On April 4, 2019, Senator Brian Schatz (D-HI) sent a letter to the National Institutes of Health (NIH) Director Francis Collins and the U.S. Food and Drug Administration (FDA) Commissioner Scott Gottleib seeking information about NIH and FDA’s psychedelic research agenda and findings.
On June 13, 2019, NIH and FDA (through the now-acting Commissioner of Food and Drugs, Norman E. Sharpless), responded with information about past and current NIH efforts to fund investigations into the medical uses and mechanisms of action of psychedelic substances.
MAPS is grateful for the agencies’ ongoing support of scientific research, and celebrates FDA’s March 2019 approval of Spravato (esketamine) for treatment-resistant depression in adults as an acknowledgment of the therapeutic potential of psychedelic substances.
However, many assertions in this response letter are based on observational or retrospective research with poly-drug users in non-medical settings, or animal experiments using frequent and high dose administrations, not remotely comparable to the doses or frequency of administration used in human clinical trials. For example, Phase 2 and 3 protocols for MDMA and psilocybin, and even Spravato (esketamine), use limited single-dose regimens, so the substances are not taken daily or for long-term use, and are always delivered under supervision in a clinic. The evidence presented in this letter fails to distinguish safety profiles of substances used in controlled clinical contexts from recreational, poly-drug use contexts. Additionally, this letter paints an incomplete picture by under-reporting findings from controlled clinical psychedelic research.
These oversights impede an accurate understanding of psychedelics’ actual risks and benefits. In support of NIH and FDA’s commitment to an evidence-based relationship with this important topic, we respectfully share some clarifications and additional research below.
MAPS is encouraged by NIH and FDA’s support (non-financial) for our research into MDMA-assisted psychotherapy for PTSD, anxiety in terminally ill patients, and for social anxiety in autistic adults, among other indications. As the first organization sponsoring clinical research into the use of MDMA as a treatment for mental health indications, MAPS believes, based on our data thus far, that MDMA can benefit millions of people living with these conditions.
The side effects listed in this letter provide an incomplete picture of MDMA, focusing overwhelmingly on negative side effects reported from non-clinical research. In fact, none of the neurocognitive effects listed in this letter were cited in randomized clinical trials. The MDMA Investigator’s Brochure (IB), a regularly updated literature review of over 600 relevant animal, clinical, and epidemiological studies, concludes that MDMA’s physiological effects are mild when consumed at common recreational and therapeutic doses, and “likely to be well tolerated by healthy individuals.” Vital sign measurements in clinical trials, including heart rate, blood pressure, and temperature rarely reach “elevations that exceed those seen after moderate exercise.” There have been no adverse events related to liver or kidney damage in controlled clinical trials of MDMA.
In a particularly glaring example of one-sided data selection, this letter reports that MDMA side effects include “decreased interest in and pleasure from sex,” yet fails to include the far more commonly reported and opposite effects of MDMA. For example, one study on the “subjective effects of MDMA on human sexual function” found that over 90% of participants reported that their “desire and satisfaction were moderately to profoundly increased by MDMA.” This incomplete presentation of research throughout the letter undermines confidence in the agencies’ abilities to make evidence-based decisions.
The research referenced also fails to account for factors that impact the reliability of the data. For instance: this letter suggests that while “research on MDMA’s effects on the human brain is not conclusive at this time…a number of studies show that long-term, heavy MDMA use is associated with cognitive deficits, including problems with learning and memory.” However, since the mid-2000s researchers with expertise in the field have pointed to flaws in retrospective research, including non-random selection, reporting use of other substances, including alcohol, and enrolling participants whose use of “ecstasy” is much higher than average use in the general population or in any clinical trials. While this does not completely invalidate the findings, it calls into question causality and certainty.
