Ketamine, a glutamate psychedelic, was originally approved by the FDA in 1962 as an anesthetic. However around 2000, sub-anesthetic doses also were found to have significant antidepressant properties. It soon became apparent that ketamine was a major breakthrough for treating depressed patients who don’t respond to traditional antidepressants.
However, another class of psychedelics, the serotonin-like psychedelics (including psilocybin, LSD and ayahuasca), may be even better. While ketamine requires approximately weekly dosing to maintain antidepressant effectiveness, is potentially addictive, and can be lethal in overdose, the serotonin-like psychedelics are generally considered nonaddictive, less toxic, and appear to have longer-lasting therapeutic effects.
During the 1960’s, numerous investigators provided evidence that the serotonin-like psychedelics have therapeutic value. However, an obstacle to their current use is that virtually all of them are now classified as DEA schedule-1 drugs. This classification normally makes them illegal for any purpose. However, in recent years, as more information has become available, and with lobbying by medical and scientific professionals, the governmental perspective on their illegality has “softened”.
And finally in 2018, as a step towards possibly legalizing therapeutic use, the FDA granted “breakthrough status” to psilocybin. This status allowed FDA-approved medical professionals to treat depression on an experimental basis. Unlike earlier treatments, these FDA-approved treatments must meet the exacting standards of FDA Phase II and III drug trials and are designed to examine therapeutic effectiveness under highly controlled conditions, determine the best treatment protocols, and also characterize any issues that might arise. Ultimately, this research could be used to determine whether FDA would approve psilocybin for more widespread therapeutic use.
However, current societal views on the therapeutic use of psilocybin encompass the full range of possibilities. For example, the “official” position of the DEA, is that serotonin-like psychedelics (including psilocybin) are “hard drugs” whose extreme dangers outweigh any benefits (much like heroin, another schedule 1 drug) . On the other hand, many psychiatric experts (e.g. Reiff et al, 2020), as well as the FDA, believe serotonin-like psychedelics have medical value but that more research is necessary before formal approval can be granted. At the other end of the spectrum, the state of Oregon recently “jumped the gun” and legalized psilocybin for therapeutic use by state-licensed professionals. There are obvious parallels to the disjointed process by which cannabis (another DEA Schedule 1 drug) is being legalized here in the U.S.
Brief History of the Therapeutic Use of Psychedelic Drugs.
Psychedelics have been used since before recorded history for both religious and medicinal purposes. However, their “discovery” by western medicine was relatively recent. One of the earliest uses was a synthetic form of mescaline (a catecholamine-like psychedelic) as an adjunct to psychotherapy in the late 1930’s. However the first use of a serotonin-like psychedelic was likely that of LSD in the early 1940’s. LSD does not occur in nature and was first synthesized in the late 1930’s by Albert Hofmann, a Sandoz pharmacologist. However, its psychedelic properties weren’t discovered until 1943, when Hofmann accidentally dosed himself and had the first LSD “trip.” The implications quickly became obvious and shortly thereafter, Sandoz began making LSD available to psychiatrists and scientists under the brand name Delysid.
Over 2000 papers were published between 1960 and 1966 on the therapeutic uses of LSD! LSD was seen both as a model for understanding schizophrenia and as a treatment for a wide range of disorders, including depression, anxiety, schizophrenia, alcohol abuse, migraines, gambling and homosexuality. Therapeutically, it was used mainly for patients that did not respond to conventional treatments. Three different approaches were used: 1) Psycholytic therapy where LSD was used in conjunction with traditional Freudian psychoanalytic therapy; 2)Psychedelic Chemotherapy employing a more limited psychotherapeutic approach and 3) Psychedelic/Peak Therapy that attempted to induce a “mystical-like” experience. Evidence supported all three approaches as having value for some disorders and all were considered safe in controlled medical settings. While LSD dominated this early phase of psychedelic research and therapy, other psychedelics such as mescaline and psilocybin were also used. Unfortunately this early work is open to alternative explanations because it was performed before medical research began using modern research methods.
However, before modern research methods could be applied, these psychedelics were declared illegal. One factor leading to their illegality was the increasing recreational use of LSD in the 1960’s by “hippies”, whose counterculture perspectives many found threatening. “Turn on, tune in, and drop out” was a famous expression of the hippie movement popularized by Timothy Leary, a Harvard Professor and a leading proponent of recreational psychedelic use. As recreational use was not as controlled for dosage, mindset, and setting as medical use, the incidence of “bad trips” became more common. The resulting increase in emergency room visits and suicides following recreational use certainly contributed to the negative public opinion. In the 1960’s, there were also disturbing reports that the military had been trying to “weaponize” LSD as both a truth serum and as an incapacitating agent. There were also reports of the bad physiological effects of LSD, including chromosomal breakage, which were later proven incorrect. However, by the mid 60’s the damage to LSD’s reputation had been done and, the Drug Abuse Control Amendments passed in 1966 severely limited LSD sales and use. In response, Sandoz stopped making LSD, and LSD’s use in medical treatment and research was largely brought to a halt. And in 1970, the Comprehensive Drug Abuse Prevention and Control Act took it a step further and prohibited the therapeutic use of LSD and psilocybin altogether.
Public antipathy toward traditional psychedelics continued through the 1970s and 80s. This perspective was reinforced by Nixon’s “war on drugs.” Research proposing links between LSD and schizophrenia was also published at this time. At the same time, underground recreational and therapeutic use continued in the US and western Europe, with more open therapeutic use in Eastern Europe.
