The Fifth Annual

Low-Dose

Naltrexone Conference: A Review

by Emily Kane, ND

As daily opioid overdose surpasses motor vehicle accidents as a cause of premature death in the US, interest in naloxone and naltrexone has spiked. Training primary-care providers, pharmacists, friends and relatives of addicts, and legislators in the judicious use of the various forms of naloxone (Narcan, Vivitrol) will save many lives. Naloxone is an opioid antagonist that binds to the mu opioid receptors found on most cells, preventing activation of the opioid response, and mostly used in emergency settings to prevent opioid (e.g., heroin) overdose death. Naltrexone is a similar opioid antagonist but with a shorter half-life and slower uptake than Naloxone. Unlike naloxone, naltrexone is well absorbed orally and transdermally. My purpose in reviewing the 5th Annual LDN conference in Orlando, Florida (February 29–21, 2016), is to increase awareness of the broad-spectrum efficacy of naltrexone, used in very low doses, in alleviating human suffering.

The conference organizer, energetic LDN patient and advocate Linda Elsegood, along with many volunteer members of her family and staff, runs the LDN Research Trust, based in England. A summary fact sheet for everything LDN, including the 176 disease indications, per published research, is available on its website.¹ Another available resource is a video of Dr. Alex Vasquez interviewing a seasoned LDN prescriber.²

The trust has, hot off the press, an informative and fascinating book about the mechanism and uses of LDN that would be a good investment for anyone interested in the topic: The LDN Book.³ One of my favorite chapters in the book is a delightful romp through LDN history, starting with early humans’ fascination with narcotics, by Scottish pharmacist and pharmacy owner Stephen Dickson.

The more recent back story for LDN starts with the late researcher and neurologist Bernard Bihari. Bihari considered himself a primary-care physician and was living in New York City during the height of the AIDS epidemic in the 1980s. The city commissioned him to study the disease and gave him a large budget, because new victims were dropping like flies. Bihari noted that many of the advanced AIDS patients were also heroin addicts, and he became interested in measuring endorphin levels. This was an expensive undertaking, but Bihari had the funds and knew that helping addicts get off heroin could only improve their health. Bihari was able to show in an AIDS patient group that taking naltrexone regularly slowed or even halted the gradual destruction of CD4 cells. His trial group death rate was vastly lower than controls. This effect was not from LDN alone, but synergistic with the newer (at the time) antiretroviral drugs. Bihari also noted, almost incidentally, that when lower doses of naltrexone were given, there was a positive endorphin response compared with the endorphin suppression found when doses more typical for opioid addition were given. Opioid addiction is treated by blocking the effect of the opiate with 50 to 200 mg of naltrexone or naloxone daily, which inhibits any desired effect of the opioid for 24 hours. Bihari was assessing different dosing schedules and saw that giving very low doses of naltrexone actually stimulated endorphin production, rather than blocking it. At first he didn’t believe these results, so he repeated them. A colleague in Milan (Dr. Maria Garoni) verified this finding. Bihari’s work triggered a flurry of research assessing the importance of endorphins in the regulation of the immune system. A few years later, Dr. Ian Zagon speculated that low doses of naltrexone producing rebound uptick in endogenous endorphins could be used therapeutically. In 1986 Zagon demonstrated that opiate receptors were present inside multiple types of immune cells, and published nearly 300 research papers on LDN and endorphins. Quoting directly from The LDN Book, per Zagon, the basic mechanism of action for LDN is as follows:

1. Many outward diseases are expressions of a malfunctioning immune system.

2. The immune system is regulated by endorphins, which have a primary action on opiate receptors.

3. Blocking opiate receptors briefly using naltrexone causes an upregulation in the production of endorphins, which can act in an immunomodulatory way to correct immune system malfunction.

4. Cell proliferation is also mediated by a subtype of endorphins and can be suppressed by endorphins, which is applicable to some forms of cancer.

Endorphins and inflammation are not the whole picture, however. Naltrexone also binds to the group of receptors called toll-like (TLRs), first demonstrated by Christiane Nüsslein-Volhard in 1985 to recognize a wide range of antigens and initiate signaling pathways that trigger the appropriate immune response.

