Tag: Psychedelic Psychiatry

04/16/24

Psychedelics as the Newest Psychiatric Craze, Part 2

Image by Gordon Johnson from Pixabay

On December 12, 2023 the MAPS Public Benefit Corporation announced it submitted a new drug application (NDA) to the FDA for MDMA-assisted therapy. MAPS PBC (now called Lykos Therapeutics) requested the FDA grant a priority review, given that MDMA received a Breakthrough Therapy designation in 2017. The FDA has 60 days to determine whether the NDA will be accepted for review and whether it will be a priority or standard review (six months or ten months, respectively). If approved by the FDA, the DEA will be required to reschedule MDMA making it available by prescription for medical use. The CEO of MAPS PBC said, “If approved, MDMA-assisted therapy would be the first psychedelic-assisted therapy, which we hope will drive additional investment into new research in mental health.”

Not everyone thinks FDA approval MDMA-assisted therapy is a good idea. The psychiatrist Allen Frances said the benefits in the active group were not much greater than the benefits in the placebo group. The cost of treatment would put it out of the reach of many potential patients, adding huge costs while providing only a small, benefit. Eric Turner, a former reviewer of psych drugs for the FDA, said he doubted the touted difference between MDMA and placebo groups was as big as it seems because the trials weren’t truly blinded. He didn’t think the MDMA trials met the FDA’s usual criteria for a well-controlled study.

The double-blind methodology in the Phase 3 Clinical trials was clearly ineffective and the dramatic results reported should be tempered with this in mind. The miniscule population size of participants for both trials also raised serious questions about an FDA approval. Phase 3 clinical trials are recommended to contain 300 to 3,000 participants by the FDA; the MAPS trials had 79 and 104 participants.

In Never Enough, Dr. Judith Grisel voiced her reservations with MDMA as a recreational or therapeutic drug. Grisel has a unique position as a neuroscientist and person in long-term addiction recovery. She said MDMA (ecstasy) is both a stimulant and a hallucinogen. Structurally, it fits better with the stimulants. “Amphetamine, methamphetamine and MDMA all acutely interact with monoamine transporters to block reuptake and cause release of dopamine, norepinephrine, and serotonin from nerve terminals.”

Ecstasy is not at all similar to LSD or psilocybin, though, and like that of other stimulants its ability to block reuptake of monoamines is what leads to enhanced energy, endurance, sociability, and sexual arousal, justifying its reputation as a perfect party drug.

It reaches peak concentration in the blood after two hours and has a half-life of about eight hours. Within an hour of taking MDMA, there is a huge increase in serotonin and other monoamines, followed by a reduction that develops over days as the drug is slowly metabolized. “As a result, people frequently experience aftereffects such as lethargy, depression, and memory or concentration problems” for a few days. Grisel acknowledged the acute effects make the short-term dip well worth it for some.

The drug greatly enhances a sense of wellbeing and produces extroversion and feelings of happiness and closeness to others, due in part to the fact that it impairs recognition of negative emotions, including sadness, anger, and fear. Affective neuroscience (the study of the brain’s role in moods and feelings) has demonstrated quite clearly that we can’t feel what we can’t recognize, so this pro-social bias seems perfectly engineered and helps explain why ecstasy is called the love drug and has been adopted for use by marriage counselors. In terms of unpleasant acute effects, the drug can cause overheating, teeth grinding, muscle stiffness, lack of appetite, and restless legs.

Grisel thought regular users were headed for a lifetime of depression and anxiety. Research in rats and primates suggests moderate to high doses of MDMA damages nerve terminals, perhaps permanently. “For example, primates given ecstasy twice a day for four days (eight total doses) show reductions in the number of serotonergic neurons seven years later.”

It seems MDMA causes non-repairable damage, especially to serotonergic neurons, leading to degeneration of axons and loss of connection between cells. These neurotoxic effects suggest that this drug is anything but innocuous. Though we’re not exactly sure how regular or semi-regular recreational use affects the human brain, because these studies would require autopsies (and control groups!), in my view it doesn’t look good. For instance, the extent of MDMA use in humans is positively correlated with the decrease in serotonergic function.

Grisel thought a study by Taurah, Chandler and Sanders published in Psychopharmacology should be read by everyone thinking of using the drug. The aim of their study was to see whether MDMA produced lasting effects on humans, as it did in animals. The loss of serotonin and norepinephrine function would be predicted to produce depression, impulsivity, and cognitive impairment “because serotonin transmission is so critically involved in mood, behavioral regulation, and thinking.” Their study included almost a thousand participants, about 20% who were drug naïve. The rest were equally divided among five groups of recreational drug users.

