Tag: psychedelic therapy

01/17/23

The Eye of the Beholder with Psychedelic Therapy

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Classical psychedelic drugs such as psilocybin, LSD, and mescaline were used and researched regularly in psychiatry before they were placed in Schedule I of the UN Convention in 1967 and in Schedule I of the US Controlled Substances Act in 1970. These actions legally defined these psychedelics as having no accepted medical use and a high potential for abuse. Without a clinical focus and the widespread use of LSD within the 1960s counterculture movement, research rapidly dwindled. But there has been a resurgence of clinical research interest in the use of psychedelics for psychiatric disorders such as major depression, PTSD, anxiety and addiction.

In “Psychiatry & the psychedelic drugs,” Rucker, Iliff and Nutt described clinical trials using psychedelics pre and post prohibition. They also discussed the methodological challenges of preforming good quality clinical trials, and suggested an approach to the existing legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.

Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called ‘psychoneurotic’ disorders sometimes benefited considerably from their tendency to ‘loosen’ otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low.

The term ‘psychedelic’ was coined by Humphry Osmond in a letter he wrote to Aldous Huxley in 1956. Osmond combined two ancient Greek words, psyché, meaning soul or mind; and delein, meaning to reveal. So psychedelic means ‘soul revealing.’ The earliest direct evidence for the use of psychotropic plants dates to around 3700 BC in the northeastern region of Mexico. Carbon-dated buttons of peyote and red beans containing mescaline were found in caves used by humans for habitation. Arthur Heffter isolated mescaline from the peyote cactus in 1897.

Albert Hofmann first synthesized LSD in 1938. Coming at a time before there were effective medicinal therapies, the discovery of LSD was of interest to psychiatry. Acute LSD intoxication appeared to mimic some of the symptoms of acute psychosis and drew the research interest of Humphry Osmond. There also seemed to be an increased awareness of repressed memories and other elements of the subconscious, which suggested it could be helpful in psychotherapy. Trials in depressive, anxious, obsessive and addictive disorders in conjunction with psychologically supportive contexts reinforced that view. “By the end of the 1960s, hundreds of papers described the use of mescaline, psilocybin and (most frequently) LSD in a wide variety of clinical populations with non-psychotic mental health problems.”

The widespread use of LSD outside of the carefully orchestrated clinical and research settings and the growing reports of adverse effects when under the influence of LSD and other psychedelics led to prohibition. Medical use stopped quickly when doctors could no longer prescribe it. The following graph taken from “Psychiatry & the psychedelic drugs” depicts how the annual number of publications listed in PubMed rapidly decreased after 1968.

Recently, there have been several studies and randomized controlled trials using psychedelics with various nonpsychotic disorders. In “LSD: can psychedelics treat mental illness?,” written by Anya Borrissova for the Mental Elf blog, Borissova reviewed the findings of Fuentes et al, “Therapeutic Use of LSD in Psychiatry.” This was a systematic review of randomized-controlled clinical trials with LSD. The authors identified 11 studies that met their inclusion criteria: randomized controlled trials of LSD that involved patients with a mental illness diagnosis. The qualities of the studies was scored with the Cochrane Collaboration Risk of Bias Assessment tool.

Seven of the 11 trials had recruited individuals diagnosed with what is now referred to as alcohol use disorder (AUD), 1 for AUD or neurotic diagnosis, 1 for heroin use disorder, 1 for anxiety associated with life-threatening diseases, and 1 with a neurotic diagnosis (depression, anxiety). The publication dates ranged from 1966 to 2014, which covered several changes in how mental disorders were labeled by the four different editions of the DSM, the 2nd through the 5th. The majority of the studies had a low risk of selection, attrition detection and reporting bias, as measured by the Cochrane Collaboration Risk of Bias Assessment tool. However, five of the studies had a high risk of bias due to blinding.

With the studies of alcohol use disorder, a significant effect of LSD was observed in four studies. “However, this effect was related to quality of life and general health in some of the studies, with no clear improvements in alcohol abstinence.” While there was a substantial improvement in total abstinence for the LSD group, there were not significant differences in the global adjustment scale. With regard to the two studies of neurotic symptoms, one study showed statistically significant improvement in symptoms at 6-8 weeks in most measurements. But it failed to reach statistical significance in six months, although all groups showed significant differences in a large number of variables. Fuentes et al concluded that LSD was a potential therapeutic agent in psychiatry; with the strongest evidence for its use in treating alcoholism.