However, psychedelic therapy began making a comeback in the 1980’s, but with MDMA (commonly known as Ecstasy or Molly) rather than LSD. MDMA is a synthetic catecholamine-like psychedelic first synthesized in 1912 but not widely used as a psychotherapeutic drug until late 1970’s and early 1980s.
[As an aside, when MDMA began being used therapeutically in the 1980’s, it fell into a category that nowadays would be called “designer drug”. Until the DEA puts a new drug into one of its 5 schedules, there are no legal restrictions on its recreational or therapeutic use. However, a new drug cannot be scheduled until the DEA becomes aware of it and is able to study its effects. Unfortunately, this delay provides a window of opportunity for unscrupulous parties to develop and legally sell newly synthesized “designer drugs” before the DEA can schedule them.
While designer drugs sometimes work as advertised, they typically come with little or no toxicology or pharmacology. In some cases, particularly with designer opioids, the outcome has been disastrous. Despite the DEA making changes to attempt to close this “loophole”, the problem has only gotten worse. The most common designer drugs today are in the opioid, anabolic steroid, and psychedelic categories although there are also designer stimulants, sedatives, and viagra analogs as well as synthetic cannabinoids, synthetic cathinones and αMSH analogs (for tanning).]
By the late 1970’s, some psychiatrists were finding MDMA to be a more than adequate replacement for LSD. MDMA is not a classical serotonin-like psychedelic, but rather falls into the catecholamine-like category because its molecular structure closely resembles the catecholamines, norepinephrine and dopamine. The structure and effects of MDMA are similar to amphetamine, a drug that pharmacologists sometimes also place in the catecholamine-like psychedelic category. Amphetamine and MDMA both cause sympathetic arousal (i.e. “fight or flight” physiology) through increasing norepinephrine levels, are rewarding through increasing dopamine levels, and are psychedelic through binding the serotonin 5-HT2A receptor. The differences between MDMA and amphetamine are largely a matter of degree. While amphetamine is more potent in stimulating sympathetic arousal, MDMA is more potent in stimulating psychedelic responses.
Psychotherapists found MDMA to have several desirable properties when compared to LSD. MDMA is shorter acting and produces a gentler, more rewarding, and more manageable psychedelic effect than LSD. Through promoting empathy and bonding, it appears to help patients work through emotional trauma and depression and appears particularly useful for treating Post Traumatic Stress Disorder (PTSD).
Although psychotherapists had hoped to confine MDMA to therapeutic use only, by the mid 1980’s it too was “discovered” by recreational users, most notably for its use at “rave” dance parties. While MDMA was considered safe in controlled medical settings, the same could not be said for its recreational use. The main problem was, when coupled with strenuous dancing, MDMA could cause hyperthermia and salt imbalance which could result in kidney and liver damage, and even death. Further adding to public disaffection was a published primate study showing that “recreational dosages” of MDMA caused brain damage. However, the paper was later shown to be incorrect and had to be retracted. In contrast, evidence from therapeutic settings did not provide evidence of long-term harm. In 1985, the DEA nonetheless overruled input from medical professionals and placed MDMA in an emergency 1-year Schedule-1 category that prohibited both recreational and medical use. The scheduling was later made permanent.
In the 1990’s other psychedelics began to be explored for therapeutic potential, such as DMT, the active ingredient in ayahuasca. There was also research using some of the newly synthesized catecholamine-like “designer” psychedelics before they could be scheduled by the DEA. However, underground therapy in the US and legal research elsewhere continued to be performed.
The situation began to turn around in the early 2000’s with the development of research centers for psychedelic research at prestigious universities, such as Johns Hopkins, and Harvard here in the U.S. and Imperial College London and Bristol University in the U.K. and funding by a number of organizations supporting psychedelic research. Some of the early research at these centers debunked many of the earlier negative findings. For example, when the concurrent use of other recreational drugs was accounted for, there was much less evidence for the serotonin-like psychedelics having severe negative effects.
By 2018, the tide had turned to the extent that the FDA granted breakthrough status to psilocybin and MDMA for their therapeutic use in treating depression and PTSD respectively. This status allows qualified clinician/scientists to obtain permission to perform research that meets the stringent methodological standards of the FDA. So far the results look promising. So promising in fact, that, as mentioned earlier, the state of Oregon, in advance of federal approval, has gone ahead and set up a state-wide program for the therapeutic use of psilocybin.
In the next post, I review some recent studies on the effectiveness of the serotonin-like psychedelics, psilocybin, ayahuasca, and LSD, in treating depression as well as the general procedures used in these therapies. I also present some ideas on how these psychedelics have antidepressant effects.
Reiff, C. M., Richman, E. E., Nemeroff, C. B., Carpenter, L. L., Widge, A. S., Rodriguez, C. I., . . . McDonald, W. M. (2020). Psychedelics and psychedelic-assisted psychotherapy. Ajp, 177(5), 391-410. doi:10.1176/appi.ajp.2019.19010035
Sessa, B. (2016). The history of psychedelics in medicine. In von Heyuden, M. et al (Ed.), Handbuch psychoaktive substanzen (pp. 1-26). Heidelberg: Springer -Verlag. doi:10.1007/978-3-642-55214-4_96-1
Tullis, P. (2021). The rise of psychedelic psychiatry. Nature, 589, 506-509.