The researchers assessed a variety of measures including several associated with mood and cognition. There were two major findings. First, former and current ecstasy users were virtually identical, and second, these groups showed significantly more clinically relevant levels of depression, impulsiveness, poor sleep, and memory impairment. Again, these were recreational users, many had not had taken the drug for years, and still deficits were strikingly evident.

Grisel then related how her interactions with MDMA users matched the findings of Taurah, Chandler and Sanders. She described an encounter with a former undergraduate student, eager to gain research experience, who worked in her laboratory one summer. While he became less reliable as the weeks went on, she said he made up for it “by offering clever and insightful ideas about experimental design and interpretation, and when he was on, he was really very good.” She learned he worked as a DJ for local raves and told her that MDMA helped him “stay in the groove for the many hours of partying.”

The next summer he again applied to do research with her. While she wasn’t thrilled with the prospect, she remembered how undergraduate research experiences were significant in her own transition from a drug user to a drug researcher. “It didn’t go well. He was all over the place with his ideas, mads as many mistakes the first week as most newbies make in a semester, and couldn’t remember what we’d discussed from hour to hour, let alone day to day.” Grisel had to let him go, and when talking about the probable cause of his dramatic slip, he said it might be because he’d done “too much molly.”

I bumped into him a few years later while I was attending a scientific meeting in the same town which he worked as a bartender. More recently, I learned that a persistent state of chronic despair drove him to suicide.”

MAPS PBC changed its name to Lykos Therapeutics on January 5, 2024. This led to the FDA accepting Lykos Therapeutics’ New Drug Application (NDA) for MDMA-assisted therapy for PTSD on February 9, 2024. The FDA granted the application priority review and set a target action date of August 11, 2024 to make the review determination.

MAPS has been persistently and progressively chipping away at getting MDMA-assisted therapy approved to treat PTSD for many years. Let’s be careful to not release a so-called “treatment” that makes things worse for troubled people. For more on the concerns with FDA approval of MDMA-assisted therapy, see “Don’t Roll the Dice with MDMA.” For more information on concerns and reservations with psychedelics as the newest psychiatric craze, see Part 1 of this article.

02/6/24

Psychedelics as the Newest Psychiatric Craze, Part 1

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In October California Governor Gavin Newsom vetoed a bill that would have decriminalized the possession and personal use of several plant-based hallucinogens, including psilocybin, mescaline and dimethyltryptamine (DMT), saying more work needed to be done on treatment guidelines. The legislation would have decriminalized possession before setting up regulatory treatment guidelines, with the California Health and Human Services Agency supposed to make recommendations to lawmakers after the consequences of decriminalization. The bill would not have arrested or prosecuted individuals who possessed limited amounts of plant-based hallucinogens. Also, the bill did not legalize the sale of these psychedelics. They are still illegal under federal law.

Public opinion was said to have shifted on using psychedelics to treat trauma and other disorders such as depression, and alcohol use disorder. There has been a significant amount of interest in the potential of psychedelics for mental health that includes encouragement and discouragement of treating psychiatric conditions with them. Sandy Cohen opened her article “Do psychedelics have a role in psychiatric treatment?” for UCLA Health, with the provocative question, “What if there was a medication that could significantly reduce symptoms of treatment-resistant depression in a single dose?” A UCLA Health psychiatrist, Walter Dunn, described two studies where psilocybin was found to have a significant reduction in symptoms of treatment-resistant depression. He said these results were unprecedented: “We have nothing that works this well.”

Dunn said the coverage in mainstream media and books aimed at lay audiences (such as Michael Pollan’s book, How to Change Your Mind) have raised interest and curiosity in psychedelics. He said when he goes to dinner parties and people discover his work is with psychedelic drugs, “I’m talking about them for the rest of the evening.” According to a UC Berkeley Psychedelics Survey, 61% of registered American voters support legalizing regulated therapeutic access to psychedelics. Thirty-five percent of those supporters said they strongly support such action. But there were 35% who opposed it and 69% did not see it as something “for people like me.”

We are in a historic moment in the space for psychedelic science, research and also mental health in general. . . There hasn’t been any time in modern psychiatry where there has been so much interest, awareness and discussion around a potential mental health treatment.

Dunn acknowledged the drugs come with risks, which was one of the reasons the FDA has been cautious about the trials being run. “These are not benign medicines. Anything that can help you can harm you.” He discussed how the FDA was set to consider MDMA-assisted therapy for PTSD in 2024. It’s still unclear whether or not the FDA will want a Risk Evaluation and Mitigation Strategy (REMS), if these treatments are approved. A REMS could require psychedelic-assisted therapy to included two specially trained and certified clinicians during the psychedelic experience. If a REMS is required by the FDA for MDMA-assisted therapy, it would reduce the pool of therapists who could administer the treatment and decrease access even as it enhances safety.