Borissova said the heterogeneity of the studies did not allow for a meta-analysis, which made it difficult to draw firm conclusions. The earlier studies had different methodologies than what is used now, which limits the application of the results to modern research. The use of the gold standard of the double-blind methodology with psychedelics is extremely difficult, if not impossible to achieve, and five studies had a high risk of bias for blinding. The psychiatric diagnostic categories were also different in studies done over such a wide range of time. How the studies defined their ‘control group’ varied, with those that failed to use an active placebo having questionable validity.

When discussing the implications of Fuentes et al, she said LSD generally appears to be safe and potentially effective. The lack of consistency between the studies may have limited their ability to find an LSD effect. “On the basis of this review, we cannot conclude that there is strong evidence of positive effects.” She did think change in scheduling the drugs to allow for easier research into LSD was justified. Tellingly, she ended with this caution: “Psychedelic research inspires a lot of excitement; the danger is that this turns into hype.”

There has been a growing interest in psychedelics as an agent for reaching peak experiences, for self-care or wellness, and as an instrument of therapeutic change. Michael Pollan explored this psychedelic ‘renaissance’ in his 2018 best-selling book, How to Change Your Mind. In a New York Times article, he said now when you leave the airport in Quito, Ecuador, there are people with signs that say: ‘ayahuasca ceremony’ instead of ‘taxi.’ “These people became shamans, like last week. People are getting hurt.” He had positive things to say about his experiences with psilocybin, but cautioned against legalization: “Psilocybin has a lot of potential as medicine, but we don’t know enough about it yet to legalize it.”

The promise of pre-prohibition LSD and psychedelic studies and their potential as therapeutic agents has to be replicated within a modern, controlled context. A 2016 paper by Rucker with different researchers than those cited above, “Psychedelics In the Treatment of Unipolar Mood Disorders,” elaborated on some of the difficulties inherent in designing trials with psychedelics. Blinding is largely impossible. Therapeutic doses of psychedelics produce subjective and objective changes in thinking, feeling and behavior that are usually obvious to both the participant in the study and the observer. Because of this, placebo control is problematic because the absence of the psychedelic effect is obvious. The ‘set’ (psychological state) and ‘setting’ (the interpersonal and physical environment) within which the drug is experienced are inextricably linked to the therapeutic effect.

It appears that a particularly careful and well-considered balance between the needs of the participants and the needs of the trial will be required in studies using psychedelics. . . Trial designers will need, similarly, to be detailed and explicit about the environmental and psychotherapeutic milieu in which a study is to be performed. Clinical trials using psychedelics will need to be sufficiently methodologically detailed at the point of publication to allow genuine replication. Scientific mechanism studies will need, ideally, to be pursued alongside clinical trials if this is pragmatic and ethical. Within this multi-pronged approach to evidence gathering, and a sufficient degree of definition, replicable results and common threads of insight into the nature and applicability of psychedelics to medicine in general, and to psychiatry in particular, should emerge with time.

In “Psychedelics In the Treatment of Unipolar Mood Disorders,” Rucker et al referred to and quoted Rick Strassman’s 1984 literature review, “Adverse reactions to psychedelic drugs.” Strassman noted that the description and reporting of adverse reactions to psychedelics was subject to the investigators’ attitudes towards psychedelics.

With the available data, it appears that the incidence of adverse reactions to psychedelic drugs is low when individuals, both normal volunteers and patients, are carefully screened and prepared, supervised and followed up, and given judicious doses of pharmaceutical quality drug. The few prospective studies noting adverse reactions have fairly consistently described characteristics predicting poor response to these drugs. The majority of studies of adverse reactions, retrospective in nature, have described a constellation of premorbid characteristics in individuals seeking treatment for these reactions where drugs of unknown purity were taken in unsupervised settings.

The authors repeated an assessment of the perceived psychotherapeutic mechanism identified by Betty Eisner and Sidney Cohen in their 1958 article, “Psychotherapy with Lysergic Acid Diethylamide.” Eisner and Cohen said their review of the existing literature in 1958 suggested that 1) LSD lessened defensiveness; 2) there was a heightened capacity to relive early experiences with accompanying release of feelings; 3) therapist-patient relationships were enhanced; 4) there was an increased appearance of unconscious material. Eisner and Cohen went on to describe their exploration of the therapeutic possibilities of LSD with 22 patients with diagnoses ranging from neurotic depression, anxiety, character disorder, borderline personality and schizophrenia. Improvement was noted in 16 of 22 cases, where improvement was judged as continued success in behavioral adaptation.

Rucker et al concluded that psychedelic therapy may represent a kind of “catalyzed psychotherapy,” where the psychedelic drug hastens the breakdown of entrenched, maladaptive ways of thinking and behavior in supportive environments. While the evidence from pre-prohibition literature is unsystematic and methodologically inadequate, it suggests further research is worth doing. But there are limitations to the future research of psychedelic psychotherapy that researchers need to be aware.