From 1989-2002, the federal government granted Dr. George Ricaurte, cited as “[a] leading researcher in MDMA toxicity studies” by the U.S. Sentencing Commission in 2001, over $14.6 million for MDMA and MDMA-related research. However, Ricaurte’s studies that administered MDMA are misleading because of the extremely high doses he used in the animal research. In several of his most inflammatory studies, Dr. Ricaurte was forced to publish numerous retractions after admitting to mistakenly administering methamphetamine, not MDMA, to the animals in his studies.*
As the MDMA Investigator’s Brochure explains: “Repeated very high doses of MDMA in animals reduce total serotonin levels in the brain, impair transport of serotonin, and cause psychobehavioral changes such as increased anxiety…the majority of these studies employed large doses of MDMA that overestimated human-equivalent doses, with findings now clearly indicating that doses used in nearly all rat and most primate studies are inappropriately high for comparison to use in clinical settings and are more pertinent toxicological effects of MDMA.”
This response letter also notes that the NIH-funded MDMA mechanism of action research could “pave the way to the development of compounds with improved safety or efficacy profiles and reduced abuse liability.” However, this statement neglects to include that MDMA, when used in clinical contexts, has not been shown to increase problematic Ecstasy or MDMA use or other drug-seeking behaviors, and that the phase 2 data that supported a Breakthrough Therapy Designation by the FDA showed MDMA-assisted psychotherapy had greater efficacy and a better safety profile than the other available pharmaceutical treatments currently approved for PTSD, Zoloft (sertraline) and Paxil (paroxetine). This letter cites negative effects after “moderate use of MDMA,” but did not cite adverse event profiles from six published phase 2 studies which administered MDMA 2-3 times (spaced a month apart), or note that in clinical trials there has been no reported “spike[s] in body temperature that can occasionally result in liver, kidney, heart failure, and even death.”
Like claims about MDMA’s neurotoxicity, claims made about MDMA’s abuse liability, including persistent use or withdrawal, frequently rely on data collected about Ecstasy (which often contains other drugs in addition to MDMA, and sometimes no MDMA at all), and typically also included data from poly-drug users. Neither persistent use nor withdrawal are reported in clinical populations.
We hope to see more funding from federal agencies into therapeutic applications of MDMA, with a focus on clinical drug development trials, as well as public health research on the long term effects of MDMA use.
Spravato’s Breakthrough Therapy Designation from FDA relied in part on studies (some funded by NIMH) into the effective off-label use of generic (racemic) ketamine in sub-psychedelic doses, usually by intravenous infusion, as a treatment for depression. Most of the research about ketamine as a psychiatric intervention falls into this low-dose, sub-psychedelic category which includes both the infusions and nasal spray, and does not include therapy.
Many practitioners working with generic ketamine have found that ketamine-assisted psychotherapy, or KAP, can be “an effective method for decreasing depression and anxiety in a private practice setting, especially for older patients and those with severe symptom burden.” Unlike the dominant perspective which sees ketamine’s secondary effects as undesirable, this style of practice utilizes ketamine’s “biological, experiential, and psychological impacts” as adjuncts to therapy. Many ketamine practitioners report that patients experience more durable improvement with the addition of therapy, preparatory work, and integration sessions.
A third style of ketamine practice involves purposely inducing psychedelic or “visionary” doses via intramuscular injection. Although there is a growing body of psychiatrists and clinicians who are providing patients with psychedelic doses of ketamine, there is a gaping hole in research as it pertains to this application. Further research is needed to understand ketamine and its potentially broad applications as a mental health intervention.
Off-label ketamine use has rapidly expanded in the last decade, in part as a result of generic ketamine’s extremely low cost and availability; a single dose can cost as little as $2, and it is already available in hospitals and medical centers around the world due do its extensive and well-known use for anesthesia and pain management. However, Spravato costs $590 to $885 per physician-administered dose, which decreases access to this critical treatment for many.
Similarly to MDMA, the side effects this letter presents for ketamine include data outside of clinical populations, including polydrug users. In fact, clinicians utilizing ketamine as a treatment for depression in KAP or psychedelic doses often report the opposite of many of the side effects listed; when patients experience effective relief from depression and other conditions, their issues with memory, cravings, or problematic substance use actually decrease.
The relatively small amount of information about ibogaine provided in this letter reflects the agencies’ incomplete analysis of ibogaine’s benefits and risks in the context of the United States overdose crisis.
