid Receptors on Cells from the Immune System, Clinical and Diagnostic Laboratory Immunology, Sept 2000, p 719-723
7b Michel Salzet, Didier Vieau, Robert Day, Crosstalk between nervous and immune systems through the animal kingdom: focus on opioids, Trends Neurosci (2000) 23, 550-555
8 UCDavis Health System, Children with autism have distinctly different immune system reactions compared to typical children, News release from UC Dvis M.I.N.D. Institute, 5/2006
9a www.lowdosenaltrexone.org: LDN and HIV/AIDS—“Low Dose Naltrexone in the Treatment of Acquired Immune Deficiency Syndrome, a paper presented in 1988 to the International AIDS Conference in Stockholm, Sweden, describing in detail the 1986 LDN HIV/AIDS clinical study.
9b www.lowdosenaltrexone.org: LDN and HIV/AIDS—“Low Dose Naltrexone in the Treatment of HIV Infection,” an informal description of the results in Dr. Bernard Bihari’s private practice through Sept 1996
10 Liling Yang, Shuxing Wang, Backil Sung, Grewo Lim, and Jianren Mao1 From the MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 “Morphine Induces Ubiquitin-Proteasome Activity and Glutamate Transporter Degradation,” Received for publication, January 30, 2008, and in revised
form, May 16, 2008 Published, JBC Papers in Press, June 6, 2008, DOI 10.1074/jbc. M800809200
11 Leonidas C. Goudas, MD, PhD*, Agnes Langlade, MD, PhD‡, Alain Serrie, MD, PhD‡,Wayne Matson§, Paul Milbury§, Claude Thurel, MD‡, Pierre Sandouk, MD\ , and Daniel B. Carr, MD, FABPM*†-Depts of *Anesthesia & †Medicine, New England Med Ctr & Tufts University School of Medicine, Boston, Massachusetts; ‡Centre de Traitement de la Douleur, Hopital Lariboisiere, Paris, France; §ESA Corporation, Chelmsford, Massachusetts; and \INSERM, Paris, France, “Acute Decreases in CBS Fluic Glutathioe Levels after Intracerebroventricular Morphine for Cancer Pain.