Clinical Trials for LDN

Updated: Feb 3, 2008

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Around the globe, there has been a quantum leap forward in the number of ongoing research studies on LDN—2007 has definitely been a banner year. Here is a capsule look at a number of such projects.

Developments that are detailed below:

• A Phase II placebo-controlled clinical trial of LDN for Crohn’s disease at Penn State.
• The Institutional Review Board in Bamako, Mali, approved plans in September 2007 for a clinical trial of LDN in HIV-infected citizens of Mali—the first scientific study of LDN for HIV/AIDS in Africa—and it was implemented in October 2007.
• A multi-institutional clinical trial of LDN for MS in Italy, which includes endorphin measurements, completing in fall 2007.
• A study of LDN in the treatment of MS at the University of California, San Francisco, implemented in early 2007.
• A clinical trial of LDN in the treatment of fibromyalgia at Stanford Medical Center implemented in October 2007.
• A study by the MindBrain Consortium in Akron, Ohio of, especially, the affective changes in MS treated with LDN, beginning late 2007.
• An animal research study at Penn State of naltrexone in a model of a disease that mimics MS, under a small grant from the National MS Society.
• Animal research on neurodegeneration at NIEHS has suggested a protective role for naltrexone.

> LDN for Crohn’s disease—Penn State College of Medicine, Hershey, PA

Dr. Jill Smith’s original article, "Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease," was published in the Jan 11, 2007 online edition of the American Journal of Gastroenterology (2007;102:1–9) [print edition Apr '07]. This was the first clinical study of LDN published by a US medical journal. Dr. Smith, Professor of Gastroenterology at Pennsylvania State University's College of Medicine, found that two-thirds of the patients in her pilot study went into remission and fully 89% of the group responded to LDN treatment to some degree. She concluded that “LDN therapy appears effective and safe in subjects with active Crohn’s disease.” That open-label Penn State trial demonstrated the efficacy of LDN in a small group of patients.

As a result, Dr. Smith received an NIH grant that permitted a more definitive Phase II placebo-controlled clinical trial, which by October 2007 had already studied about one-half of the 40 patients it plans to include. With many patients yet to be added to the study, Dr. Smith remains very optimistic about the usefulness of LDN in inflammatory diseases of the bowel, such as Crohn’s disease. (See the trial website.)

> LDN for HIV—Mali, Africa

In September 2007, after years of preparatory efforts by many advocates, the Institutional Review Board in Bamako, the capital of Mali, finally approved plans for a clinical trial of LDN in people who are HIV-infected—the first scientific study of LDN for HIV/AIDS in Africa. Signing up of the volunteer subjects has already begun. The neurologist Dr. Jaquelyn McCandless has taken on the responsibilities of “Expatriate Clinical Monitor” for the medical aspects of the trial.

The study, which should last for some 9 months, involves 3 study groups: LDN treatment only; LDN plus antiretroviral drugs; and only antiretroviral drugs. The volunteer subjects must be 18 years of age or older and must have reduced CD4 counts in the 275 to 475 cells range at the outset. Laboratory studies will be rechecked at 12-week intervals.

The research team is led by Dr. Abdel Kader Traore and other health officials at the University Hospital in Bamako. Irmat Pharmacy of Manhattan has volunteered to supply all of the needed LDN and matching placebo capsules at no cost. In addition, the plans include careful attention to counseling aimed at improving preventive health practices for women and children. Dr. McCandless is actively seeking philanthropic donations (e-mail her here). For further details, please see the linked Developing Nations Project page.

Both Dr. McCandless and her colleague husband, Jack Zimmerman, plan to be in Mali to supervise the early steps of the study.

> LDN for MS—Milan, Italy

A long-awaited pilot study of low dose naltrexone therapy in multiple sclerosis was run by the Milan neurological researcher, Dr. Maira Gironi. Several northern Italian hospitals began enrolling patients for the study during the first week of December 2006. Dr. Gironi reports that the 6 months of LDN treatment was completed in August. Importantly, Dr. Gironi’s research team in Milan has long been a locus for significant research on endorphins in relation to illness, and this study has been tracking accurate assessments of the patients’ beta-endorphin levels in response to their LDN treatment.

The subjects were 40 patients affected with Primary Progressive MS. They are receiving periodic follow-ups over several months, after which Gironi expects a final data analysis will be done and the study readied for possible publication.

In October 2007, much of the data were presented at the European Congress of MS in Prague:

We have approached a 6-months, pilot, multicentric, open-label, therapeutic study with LDN aimed at evaluating its safety and efficacy on spasticity, pain and fatigue occurring in 40 pts with PPMS.

Clinical and biochemical evaluations are performed at different time points during the study. Appropriate scale for testing spasticity, pain and fatigue (e.g. Ashworth, Fatigue Severity Scale, Visual Analogue Scale) are used as an integral part of the periodical neurological examination. Beta-Endorphin levels in peripheral blood mononuclear cells are also measured by radioimmunoassay.