Now, in 2016, we also know that the broad mechanism of action of LDN is at least in part due to racemic isomers which have different and complementary functions. Mostly humans only have receptors for one isomer of a given molecule. However, in the case of naltrexone, the levorotating molecule fits into mu-opiate receptors and causes a brief suppression, then rebound proliferation of endorphins, mostly beta-endorphin and met-enkephalin. The dextro isomer fits into receptors for various mediators of inflammation (cytokines, NF kappa-b) and suppresses them, via TLR antagonist mechanism.

The 2½ day conference featured 25 speakers, mostly physicians and pharmacists. The conference attendees were a mix of health-care providers, pharmacists, and patients – a format recognized as salutary at least a decade ago by this publication. It is beneficial for all to have a variety of stake holders on site when expanding consciousness about health and well-being.

Learning of the breadth of LDN’s therapeutic potential was a highlight of the conference, and this feature cannot be adequately elucidated here. Lecturers gave clinical evidence (some with patient numbers in the 100s) of benefit in chronic pain disorders, Crohn’s, ulcerative colitis, IBS, SIBO, rheumatoid arthritis, sarcoidosis, psoriasis, polymyalgia rheumatica, FM, CFS, RLS, asthma, fertility, many autoimmune disorders, and many cancer types (endorphins boost apoptosis). This review will focus on the neurodegenerative disorders presented, since these are increasingly prevalent and conventional remedies are largely unsatisfactory. The brain disorder case studies helped by LDN presented over the weekend include autism, alcoholism, ALS, depression, dissociative disorder, MS, and PTSD.

Let’s start with alcohol addiction disorder, a condition from which 1 person dies every 10 seconds in the US, wherein addiction is moralized (“why can’t you just stop?”) and monetized (detox and dry-out facilities are big business). Treatment is often punitive or court mandated. We learned about a revolutionary method for curing alcohol addiction via the Sinclair Method, which uses naltrexone in slightly higher than LDN dosing, immediately before drinking, to neutralize the desire to continue to drink. This method has been used successfully in Finland to cure over 70,000 alcoholics. For more info visit www.cthreefoundation.org or www.onelittlepillmovie.com. The Sinclair Method claims a 78% long-term success rate, which is unheard of with detox or Twelve-Step programs. Over 120 clinical trials document this success. Check it out and spread the work.

There was not a lot of discussion of ALS, a currently incurable condition, but it was mentioned several times during the conference, and these patients may benefit from LDN, though no clinical trials exist. As an older, generic, drug, no return on investment exists for Big Pharma to develop LDN. One of the overarching purposes of the LDN Research Trust is to stimulate interest in deep research without need for financial motive. As an aside, this problem in research is one of the many compelling reasons to have a single-payer health-care system – wherein it actually becomes financially interesting to prevent and cure, rather than “manage” disease. The neuropathology of ALS is characterized by pathologic inclusions within both upper and lower motor neurons and glia. The conference’s opening lecturer, Dr. Pradeep Chopra (MD from Harvard Medical School and now instructor at Brown Medical School) emphasized that focusing on glial cells, as opposed to solely on neurons, was an important shift in thinking about treating pain and neurodegenerative diseases. Glial cells are so named because they were previously thought to be merely a “glue” for holding neurons in place. Now we know that glial cells play a critical house-cleaning role by modulating inflammation. When activated, they can release many pro-inflammatory chemicals including cytokines and chemokines, and increase TLRs on nearby cells. LDN blocks TLR4 signaling, and upregulates the opioid growth factor-OGF receptor axis, which blocks the release of cytokines, including IL6, IL12, TNF-alpha, and NF-kappa-beta. This dual actual of LDN (analgesic and anti-inflammatory) was revisited numerous times over the weekend, and is presumably the mechanism of benefit for ALS.

Depression and anxiety are extremely common clinical presentations, and over time these emotional conditions can create physical problems as well. Several presenters praised the benefits of LDN in “mind-body” problems, with a focus on the critical important of addressing the mental well-being of the patient when treating any disease. Hypnotist Lachlan Cox presented compelling evidence that emotions drive our pain. As an example, the mechanism of phantom limb pain is that the memory of the injury is stored in the limbic system. Ignoring physical sensations can amplify them. Find more about his work at www.focusperformance.pt.