For FDA drug approval, data must demonstrate that the benefits of a treatment outweigh the risks. If a drug can potentially treat intractable, life-threatening illnesses, then the balance of risk-benefit shifts. The agencies’ response about ibogaine does not reflect a balanced analysis considering the critically high risk of fatality from untreated opioid dependence: More than 130 Americans die each day from opioid overdoses.
This letter asserts that ibogaine is too dangerous to be utilized as a treatment; however, very little data has been collected in clinical settings, so the perception of ibogaine’s danger comes from data collected mostly outside of controlled settings (or from animal data). In medicalized settings, ibogaine-related deaths are rare when people are properly screened and determined to have healthy cardiovascular systems and observational studies outside of the United States have shown promise in ibogaine’s effectiveness as a treatment for opioid use disorder. But more Phase 1 trials are needed to evaluate the safety profile of ibogaine in clinical contexts.
Further research is also needed to determine whether altering any of a number of elements about ibogaine treatment could increase its safety profile. Ibogaine may be effective with a very low number of applications (one or two) compared to drugs that are used over longer periods of time. Some researchers are currently studying titrated small doses of ibogaine, which increases its safety profile, but still demonstrates potential curbing physiological opiate withdrawal symptoms.
LSD and PSILOCYBIN
LSD and psilocybin are two different molecules; combining them into one category in this letter demonstrates a lack of specificity which undermines accurate understandings of each substance. For instance, this response letter purports that effects for both substances last “as long as 6 to 12 hours,” though psilocybin and LSD have distinctively different onset lengths: psilocybin usually lasts between 4 and 6 hours, and LSD can last between 8 and 15 hours.
The letter asserts that “little is known” about the long-term effects of psychedelic substances. Though insufficient research has been devoted to understanding psychedelics’ long term effects, a literature review seeking to understand if “hallucinogens cause residual neuropsychological toxicity” concluded: “there are few, if any, long-term neuropsychological deficits attributable to hallucinogen use.” Additionally, substances like psilocybin and ibogaine have been utilized for centuries by indigenous populations around the world in the form of mushrooms and iboga (respectively). Even LSD has been used for over 75 years in the US and Europe, both within and without of clinical contexts. However, myths about the use of psychedelic substances continue to pervade public consciousness.
The federal agencies refer to HPPD multiple times in the letter as a concerning long term effect of psychedelic use. However, a literature review entitled “Hallucinogen persisting perception disorder: what do we know after 50 years?” asserts that “HPPD appears to be a genuine but uncommon disorder,” and another study on the topic reports that HPPD “is rarely encountered in clinical setting.” More research is needed to better understand HPPD, but it’s clear that clinical, therapeutic contexts decrease the already-rare likelihood of onset.
Mechanism of action research is important, but funding psychedelic drug development research is critical and timely, as rates of suicide, substance use disorders, and mental health crises continue to climb. MAPS stands with NIH and FDA’s assertion that further research is necessary to better understand psychedelic substances. MAPS strongly encourages NIH and FDA to focus more on therapeutic drug development research with a more immediate and direct impact on treatment outcomes, rather than mechanistic basic science research which currently receives significant portions of federal funding dedicated to psychedelic research. MAPS also supports NIH and FDA’s efforts to better understand the long-term effects of psychedelic substances in medical, and other, settings, and believes that more public health-based, longitudinal data should also be collected.
We hope that these comments and suggestions will help refine the agencies’ research agenda in the future. Despite our concerns, we are incredibly encouraged by this letter, and we are hopeful that NIH will increase funding of therapeutic and longitudinal psychedelic research.
Ismail Lourido Ali, J.D., Policy & Advocacy Counsel, (MAPS)
Allison Feduccia, Ph.D., Senior Clinical Data Scientist, (MAPS PBC)
Ilsa Jerome, Ph.D., Medical Coder and Data Analyst, (MAPS PBC)
Natalie Lyla Ginsberg, M.S.W., Policy & Advocacy Director, (MAPS)
*CORRECTION (July 5, 2019): The original text of this statement included the sentence, “The original research used to make claims about MDMA’s neurotoxicity didn’t even actually use MDMA.” This sentence has been removed and the text below has been updated to clarify that some of Ricaurte’s other research did use MDMA, though not in the retracted study.