So far, 40 pts with a diagnosis of PPMS, according to McDonald criteria, have been enrolled in the study (19 males, 21 females, mean age 53.4 years, mean age at onset 41.2, mean Expanded Disability Status Scale 5.5). Optimization of [gabaergic and/or serotoninergic] drugs has been performed in all pts before the enrollment. Opioid-containing-drugs, immunosuppressive or immunomodulator drugs were considered as a contraindication to study enrollment.

Transitory haematological abnormalities (increase of liver enzymes, hypercholesterolemia), mild agitation and sleep disturbance were the commonest adverse events. Only two drop-outs occurred (one for protocol violation and one for severe increase of hypertonia). In conclusion, LDN has shown, so far, to be a safe treatment in PPMS. We are now collecting and analysing efficacy results.

Dr. Gironi’s general impression of how the trial is proceeding thus far was as follows: "LDN could be useful for a quite good number of MS patients affected with spasticity, fatigue, and pain. A subjective improvement on fatigue has been [experienced] overall".

[Editor’s Note: we excitedly await the report of final results to see the anticipated correlation between the LDN treatment, Beta-endorphin levels, and clinical status improvement.]

> LDN for MS—University of California, San Francisco, CA

A study of LDN in the treatment of MS at the University of California, San Francisco, was implemented in early 2007 by neurological researcher Bruce Cree, MD, and colleagues. Some 80 patients with MS were involved in this double-blind, “Randomized, Placebo-Controlled, Crossover-Design Study of the Effects of Low Dose Naltrexone on Quality of Life as Measured by the Multiple Sclerosis Quality of Life Inventory.” Each subject received either LDN or a placebo for 8 weeks, followed by one week without either, and then a further 8 weeks on the the alternate capsule. A substantial contribution toward the study has been made by the the LDN for MS Research Fund.

Dr. Cree reported as follows:

"The study is fully enrolled with 80 subjects and was closed for enrollment as of July. The trial will complete in November, with preliminary analysis occurring in December 2007. Final analysis and preparation for presentation will occur in the months to follow. If the trial is positive my intention is to send a late breaking news abstract to the American Academy of Neurology. My impression is that LDN is well tolerated due to the very few adverse events reported thus far. I have no clinical impression with regard to efficacy because the study is placebo controlled, blinded, and all patient evaluations are performed via questionnaire."

> LDN for Fibromyalgia—Stanford, California

A clinical trial of LDN for the treatment of fibromyalgia at Stanford Medical Center is currently ongoing. Additional information can be found at clinicaltrials.gov.

> LDN for MS—Akron, Ohio

In May 2007, the MindBrain Consortium and the Department of Psychiatry of Summa Hospital System of Akron, Ohio, along with the nearby Oak Clinic for the treatment of Multiple Sclerosis, announced a new scientific study of the effects of treating MS with low dose naltrexone. Psychologist David Pincus and his colleagues are coordinating the study. It is a 16 week, double-blind, randomized, placebo-controlled, crossover-design analysis of 36 patients with either progressive or relapsing-remitting MS. The study will examine symptom severity as well as any changes in quality of life, sleep patterns, and affective states.

In early October 2007, Dr. Pincus wrote as follows:

"We have enrolled more than 20 of the 36 people intended; we expect to be fully recruited within the next 3 or 4 weeks, and, three months following the end of enrollment we will have all the data. The study is going well, a couple of people have dropped out or been removed for one reason or another, but none because of a problem with sleep. One patient had sleeping issues for a few nights, but then has been ok. We are looking at the psychoactive properties of LDN as well as assessing improvement of MS symptoms, and hope to find some changes in perception of energy level that correlate with personality type and amount of dreaming reported. I can’t say for sure how long data analysis will take, but all elements of data collection are occurring well and there is no reason to think that we will have a great delay in time for analysis. If we are permitted, I will pre-announce outcomes to your website as soon as we have them available."

> Research on Neurodegeneration at NIEHS Suggests a Protective Naltrexone Role

J.S. Hong, Ph.D., head of the Neuropharmacology Section of the Laboratory of Pharmacology and Chemistry at the National Institute of Environmental Health Sciences, finds that "morphinan" drugs, including naltrexone and naloxone, are able to reduce inflammatory reactions in microglia brain cells in animal studies. Such inflammation is believed to be central to the progressive neurodegenerative effects seen in disorders such as Parkinson’s disease and Alzheimer’s disease. Hong’s report, summarizing the role of microglia in inflammation-related neurodegeneration and the potential of therapy using morphinans, appears in a January 2007 issue of Nature Reviews Neuroscience [8(1):57-69].

> Research at Penn State to Use LDN and Animal Model of MS

The National Multiple Sclerosis Society “awarded a small Pilot Award to Ian Zagon [Ph.D.] at Pennsylvania State University in Hershey, PA for the term of 09/01/2006 through 08/31/2007 in the amount of $44,000. The title of his project is ‘Role of opioid peptides and receptors in MS.’ This study will be treating an animal model of MS daily with either a high dose of naltrexone or a low dose of naltrexone to determine whether naltrexone influences disease course.” The published report is awaited.