As discussed above, it is essentially impossible to develop a double-blind methodology with psychedelics because of the unique characteristics of the drugs. This opens investigations into psychedelic therapy to the potential bias of the researchers—one that cannot be eliminated. Strassman raised this warning in Rucker et al, where he was quoted as saying it is important to use caution when discussing the idea of adverse reactions to psychedelic drugs. Whether the researcher views the drug-induced state as a pathological one, or as trying to reach a “higher” level of consciousness, “The description and/or reporting of adverse reactions to psychedelics is, therefore, subject to some degree of investigators’ perspective on the use of these drugs.”

Given the potential bias of researchers into psychedelic therapy and the current inability of medical research to neutralize it, caution when interpreting the conclusions of any research is necessary. As Anya Borissova said, although psychedelic research inspires a lot of excitement; “the danger is that this turns into hype.” This danger cuts both ways, whether a particular researcher sees the drug-induced state as a pathological one, or as an attempt to reach a “higher” level of consciousness. At the very least, it seems researchers should declare any personal bias with regard to psychedelics within any written or published research into psychedelic therapy.

As an illustration, does knowing that Betty Eisner and Sidney Cohen both personally used LSD at least once (and probably more than just once) alter your assessment of their endorsement of psychedelic therapy? It was 1958 and their failure to do so is not an ethical misstep, but that awareness added to the inability to adequately blind their research should lead to some reservations with their conclusions endorsing psychedelics. Michael Pollan acknowledged the concern of potential bias in psychedelic research:

Western science and modern drug testing depend on the ability to isolate a single variable, but it isn’t clear the effects of a psychedelic drug can ever be isolated, whether from the context in which it is administered, the presence of the therapists involved, or the volunteer’s expectations. Any of these factors can muddy the waters of causality. And how is Western medicine to evaluate a psychiatric drug that appears to work not by means of any strictly pharmacological effect but by administering a certain kind of experience in the minds of the people who take it?

It seems impossible for psychedelic psychotherapy to be separated from its set or setting; and for research into its effectiveness to be reliably evaluated by a double blinded research methodology. The effectiveness (or not) of psychedelic therapy will necessarily be in the eye of the researcher and beholder.

For more on Betty Eisner, Sidney Cohen and early LSD research look, see: “Bill W. and His LSD Experiences.”

Originally posted on October 13, 2020.

04/12/22

The Psychedelic Pendulum and Psychiatry, Part 2

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On October 12, 1955 psychiatrist Sidney Cohen took LSD for the first time. Expecting to feel catatonic or paranoid because LSD was then thought to produce a temporary psychosis, he instead felt an elevated peacefulness, as if the problems and worries of everyday life had vanished. “I seemed to have finally arrived at the contemplation of eternal truth.” He immediately began his own LSD experiments, even exploring whether it could be helpful in facilitating psychotherapy, curing alcoholism and enhancing creativity. But on July of 1962 in The Journal of The American Medical Association, he warned of the dangers of suicide, prolonged psychotic reactions, and said: “Misuse of the drug alone or in combination with other agents has been encountered.”

The history of psychedelics seems have followed this pendulum swing from hope and promise, to disappointment and warnings, and then back again to hope and promise. In Part 1 of this article, we looked at the current promise of psychedelic therapy and treatment and mentioned its use to supposedly enhance creativity. Here we’ll take a closer look at the present-day concerns and reservations with the proposed use of psychedelics as therapeutic tools. Tellingly, they haven’t change much since Cohen co-authored “Complications Associated with Lysergic Acid Diethylamide (LSD-25).”

In “Psychedelics—The New Psychiatric Craze,” Joanna Moncrieff acknowledged the “increasingly fashionable” interest in psychedelics as a medical treatment, but wondered if they weren’t just “a powerful form of snake oil.” She noted the ever-lengthening list of problems they were recommended to treat, which included PTSD, depression, anxiety, addiction, chronic pain and distress associated with having a terminal illness. The rationale behind the trend was said to be confusing and contradictory.

On the one hand, psychedelics are promoted as assisting the process of psychotherapy through the insights that the ‘trip’ or drug-induced experience can generate – on the other they are claimed to represent a targeted medical treatment for various disorders, through correcting underlying brain deficiencies.