Dr. Ulrich Lanius, a psychologist, presented on “Traumatic Stress, Dissociative Smptoms and Consciousness.” Dissociative symptoms include amnesia, depresonalization, inability to feel emotions, flashbacks, identity confusion, and somaticization. He talked about how, years ago, he came to an impasse with his usual method (EMDR) and recognized a similar “blankness” in patients with severe PTSD and those with high blood opioid levels. An Internet search brought him to naltrexone and he worked with a prescriber, using 50 mg, at first. It worked; blocked patients opened up and therapy interventions became useful. Later, he found Bihari’s work and switched dosing to 3 mg, which worked even better and remains Lanius’s preferred dose. Pape and Woller have a paper on LDN and PTSD from 2015 available on PubMed; 11 of 15 subjects had positive and lasting effects.

Day 2 started with a presentation of LDN for MS by Dr. Jarred Younger, “Calming the Microglia: A Future Method for Treating MS.” Well, the future is here and a 2015 chart review of 215 MS patients using 3.5 mg LDN daily, for average duration of 804 days, showed 60% improvement in fatigue, 60% improvement in overall disease severity, and with minimal side effects. Early treatment is key. Another presenter, Dr. Patrick Crowley, who has treated over 150 MS patients with only LDN (no other therapy), states that LDN is more effective than interferon. The pathophysiology of MS is demyelination due to deficits in microglial and oligodendrocyte function, triggered by many potential pathogens including hydrocarbon or heavy metal exposure, obesity, microbial infection, and so on, all of which cause inflammatory chemicals like NO to be overexpressed. These noxious chemicals make their way through the lymphatic system deep into the body, creating “autoreactive” T cells. Ultimately these antigenic T cells leak into the brain and attack axons, leading to relentless neuroinflammation. We have many anti-inflammatory remedies, but most do not cross the blood–brain barrier. LDN does. LDN reduces the inflammatory response to toxic T cells in the CNS. It is best used immediately after the first MS “attack,” because then it has potential to put the patient into permanent remission. Younger is raising funds to create an MS/LDN trial. He’s looking at a medium-sized pilot trial with about 60 patients; his budget is around $300,000. He is hoping that this will stimulate interest in a more comprehensive 4-year trial that can include labs and radiologic follow-up; this would cost $2 to $3 million. Any interested researcher or donor please contact him at Younger@uab.edu.

Day 3 began and ended with spectacular information on autism spectrum disorder. Lecturer Brian Udell, MD, has had other subspecialties during his medical career but asserts that the autism spectrum population has more savants than any other patient population he has worked with. After the lectures wrapped up, we were treated to a 20-minute virtuosic piano recital by one of Udell’s young patients, age 10, who is clearly a musical genius. Udell started working with Jacob Velazquez when the boy was 4. His parents brought him in due to extremely violent and aggressive behavior that crescendoed after the birth of his sister, who also is autistic and much improved on LDN. Check Jacob’s many inspiring piano concerts available on youtube.com.

I asked Udell in the lobby after the concert if he speculated on why autistics were more likely to display creative or mathematical genius. He shared a theory given to him by a colleague, which is that for some reason, during embryological development, the brains of autistic children do not “self-prune” and they ultimately have access to a lot more information. I was not familiar with neural pruning in utero, but it makes sense that as we develop, we respond to stimuli, noxious or beneficial, and grow new cells accordingly. The multitude of noxious stimuli in our environment today (gluten, GMO soy, Roundup, endless plastic) is undoubtedly why autism is so much more prevalent. It’s not only the mercury in the vaccines – mercury, fortunately, has largely been removed from children’s vaccines. In opening his lecture, Udell quipped that this week he got 6 or 7 bulletins about Zika virus, which has maybe 2 cases in Florida, whereas 1 in 4 boys are now being born autistic. Autism is the pandemic, not Zika!

Conventional medicine uses heavy duty drugs designed for adults on toddlers with brain problems. This is overkill and inappropriate. In 2006 Dr. Jaquelyn McCandless developed a protocol for administering topical LDN at 9 PM when the child is asleep. Udell has used this protocol very successfully in hundreds of cases.

