www.lowdosenaltrexone.org www.ldninfo.org

Clinical Trials for LDN

Updated: Mar 16, 2010

In Brief Recently Published Clinical Trials Clinical Trials in Progress Animal Trials Past Completed Clinical Trials LDN Homepage

In Brief

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

Developments that are detailed below:

  • A study of LDN in the treatment of MS at the University of California, San Francisco, published in February 2010.
  • A multi-institutional clinical trial of LDN for PPMS in Italy, which includes endorphin measurements, completed in fall 2007, published in September 2008.
  • A Phase II placebo-controlled clinical trial of LDN for Crohn’s disease at Penn State.
  • A Phase II placebo-controlled clinical trial on the efficacy of LDN for children and adolescents with Crohn’s disease at Penn State.
  • A clinical trial of LDN in HIV-infected citizens of Mali—the first scientific study of LDN for HIV/AIDS in Africa—implemented in October 2007.
  • A clinical trial of LDN in the treatment of fibromyalgia at Stanford Medical Center, published in May-June 2009.
  • A study by the MindBrain Consortium in Akron, Ohio of, especially, the affective changes in MS treated with LDN, begun 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, suggesting a protective role for naltrexone.

Recently Published Clinical Trials of LDN

[Note: all boldfacing, below, was so chosen by the editor.]

> LDN for MS—University of California, San Francisco

Bruce Cree, MD and co-researchers at the Multiple Sclerosis Center at UCSF published their study “Pilot Trial 0f Low Dose Naltrexone and Quality of Life in MS” in the online Annals of Neurology on 19 Feb 2010.

The study began in early 2007. 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 was made by the voluntary LDN for MS Research Fund.

The results were published in February 2010 in the Annals of Neurology (full pre-publication text available here):

Pilot trial of low dose naltrexone and quality of life in MS
Bruce A.C. Cree, Elena Kornyeyeva, Douglas S. Goodin
Multiple Sclerosis Center at UCSF

Abstract

Objective:
To evaluate the efficacy of 4.5 mg nightly naltrexone on the quality of life of multiple sclerosis patients.

Methods:
This single center, double-masked, placebo-controlled, crossover studied evaluated the efficacy of eight weeks of treatment with 4.5 mg nightly naltrexone (Low dose naltrexone or LDN) on self reported quality of life of MS patients.

Results:
80 subjects with clinically definite multiple sclerosis were enrolled and 60 subjects completed the trial. 10 withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS related adverse event and 1 for perceived benefit. Database management errors occurred in 4 other subjects and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial’s statistical power. LDN was well tolerated and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3 point improvement on the Mental Component Summary score of the SF-36 (P=.04), a 6 point improvement on the Mental Health Inventory (P<.01), a 1.6 point improvement on the Pain Effects Scale (P=.04) and a 2.4 point improvement on the Perceived Deficits Questionnaire (P=.05).

Interpretation:
LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.


Figure 2: SF-36, PCS=physical component summary scale score, range 13.6 – 61.9 baseline 34.9. MCS=mental component summary scale score, range 15.6 – 70.0, baseline 44.2.

Figure 3: PES=pain effects scale, range 6 – 30, baseline 16.1. MHI=mental health inventory, range 0 – 100, baseline 63.5

> LDN for Fibromyalgia—Stanford University, Palo Alto, California

A single-blind, small clinical trial of LDN for the treatment of fibromyalgia was begun at Stanford Medical Center in June 2007; principal Investigator Sean Mackey and sub-investigator Jarred Younger. The results were published as “Fibromyalgia Symptoms are Reduced by Low-Dose Naltrexone: a Pilot Study” in Pain Med. 2009 May-Jun;10(4):663-72. Younger reports:

The LDN trial on 10 individuals gave us encouraging results. The findings warranted a larger, double-blind trial [involving] individuals with fibromyalgia, which is ongoing now in the San Francisco Bay area. We are also pursuing a small trial of LDN for pediatric fibromyalgia patients.

Additional information can be found here.

> 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 and colleagues. 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 2007. 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. PPMS is an uncommon form of multiple sclerosis that progresses inexorably and for which neurologists have never had an approved treatment to offer.

Results were published in September 2008:

Multiple Sclerosis. 2008 Sep;14(8):1076-83.
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.

Institute of Experimental Neurology (INSPE) and Department of Neurology, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy; Fondazione Don Carlo Gnocchi, IRCCS, Milan, Italy.

Abstract: A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

[Editor’s Note: That only one patient showed any progression of PPMS during the six-month period of this trial is extraordinary, as is the occurrence of a statistically significant reduction in spasticity. Two major adverse events were reported but were unassociated with MS or with LDN: one patient had previously unrecognized polycystic kidney disease and the other was diagnosed with metastatic lung cancer.]

Clinical Trials in Progress or Awaiting Publication

> 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. The 40 patients completed the study in 2009 and publication is awaited. Dr. Smith intends to make the general results known in an oral presentation during the first week in May 2010 at Digestive Disease Week meetings at the New Orleans Convention Center. She remains very optimistic about the usefulness of LDN in inflammatory bowel diseases, such as Crohn’s disease. (See the “Low Dose Naltrexone Therapy for Crohn’s Disease” link here.)