Joanna Moncrieff, a British psychiatrist, noted in “Psychedelics—The New Psychiatric Craze” where they were viewed as an increasingly fashionable medical treatment. But she wondered if they had any objective health benefits and were they safe. She noted where psilocybin, LSD, MDMA and ketamine were some of the psychedelics being recommended for an ever-lengthening list of problems that include depression, anxiety, addiction, and PTSD. She acknowledged some people might learn important about themselves through the effects of psychedelic drugs.

But these benefits are not medical or health effects. They are akin to the personal development people achieve through other sorts of activities and life experiences. . . And although the concept of drug-assisted psychotherapy acknowledges that it is the way the psychoactive effects of the drugs are used to promote a process of personal learning that is relevant, why not employ other, safer and cheaper methods? Why not nature-assisted psychotherapy (a walk in the park), for example?

Yet, the use of these drugs is portrayed as if they work by targeting underlying dysfunctional brain processes. Moncrieff is concerned that when psychedelics get a medical license, psychotherapy will be dropped or minimized. “As with ketamine, the tendency of all psychedelic treatment will be towards the provision of the drug in the cheapest possible way, which means the minimum of supervision and therapy.” Presciently, Moncrieff wrote her article two years ago, before the accidental death of Matthew Perry from the acute effects of unsupervised ketamine use.

She said most psychedelic research ignores the way the immediate psychoactive effects of the drugs impact people’s feelings and behavior in a way that will influence mood symptom ratings and may produce the impression of improvement.  She singled out the American Psychiatric Association’s report on ketamine treatment, which said there was compelling evidence the antidepressant effects of ketamine infusion are rapid and robust. While the APA acknowledged the antidepressant effects were transitory, they did not explain how they could be distinguished from the euphoria and other mental alterations associated with acute ketamine intoxication. “If ketamine’s effects are ‘antidepressant’ then so are the effects of all the other drugs that produce short-term euphoria including alcohol, cocaine, heroin, amphetamines, etc.”

Any powerful mind-altering drug will likely have ‘placebo’ effects. Drug-induced experience will lead people to expect they will improve or think they have improved. Psychedelic research also neglects the hours of medical supervision and professional attention associated with psychedelic treatment. Clinical contact improves people’s outcomes in depression, as was seen in esketamine trials, where a high level of professional contact seems to have exerted a powerful effect on some people.

The current craze for psychedelics also means the adverse effects are being minimised or overlooked. The ‘bad trip’ is a well-recognised phenomenon, and may not be that uncommon. Psychiatrist Rick Strassman, author of DMT: the Spirit Molecule, described how half of the 60 volunteers he injected with the powerful hallucinogen, DMT (N,N-dimethyltryptamine), experienced terrifying hallucinations and anxiety, and he discontinued his research, in part because of these effects. Science journalist John Horgan describes months of depression and flashbacks following a ‘bad trip’, and also reminds us that Albert Hofmann, who first synthesised LSD, also had doubts about it, calling his 1981 memoir LSD: My problem child.

Moncrieff ended her article by noting that while one or two doses of any drug is unlikely to do much harm, the tendency for treating mental health concerns is for long-term use. And repeated use of psychedelics is unlikely to be completely harmless. “As with so many other medical treatments, they have become popular through the potent mixture of financial interests and desperation.” There are many safer routes to promote personal development through an unusual experience. But we will be faced with a decision to legalize psychedelic-assisted treatment sooner rather than later, as MDMA-assisted therapy is expected to be submitted to the FDA for review for approval in early 2024. See Part 2 of this article for more information on the approval process for MDMA-assisted therapy.

10/6/14

As Harmless as Aspirin?

tyfon / 123RF Stock Photo
tyfon / 123RF Stock Photo

The province of Saskatchewan seems an unlikely place to give birth to “psychedelic psychiatry”  (See Erika Dyck’s article, “Hitting Highs at Rock Bottom” and a review of her book Psychedelic Psychiatry), but it’s true. In October of 1951 a British psychiatrist named Humpry Osmond became the deputy director of a Canadian Mental Hospital in Weyburn, Saskatchewan. He immediately organized a biochemical research program in order to continue the work he had begun with hallucinogens while he was at St. George’s Hospital in London.