Zagon describes the project as follows:

This research project raises the question of whether endogenous opioids and opioid receptors influence the course of MS. This is a novel and innovative concept that is valuable to explore. To test this hypothesis, we will subject rats to experimental autoimmune encephalomyelitis (EAE), a model that mimics MS. Animals will be treated daily with a high dose of [naltrexone] (HDN) or a low dose of [naltrexone] (LDN)....Our expectations are that continuous opioid receptor blockade will exacerbate the progression of MS, whereas a low dose of naltrexone will retard the course of this disease. Evidence for the involvement of endogenous opioids and opioid receptors in MS will open a new field of research related to the pathogenesis of this disease, and contribute to the development of strategies for treatment.

> Penn State Trial for Crohn's Disease

The report on this groundbreaking research—"Low-Dose Naltrexone as a Treatment For Active Crohn's Disease"—was presented on May 23, 2006 at Digestive Diseases Week, a prestigious gastrointestinal conference, by Professor Jill Smith of the Pennsylvania State University College of Medicine. Dr. Smith's research paper, "Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease," has been published by the American Journal of Gastroenterology in its January 11, 2007 edition.

Dr. Smith and her colleagues concluded that "LDN therapy offers an alternative safe, effective, and economic means of treating subjects with active Crohn's disease."

According to the news from Penn State, the National Institutes of Health has already granted $500,000 for Dr. Smith's group to continue the study. This funding should help assure a full-fledged placebo-controlled scientific trial of LDN in Crohn's disease. (Notably, Dr. Smith and her research teams are also involved in exploring the direct effects of using a form of endorphin by infusion in order to treat pancreatic and colon cancer.)

For further details, see Penn State's online news, and our multimedia coverage of Dr. Smith's keynote address at the Second Annual LDN Conference, April 7, 2006.

Below are some extracts from the trial summary that was published online by the gastroenterology conference:

Low-Dose Naltrexone as a Treatment For Active Crohn's Disease

J. P. Smith¹; H. E. Stock¹; S. I. Bingaman¹; D. T. Mauger²; I. S. Zagon³

1. Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
2. Health Evaluation Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
3. Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA.

Methods: Eligible subjects with histologically and endoscopically confirmed active Crohn's disease with a Crohn's Activity Index (CDAI) score of 220-450 were enrolled in a study using 4.5 mg naltrexone/day. Subjects were required to be off infliximab for at least 8-weeks, and this medication was not allowed during the trial. Other drug therapy for Crohn's disease utilized 4 or more weeks prior to enrollment was continued at the same dosages.... Drug [LDN] was administered orally each evening for a 12-week period. Laboratory tests, erythrocyte sedimentation rates, C-Reactive protein, and CDAI scores were assessed monthly and 4 weeks after discontinuing the medication.

Results: Seventeen patients with a mean initial CDAI^* score of 356 ± 27 were enrolled in the study. CDAI scores decreased significantly (p<0.01) with LDN, and remained statistically lower than baseline 4-weeks after completing therapy (see Figure).



Eighty-nine percent of patients exhibited a response to therapy (>70-point decrease in CDAI, p<0.001) and 67% achieved remission (CDAI score <150). QOL^* surveys indicated marked improvement with LDN. No laboratory abnormalities were noted. One subject undergoing routine endoscopic procedures showed healing of the intestinal mucosa. In both subjects with open fistulas, closure was noted with LDN. The most common side effect of LDN was sleep disturbances (7 patients).

Conclusions: LDN therapy offers an alternative safe, effective, and economic means of treating subjects with active Crohn's disease.

^*[Editor's Note: CDAI = Crohn's Disease Activity Index; QOL = Quality of Life]

> Pain Therapeutics Ends Irritable Bowel Syndrome Trials of Ultra-low Naltrexone Dosage

In December 2005, Pain Therapeutics, Inc. announced results of its Phase III study with PTI-901. [Editor's Note: PTI-901 contains only 0.5mg of naltrexone, which is well below the therapeutic dosage range for LDN—normally from 1.75mg to 4.5mg every night. LDN in the normal dosage range has been anecdotally reported quite beneficial in halting IBS.] Excerpt from PTI's announcement:

> Dr. Evers Trial in Germany for Multiple Sclerosis (MS)

Conducted in the Multiple Sclerosis Clinic of Dr. Evers Hospital in Sundern, Germany, the starting date was October 15, 2004. It is described as a short-term scientific, randomized, placebo-controlled, double-blind study involving patients with either secondary-progressive MS (SPMS) or primary-progressive MS (PPMS).

[Editor’s Note: Unfortunately, because of some early complaints of sleep disturbance, the principal investigator of this trial switched all of the study group to taking LDN at 9am in the morning, a questionable dosage time. It is generally recognized that the most effective time to take LDN is at bedtime, between 9pm and 3am, due to the fact that the endorphins for each day are always produced at their peak rate in the pre-dawn hours. A 9am dosage time, as was used in this trial, might conceivably suppress—rather than boost—a patient's immune system.]

The purpose of the study was to investigate what MS-associated symptoms are positively influenced by LDN (low dose naltrexone, 3 mg per day). The principal investigator, Dr. Mir, reported his findings at the First Annual LDN Conference in 2005, as well as on his website.