The PDR actually lists LDN (along with Abilify and Risperdal, speedy antipsychotics which cause eating disorders, diabetes, and tics, and antiseizure meds Trileptal or Depakote) for treating autism. Most pediatricians prescribe stimulants (methamphetamine) for autistics. Since amphetamines retard growth, they really should not be given before age 8, not to speak of their high addictive potential. Straterra never works, says Udell. He sees lots of children on Zoloft and Prozac and claims that these are horrible approaches – the kids are stoned out their minds, drooling.

The key defining features in autism spectrum are speech apraxia and disruptive behavior. A child with a low IQ probably is not autistic. Most truly autistic children have higher IQ. Autistic children do not have OCD. OCD is washing your hands over and over or counting cracks in the sidewalk. All autistic children have GI problems – abnormal flora including yeast. You can fix the gut. This is more effective than trying to put a big drug Band-Aid over repetitive behavior. Autistic kids are strong (climb walls) but have low tone (can’t do pull ups or pedal big wheels). They don’t make eye contact. Check his weekly blog: theautismdoctor.com

Autistic children can’t communicate properly. The voicebox doesn’t work normally, depriving them of the most fundamental form of communication. The most upstream problem linking these gut, immune, skin, CNS, and metabolic issues is genetics. Udell asserts that genetic mutation is the major cause of autism: it’s a combination of genetic susceptibility plus a toxic environment. He says that the DSM criteria are not helpful for autism spectrum. They were developed in the 1940s by someone who thought that psychiatric issues were caused by emotionally distant mothers. DSM parameters are not helpful when sorting out therapies for autism.

SIDEBAR

Common links for autism diagnosis include problems in these categories:

• Genetic: fragile X, Rett syndrome, trisomy, copy number variations

• GI: very common. If person acts as if they have “ants in their pants” sometimes they do. Check for parasites.

• Immunologic: asthma, eczema, food sensitivities, frequent ear infections, vaccination reactions and microbiota alterations.

• Birth complications: CP, “mental retardation,” preemies.

• Metabolic and nutritional: rampant vitamin deficiency, lipid abnormalities, picky eaters, MTHFR deficit.

• Boy (75%) versus girl prevalence

• Early presentation (at birth) versus “converts” after vaccine or other noxious exposure.

Check food allergies. High IgG represents inflammation. 10% to 15% of autistic children have very low cholesterol. The conduction system in the brain (Schwann cells) requires cholesterol. Raising lipid profiles can restore eye contact.

The most difficult children have the aggressive, self-injurious behaviors. The beta-endorphin aspect of LDN mostly helps with these. LDN does not work so well for speech apraxia, but it immensely helps immune vulnerability. Parents will say, “Since starting LDN, he isn’t sick all the time anymore.” Udell says that once various parameters of the autism spectrum are addressed, prodigies can emerge. He has a high level of extremely talented musical, artistic, and creative children in his autistic population.

During the conference, many of the LDN prescribers mentioned being shunned or derided by certain colleagues. You have to be brave to be on the frontier. One approach is to ask your skeptical colleague, “Do you really just want to use steroids again?” And then of course refer them to www.LDNresearchtrust.org.

Notes

1. Low-dose Naltrexone (LDN) Fact Sheet 2015 [Web page]. LDN Research Trust. http://www.ldnresearchtrust.org/sites/default/files/LDN%20Information%20Pack(1)_0.pdf.

2. LDN (low-dose naltrexone) conversation with Drs Carnahan and Vasquez with application for multiple sclerosis, rheumatoid arthritis, fibromyalgia, complex regional pain syndrome, irritable bowel syndrome. International College of Human Nutrition and Functional Medicine [online video interview]. http://www.ichnfm.org/#!blank/ezga0.

3. Elsegood L. The LDN Book: How a Little-Known Generic Drug (Low Dose Naltrexone) Could Revolutionize Treatment for Autoimmune Diseases, Cancer, Autism, Depression, and More. White River Junction, VT: Chelsea Green Publishing; 2016.