Increasingly, the use of these drugs is portrayed as if they work by targeting underlying dysfunctional brain processes (i.e., resetting brain processes by acting on 5-HT2A receptors). Moncrieff said claims by David Nutt, a psychopharmacologist and psychedelic researcher that psychedelics “turn off parts of the brain that relate to depression” and reset the brain’s thinking processes by their actions on the 5-HT2A receptors were “pure speculation.” She made the same judgment on a John Hopkins website that said researchers hoped to “create precision medicine treatments tailored to the specific needs of individual patients.” The charity, Mind Medicine Australia’s claim that psychedelic treatments were curative and only required 2-3 dosed sessions, that they were “antibiotics for the mind”, Moncrieff thought was a sales pitch for an expensive therapy.

In reality, psychedelics do not produce the miracle cures people are led to expect, as experience with ketamine confirms. Some people may feel a little better after a treatment, and then the effect wears off and they come for another one and another one, and get established on long-term treatment just as people do on antidepressants.

Official research also over-plays the drug’s benefits. A study published in The New England Journal of Medicine, “Trial of Psilocybin versus Escitalopram for Depression,” found no significant difference between groups in their primary outcome. The study’s discussion then pointed out that secondary outcomes had small differences, but did not consider the placebo effect of participants having a drug-induced experience. The participants were also not typical of those with depression, consisting of mainly well-educated men, almost a third of whom had tried psychedelics before. The study’s researchers said:

The patients in the trial were not from diverse ethnic or socioeconomic backgrounds. Strategies to improve recruitment of more diverse study populations are needed in studies of psilocybin for depression. Also, average symptom severity scores at baseline were in the range for moderate depression, thus limiting extrapolations to patients with severe depressive symptoms or treatment-resistant depression.

The current craze for psychedelics means adverse effects are being minimized, according to Moncrieff. Whether or not people find the effects of psychedelics enlightening or not depends on how the drug-induced experience is interpreted. This highlights the importance of staff as support people while clients are under the influence. Yet she worried that when, and if, psychedelics obtain a medical license, psychotherapy would be dropped or minimized. “The tendency of all psychedelic treatment will be towards the provisions of the drug in the cheapest possible way, which means the minimum of supervision and therapy.”

In “When Drugs of Abuse Become Psychiatric Medications,” Sara and Jack Gorman noted that some commentators have been suggesting we’re on the cusp of a new era in psychopharmacology with the potential of ketamine, MDMA and psilocybin as psychiatric treatments for depression, PTSD and other disorders. They noted how we have information about the biological mechanisms of action for all three of them. Ketamine works mainly through interaction with the brain’s glutamate neurotransmission system. MDMD and psilocybin enhance the brain’s serotonin receptors—the same system affected by SSRI antidepressants.

Unfortunately, however, we still have no firm idea if derangements in any of these neurotransmitter systems are actually the cause of any mood or anxiety disorder. There are many theories linking abnormal glutamate neurotransmission to depression, for example, and some solid data from animal studies suggesting such a link, but no definitive proof that any abnormality in glutamate neurotransmission is part of depression yet exists. We cannot say that any of these drugs work by remediating a known abnormality in the brains of people with psychiatric illnesses any more than we can say that about any of the traditional psychiatric medications.

One final issue is that regardless of the fact that currently approved medications for depression and PTSD are only partially effective for many patients, they are not usually abused or addictive. Yet ketamine, psilocybin and MDMA have long histories as recreational street drugs that can be addictive for some people. In the clinical trials done to date adverse side effects have been minimal, and with the doses and manner in which they are given, addiction is unlikely. Moreover, there are widely used, FDA-approved, psychiatric drugs with known histories of misuse—benzodiazepines and ADHD medications.

Then the Gormans asked a telling question: Is psychiatry following solid science, or going in the direction of approving the use of mind-altering street drugs as medications—and I’d add—because they have no other potential medications on the horizon?

In the journal, JAMA Psychiatry, Joshua Phelps and two others expressed concerns with the growth of industry-sponsored drug development and the assessment of psychedelic drug effectiveness. They noted the market for psychedelic substances was projected to grow from $2 billion in 2020 to $10.75 billion by 2027, “a growth rate that may even outpace the legal US cannabis market.” They said the interest in psychedelic medicine seems to hope that psychedelics will be the next blockbuster class of medicines and has led to efforts to decriminalize psychedelics at the local level, as with Oregon (see Part 1)  and other locations. Their concern is that these regulatory changes will adversely affect the quality and rigor of biomedical research with psychedelics.

Although popular excitement, policy momentum, and financial investment in psychedelics continue to increase, it is imperative that research maintains scientific rigor and dispassion to outcomes in the pursuit of improved therapeutics and new insights into the mind, brain, and consciousness that this class of molecules may well afford in the coming years. The presence of large-scale, newly established public companies as an unprecedented category of stakeholder may help to further understanding of these molecules and their possible clinical applications, but these firms also have a unique set of self-interests that must be understood and considered. Research enabled by these firms must still meet the same rigorous standards that are expected elsewhere, even if breakthrough status is warranted.

