Shorts


Jule Klotter

Microbiota Transfer Therapy for Autism

Chronic gastrointestinal symptoms are common among people with autism and neurodegenerative illnesses like Parkinson’s and Alzheimer’s diseases. Because abnormal gut microbiota has been documented in those with autism, researchers at Arizona State University (ASU) decided to test a microbiota transfer therapy (MTT) program to see if it could improve GI symptoms and autistic symptoms.1,2 The MTT technique they are using is based on the work of Australian gastroenterologist Thomas Borody.

MTT treatment begins with a course of vancomycin for two weeks to reduce pathogenic bacteria followed by a bowel cleanse with MoviPrep to remove vancomycin and remaining bacteria. Then, patients receive high-dose fecal microbiota transplant (FMT) for one to two days, followed by seven-to-eight weeks of a daily maintenance dose. The FMT is given with Prilosec, a stomach-acid suppressant, to increase the survival rate of the FMT bacteria.

The initial ASU open-label study involved 18 children with ASD and chronic gastrointestinal problems. This Phase 1 study showed that MTT safely reduced GI symptoms by 80% and significantly increased gut microbial diversity, including potentially beneficial bacteria. Moreover, most of the children showed a slow, steady improvement in behaviors. Two years later, the researchers re-evaluated the 18 participants to see if the changes in the original study had persisted.

Two years after MTT, most children still had improvement in their GI symptoms compared to baseline (before treatment). “The improvement was on average 58% reduction in Gastrointestinal Symptom Rating Scale (GSRS) and 26% reduction in % days of abnormal stools relative to baseline…similar to what we observed at the end of treatment,” according to the researchers. In addition, microbiota diversity was higher than at baseline. In fact, many children had greater diversity two years after treatment than they had at the week 18 follow-up in the original study—but the composition did not match the donor microbiome: “This suggests that the recipients didn’t retain completely the donated microbiome, but rather retained some features of it such as increased overall diversity and increase in some important microbes such as Prevotella, while finding a new state.”

Autism symptoms, assessed with the Childhood Autism Rating Scale (CARS) rated by a professional evaluator, continued to improve after the original study. Eighty-three percent of the children were in the severe category at the beginning of the original study. Autism severity decreased by 23% by the end of week 10 in the initial study. Two years later, severity was 47% lower than baseline; 17% (instead of 83%) were in the severe range, 39% were rated mild to moderate, and 44% were below the ASD diagnostic cut-off scores. In addition, parents reported that social responsiveness had greatly improved.

Whereas 89% of the children were in the severe range at baseline, using a parent-rated Social Responsiveness Scale (SRS), the percentile in the severe range dropped to 47% with 35% in the mild/moderate range, and 18% below ASD measures. These results are notable because autism symptoms tend to remain stable without major interventions.

This Phase 1 study and follow-up showed good safety and efficacy. According to information at the autism.asu.edu website, the ASU researchers are conducting a Phase 2 MTT involving adults with autism. This Phase 2 trial is randomized, double-blind, and placebo controlled. ASU researchers hope to perform a similar study with children when they have funding. Eventually, they hope these studies will lead to larger Phase 3 trials that result in FDA approval for the use of fecal microbiota transplants to treat autism. Right now, FMT is only permitted to treat people with life-threatening diarrhea due to recurrent Clostridium difficile infection.

On June 13, 2019, FDA released an important safety alert regarding use of fecal microbiota for transplantation after two immunocompromised adults, who had received investigational FMT, developed invasive infections and became seriously ill.3 One patient died. The fecal material came from the same donor. The FDA now requires that any potential donors whose medical history makes them at increased risk for multi-drug resistant organisms (MDRO) be excluded as microbiome donors. Also, FDA scientists have determined specific MDRO testing protocols to ensure that positive donor stool is not used.

MDMA-Assisted Psychotherapy for PTSD

In Winter 2018, Multidisciplinary Association for Psychedelic Studies (MAPS) began recruiting for Phase 3 clinical trials of MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD) (see https://mdmaptsd.org for details).4 The FDA requires Phase 3 trials before approving prescription treatments. FDA gave its Breakthrough Therapy Designation to the MDMA program in August 2017, based on the results of MAPS’ six Phase 2 studies, and agreed to expedite its development and review.

The MDMA-assisted psychotherapy protocol consists of 18 hours of non-drug psychotherapy that supports two or three eight-hour sessions during which the participant receives MDMA, a psychoactive drug also known as Ecstasy. A supportive team of two co-therapists prepares each participant for the first MDMA session during three 90-minute psychotherapy sessions. The clinicians follow the participant’s lead in determining the type of environment, music, etc. to be used during the MDMA sessions and remain with the participant throughout each eight-hour session.