Dr. Smith’s most recent research on the effects of LDN is a double-blind placebo controlled Phase ll study of youngsters from ages 6 to 17 with active Crohn’s disease. It was launched at Penn State in July 2008 and is expected to run until July 2010. Participants “will be treated with either naltrexone or placebo for the first 8 weeks then all subjects will receive active naltrexone drug the last 8 weeks.” For information about joining the trial, contact Sandra Bingaman, RN, at 717-531-8108 begin_of_the_skype_highlighting              717-531-8108      end_of_the_skype_highlighting or sbingaman@psu.edu. (Please 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 is placebo controlled and should last for some 9 months per patient, involves 3 study groups: LDN treatment only; LDN plus antiretroviral drugs; and only antiretroviral drugs. Because of the severe stigma attached to HIV infection in Mali, as of October 2008 the total number of participants who had reached 6 months time in all 3 groups combined amounted only to 16 people. However, Dr. McCandless reported that sign-ups were beginning to improve markedly. The volunteer subjects were 18 years of age or older and must have reduced CD4 counts in the 350 to 600 cells range at the outset for the LDN treatment only group. The other two groups must begin with CD4 counts below 350 and must be asymptomatic at that time. Laboratory studies are being rechecked at 12-week intervals. Completion of the study and data analysis is anticipated for Spring 2010.

The research team is led by Dr. Abdel Kader Traore and other health officials at the University Hospital in Bamako. Irmat Pharmacy of Manhattan originally supplied all of the original 4.5mg LDN and matching placebo capsules at no cost. However, due to untranslated English-French communications, the study was approved for 3mg LDN dosage, and that is being supplied by Skip’s Pharmacy of Boca Raton. In addition, the plans include careful attention to counseling aimed at improving preventive health practices for women and children. Both Dr. McCandless and her colleague husband, Jack Zimmerman, plan to be in Mali from time to time to supervise the study.

Dr. McCandless is actively seeking philanthropic donations (e-mail her here). The Fourth LDN Conference of October 2008 was proud to be able to donate $5,595 dollars from voluntary individual contributions.

For further details about this project, please see the linked Developing Nations Project page.

> 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 coordinated the study. It was a 16 week, double-blind, randomized, placebo-controlled, crossover-design analysis of 36 patients with either progressive or relapsing-remitting MS. The study examined 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.

One year later, Dr. Pincus reported problematic outcomes in his study, with little apparent differences between the placebo and treatment groups. After lengthy consideration with his colleagues, he wrote as follows:

We did not exclude patients on existing immunosuppressants….The existing immunosuppressants may have inhibited the LDN effects in this population.

Animal Trials of LDN

> 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: LDN for an 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 [treated] 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.”

Zagon described 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 [rodents] 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.

Dr. Zagon’s expectations were met, as is clear in the titles of the two poster presentations (below), which he gave to the World Congress on Treatment and Research in Multiple Sclerosis, held in September 2008 in Montreal, Canada. The actual data still awaited journal publication at that date:

Poster 190—Low-dose naltrexone (LDN) prevents development or delays onset and reduces severity of experimental autoimmune encephalomyelitis in mice. K. Rahn, P. McLaughlin (Hershey, Pennsylvania, USA), R. Bonneau, A. Turel, G. Thomas, I. Zagon.

Poster 216—The complete blockade of opioid receptors with naltrexone exacerbates experimental autoimmune encephalomyelitis in a mouse model. I. Zagon (Hershey, Pennsylvania, USA), K. Rahn, R. Bonneau, A. Turel, G. Thomas, P. McLaughlin.

Past Completed Clinical Trials of Low Dose Naltrexone

> Penn State Trial for Crohn’s Disease

Endoscopic Improvement in Crohn’s Colitis with Naltrexone


Figure A: Shown is the rectum of a subject with active Crohn’s Disease before starting therapy with naltrexone 4.5 mg/day. The mucosa is ulcerated, edematous, and inflamed.
Figure B: Shows the same area of the rectum in the same patient four weeks after naltrexone therapy. The lining is now healed, ulcers resolved, and the mucosa is healthy.
Copyrights: do not reproduce the above images and captions without written permission from Jill P. Smith, MD, Professor of Medicine, H-045 GI Division, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033

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).

Penn State Crohn's Trial: graph of CDAI scores during and after the trial shows significant decrease.

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:

This randomized, double-blinded, multi-center U.S. study compared a daily dose of PTI-901 against placebo in 600 women with documented IBS over a three-month treatment period. PTI-901 showed a favorable safety profile and patients reported statistically meaningful relief of IBS symptoms in the second month of treatment (p<0.02), but the drug did not demonstrate a meaningful benefit in the third month of treatment, which was defined as the primary endpoint. According to current regulatory standards, an experimental drug for chronic IBS needs to show efficacy at the end of a three-month treatment period.

The Company believes this study was well designed to detect any durable benefits of PTI-901 versus placebo in a large patient population with IBS. Based on the adequacy of the study itself, coupled with today’s clinical results, the Company is discontinuing all further clinical development activities with PTI-901.

> 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.