Not only did Osmond coin the term psychedelic, he seems to be among the first to hypothesize a chemical imbalance theory for both schizophrenia and alcoholism. Initially interested in the therapeutic properties of mescaline, Osmond noticed that mescaline produced reactions similar to schizophrenia. These findings led him to conjecture that “schizophrenia was caused by a chemical imbalance in the brain.” Oh, and he was a pioneer researcher into the psychotherapeutic benefits of mescaline and LSD for alcoholism and various mental health disorders.

Osmond heard of the discovery of lysergic acid (LSD) by Albert Hoffman and tried it himself. He discovered that LSD was more powerful than mescaline and that it produced profound changes in consciousness. By inducing a new level of self-awareness, Osmond theorized LSD could have therapeutic benefits for individuals suffering with schizophrenia. Some of his early volunteers in LSD experiments described this feeling as “a new sense of spirituality.”

According to Osmond’s co-researcher, Abram Hoffer, the idea to try LSD with alcoholics occurred one evening in 1953, when they thought that: “LSD experiences were remarkably similar to descriptions of delirium tremens, or the effects of an alcoholic ‘hitting bottom.’” They wondered if a controlled LSD-produced delirium would help alcoholics stay sober. In 1953, they gave LSD to two alcoholic patients. One person (a female) stopped drinking immediately and the other (a male) stopped six months later. Over the next ten years they tried this procedure on over 700 patients and claimed the results were similar to that first experiment. One of those alcoholics was Bill W., cofounder of Alcoholics Anonymous.

Bill’s involvement with LSD came about through his friendships with Gerald Heard, a British philosopher, and Aldous Huxley, author of the classic novel Brave New World. Bill had been a friend of Heard’s since 1944. He met Huxley through Heard. According to Pass It On, the A.A. book about Bill and the origins of Alcoholics Anonymous, it was Huxley who referred to Bill as “the greatest social architect of the century.”

Under the supervision of Humphry Osmond, Huxley used mescaline for the first time on May 5, 1953. Huxley’s short book about his experience with mescaline, The Doors of Perception, was published in 1954. Through Heard and Huxley, Bill was introduced to Osmond and Hoffman. At first, when Bill heard about Osmond’s work with LSD, he was “extremely unthrilled.” Bill was “very much against giving alcoholics drugs.” He became interested, though, when he heard Osmond and Hoffman were getting results.

Under the guidance of Gerald Heard, Bill took LSD for the first time on August 29, 1956. He was enthusiastic about his experience. He felt it helped to eliminate barriers that stood in the way of an individual’s direct experience of the cosmos and God. According to Nell Wing, then secretary to A.A., “He had an experience [that] was totally spiritual, [like] his initial spiritual experience.” Among the friends and family whom Bill convinced to try LSD was his wife Lois and his spiritual advisor, Father Ed Dowling. Watch a 1950s video of an LSD session and a discussion of its effects by Gerald Heard here.

In a letter he wrote to Sam Shoemaker in June of 1958, Bill said that he took LSD several times and had collected considerable information about it. He felt that the negative information about its “awful dangers” was far from the truth. He thought the experiments by early LSD researchers like Osmond and Hoffman showed it had no physical risks at all. “The material [LSD] is about as harmless as aspirin.” Presciently he said: “It would certainly be a huge misfortune if it ever got loose in the general public without a careful preparation as to what the drug is and what the meaning of its effects may be.”

Bill was aware of the potential dangers to A.A. that his participation in the LSD experiments could have. “I know that I must not compromise its future and would gladly withdraw from these new activities if ever this became apparent.” By 1959 Bill had withdrawn from the LSD experiments.

Despite Bill’s assertion that LSD is about as harmless as aspirin, evidence now suggests there are several potential problems with LSD. It can temporarily impair your ability to make sensible judgments and understand common dangers. So you are more prone to accidents and injuries. It may cause temporary confusion, give you problems with abstract thinking, memory and attention span.

It can also trigger panic attacks or feelings of extreme anxiety. There have been some cases of LSD induced psychosis in seemingly healthy people. Individuals with schizophrenia and depression can see their symptoms worsen under the influence of LSD. Chronic use of LSD “alters gene expression profiles in the medial prefrontal cortex.” Many of the processes altered by chronic LSD use have also been implicated in the pathogenesis of schizophrenia.

The recreational use of LSD was entirely unexpected to Albert Hoffman, the discoverer of LSD, who said:

I had no inkling that the new substance would also come to be used beyond medical science, as an inebriant in the drug scene. Since my self-experiment had revealed LSD in its terrifying, demonic aspect, the last thing I could have expected was that this substance could ever find application as anything approaching a pleasure drug.