“MDMA-assisted psychotherapy is designed with the intention to create a space for a person to come back to recognizing their own power, their own capacity to heal, to love, and to live a full life. In a safe setting, supported by two clinicians and with ample time, participants are offered the chance to address the core issues of their trauma,” explains Shannon Clare Carlin, MA.5 Each MDMA session is followed by an overnight stay onsite, seven days of telephone contact, and three 90-minute psychotherapy sessions aimed at integrating the experience.

One Phase 2 clinical trial, led by Michael C. Mithoefer, MD, involved military veterans, firefighters, and police officers with chronic PTSD (duration of 6 months or more) and a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or more.6 The participants were randomized into one of three MDMA dose groups: 30 mg (control), 75 mg, or 125 mg. Masked independent raters assessed participants at baseline and at one month after the second MDMA session (primary endpoint). After this assessment, the blind was broken; then, open-label sessions using the full dose (100-125 mg) of MDMA were conducted with all participants, using the same protocol as described above. The 125 mg group received one session (their third at full dosage), and the other two groups received three MDMA sessions. A follow-up was conducted 12 months after the final full-dose open-label session.

“At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of -58.3 [SD 9.8] and -44.3 [28.7]; p=0.001),” the authors report. The improvement in the control group was not as great (-11.4 [SD 12.7]). Symptom severity did not significantly decrease further in the active groups after the open-label sessions. Symptoms in the control group, however, did significantly decrease.

Improvement remained after 12 months. PTSD symptoms were still significantly lower compared to baseline with mean CAPS-IV total score of 38.8 [SD 28.1] at follow-up compared to 87.1 [SD 16.1] at baseline (p<0.0001).  In addition to lower CAPS-IV total scores, participants showed improvements in psychological, occupational, and social functioning measures.

A total of 85 adverse events—mostly mild or moderately severe—were reported. Anxiety, headache, fatigue, and muscle tension were the most common adverse events to occur during the MDMA session. Fatigue, anxiety, and insomnia were also reported with decreasing occurrence in the week following a session.

Four serious events also occurred, one of which was apparently associated with the treatment. A participant with premature ventricular contraction at baseline developed an acute increase in premature ventricular contractions during the third open-label session. The problem was detected by one of the therapists during routine heart rate readings. The participant was admitted to the hospital for overnight observation and cardiac assessment and fully recovered.

Low-Dose Naltrexone for Multiple Sclerosis

On internet forums, people with multiple sclerosis (MS) report experiencing benefits, such as reduced relapse rate and slowed disease progression, when using low-dose naltrexone (LDN). Naltrexone binds to opioid growth factor (OGF) receptors, displacing the endorphin OGF, which regulates cell growth and immune function. The body’s cells respond to this displacement by increasing receptor production, increasing receptor sensitivity, and increasing OGF production.7

Low-dose naltrexone blocks receptors for just a few hours before being excreted. Once LDN is out of the system, the body responds to the increased OGF and OGF receptors with a rebound effect, enhancing the regulation of cell growth and immune response. LDN’s affect on OGF activity has led to its use as a treatment for cancer and autoimmune conditions, including multiple sclerosis. While a handful of clinical trials indicate that LDN is well-tolerated and safe for MS patients, data about its efficacy is hard to find.

Michael D. Ludwig and colleagues published a 2016 retrospective study that compared a group of patients with relapse-remitting MS who received glatiramer acetate (Copaxone) and LDN as adjunct therapy (n=31) to a group of patients who refused the medication because of adverse effect concerns but agreed to take LDN (n=23).8The researchers looked only at safety, not efficacy; they wanted to see if the LDN-only patients had a higher incidence of progression or exacerbation of the disease.

The LDN-only group took 3 or 4 mg LDN for an average of 1095 days (about 3 years) with an individual range of 30-2169 days of use. The LDN-Copaxone cohort took LDN therapy for an average of 1418 days (~ 47 months). Disease progression was assessed using MRI and timed 25-foot walks.

The authors stated, “Statistical analyses between the groups, and for each patient over time indicated no significant differences in clinical laboratory values, timed walking, or changes in magnetic resonance imaging.” Yet, the details indicate that LDN-only participants seem to have fared somewhat better. Only one LDN-only patient had multiple flares during the study, compared to six patients with multiple flares in the LDN-Copaxone group; the remaining patients each had one flare during the study. About 50% in each group had stable disease, according to MRI, by study’s end; but twice as many became “slightly worse” in the LDN-Copaxone group, and no LDN-Copaxone patient “slightly improved.” In contrast, two LDN-only patients slightly improved.

Also, patients in the LDN-Copaxone group showed a statistically significant decrease between timed 25-foot walking times (taken at baseline and every 6 months thereafter) between visit 1 and visit 4: 6.3 ± 0.5 (visit 1) and 5.1 ±0.3 (visit 4). The LDN-only remained about the same 6.2 ± 0.5 (visit 1) and 5.9 ± 0.4 (visit 4). The authors conclude “These data suggest that the apparently non-toxic, inexpensive, biotherapeutic is safe and if taken alone did not result in an exacerbation of disease symptoms” in people with relapse-remitting MS.

I was unable to find any clinical studies designed to look at efficacy. The clinicaltrials.gov website lists several LDN trials for cancer patients and for people with fibromyalgia, but none for patients with MS.

Bipolar Mood Cycles and the Moon

T.A. Wehr, an emeritus professor of psychiatry at the National Institute of Mental Health (Bethesda, Maryland), decided to investigate a possible relationship between lunar cycles and mood cycles in people with rapid cycling bipolar disorder after examining the records of a patient whose moods followed a 35.5-day cycle for years.9,10 Wehr conducted a retrospective study using records from 16 additional patients with rapid cycling bipolar disorder. The patients exhibited a cyclic illness pattern, exhibiting mania for several weeks, abruptly transitioning (“within a day or so”) to an equal number of weeks with depression, and then abruptly transitioning back to mania. All 17 patients had “a frequency of 6 or more complete (mania+depression) cycles, that is, 12 or more affective episodes per year.”

“’Because people differ in how they respond to these lunar cycles, even if you were to average together all the data I’ve collected, I’m not sure you would find anything,” he told journalist Linda Geddes. “’The only way to find anything is to look at each person individually over time, and then the patterns pop out.’”  In doing so, Wehr found that some mood swings followed a 14.8-day cycle (full moon to new moon) while others followed a 13.7-day cycle (declination cycle that drives daily tides, related to Moon’s position relative to Earth’s equator). While patients did not switch moods every 13.7 or 14.8 days, switches occurred only during a specific time in the lunar cycle. The Moon’s elliptical orbit, which has a 206-day cycle, also played a role.

Wehr says, “If bi-weekly lunar cycles drive rapid mood cycles by entraining the circadian pacemaker to the 24.8-h lunar tidal day, how might one interfere with their influence? One approach would be to refrain from prescribing antidepressant medications while continuing maintenance treatment with lithium carbonate.” Antidepressants are associated with rapid mood cycling. When antidepressants were discontinued, mood cycling slowed or remained in the depression stage in nine patients.

Wehr says another approach is “to strengthen the pacemaker’s entrainment to the 24.0 h solar day. This could be accomplished by exposing patients to longer periods of darkness at night, which have been shown to increase the amplitude of the pacemaker’s phase-responses to light and strengthen its coupling to the light-dark cycle.” In fact, one patient had a complete remission by staying in total darkness from 1800 hours (6 pm) to 0800 hours (8 am) every day.

This article was originally published in Townsend Letter, October 2019.

References

  1. Kang D-W, et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Scientific Reports. 2019;9:5821.
  2. Price D. Autism symptoms reduced nearly 50% 2 years after fecal transplant. April 9, 2019.
  3. FDA. Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms.  June 13, 2019.
  4. Phase 3 Trials: Study Initiation Visits for 8 Sites Completed. MAPS 2018 annual report bulletin. Winter 2018;20.
  5. Carlin SC. Cultivating Inner Growth: The Inner Healing Intelligence in MDMA-Assisted Psychotherapy. MAPS 2018 annual report bulletin. Winter 2018;30-33.
  6. Mithoefer MC, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomized, double-blind, dose-response, phase 2 clinical trial. The Lancet. May 1, 2018.
  7. How does LDN Work?  www.ldnscience.org/ldn/how-does-ldn-work
  8. Ludwig MD, et al. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Multiple Sclerosis Journal. 2016; 2:1-11.
  9. Wehr TA. Bipolar mood cycles and lunar tidal cycles. Molecular Psychiatry. 2018;23:923-931.
  10. Geddes L. The mood-altering power of the Moon.  July 31, 2019. www.bbc.com.

Published September 23, 2023

About the Author

Jule Klotter has a master’s in professional writing from the University of Southern California. She joined Townsend Letter’s staff in 1990. Over the years, she has written abstract articles for “Shorts” and many book reviews that provide information for busy practitioners. She became Townsend Letter’s editor near the end of 2016.