Then there is another concern described by Will Hall on “Ending the Silence Around Psychedelic Therapy Abuse.” He made his decision to write about therapy abuse when he read Michael Pollan’s best-selling book on psychedelics, How to Change Your Mind. Hill thought Pollan was overly enthusiastic and largely uncritical. “All the new hype about miracle psychiatric treatments and the next wave of cures for mental disorders leaves out the risk of therapy abuse.”

He said from his perspective, as far as drugs go, psychedelics were relatively safe—safer than benzodiazepines or SSRIs. He even acknowledged that reported healings from emotional pain with psychedelics did happen. By raising an alarm about therapy abuse he said he wasn’t exaggerating the dangers of psychedelics, rather: “I’m calling for more honesty about the implications of putting psychedelics in the hands of therapists.”

He noted the inherently imbalanced power relationship of therapist and client, where there is already the potential danger of authority being misused. The therapist has too much influence over a client, and the consequences for clients are too severe to see each side as equal, according to Hall. “And so we protect clients from therapists in the same way we protect children from adults, especially from the most exploitive and extreme violation of therapist trust, sex with clients.” The risks are magnified when you add psychedelics.

Drugs affect judgment, drugs can enhance idealization, drugs can promote risk taking, drugs can lower defenses, drugs can amplify suggestibility, drugs can lead to dissociation… all drugs. Imagine if you heard therapists were giving their clients alcohol to get them talkative, lines of cocaine to get them confident, or cannabis to get them relaxed? You would easily recognize that even if some clients do benefit, the client is also put into a heightened and more easily exploited state. Despite their many unique and often positive qualities, this is still true of psychedelics. And the influence is magnified when the therapist is supplier of and expert about the drug, when the drug has a taboo cultural aura of esoteric healing powers, the media are hyping miracle cures, and scientific experts are waving their hands and calling it “medical treatment.” Add that psychedelic therapists are typically also themselves users of and true believers in these substances. The dangers are obvious.

Psychedelics present some of the same risks as any drugs. Hall said we need to name those risks, and be especially vigilant about them. Otherwise, even though some people will be helped, others will be harmed. “And as the history of psychedelic therapy abuse shows, they already have.” Hall then gave specific historical examples and details from past abuse as well as his own personal experiences.

He wasn’t alone in pointing to this safety concern with psychedelic therapy. In her article on Oregon’s experiment with legalizing psychedelics for STAT, Olivia Goldhill noted that sexual abuse has historically been a problem with psychedelic therapy. “All the usual power imbalances of patients and therapists are exacerbated in a setting where drugs can create feelings of sexual arousal.”

Hall also pointed out that with psychedelics or any other drug, “it’s called getting high for a reason—we lose our feet on the ground.” Gaining a new perspective can be illuminating, but avoidance could come instead of insight. Psychedelics also increase suggestibility, a tendency to accept the beliefs of others illustrated in hypnotic trance states and situations where there is social pressure for conformity. Psychedelics can make some people more dependent on outside influence and more reluctant to consider they may have misjudged their safety when using the drugs.

There is more Will Hall has to say about the potential for therapy abuse with psychedelics, but what we’ve reviewed lays out the concerns. I don’t agree entirely with what seems to me to be a “laissez faire” approach to people who want to use psychedelics for healing or illumination. I’d say there is as much of concern with their use as with benzodiazepines or SSRIs. And given the pendulum swing evident in the history of psychedelics as therapeutic agents, there is a swing back to disappointments and concerns ahead. As Hall astutely said,

All medical treatment outcomes are driven in part by expectation and placebo: eventually the hype around new psychiatric products wears off, and then we are on to the next marketing wave—with iatrogenic harm to patients left in the wake.

STAT said that Washington, New York, Colorado and California are all considering some form of legalizing psychedelics. Other states are enacting decriminalization measures. If Oregon-style legislation spreads to other states, the potential market for legalization will get bigger. Field Trip, a company with a series of clinics used for ketamine therapy plans to set up clinics in Oregon. “Oregon is just the first step. But there’s a big wave coming almost certainly.”

03/24/20

The Unique Scientific Value of Ibogaine Part 3

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In a March 6, 2019 interview with The New York Times, Gwyneth Paltrow was asked what the next big thing Goop would be plugging, and she responded: “I think how psychedelics affect health and mental health and addiction will come more into the mainstream.” At the time, she confessed she had never used psychedelics and was terrified at the process. And yet, she acknowledged there seemed to be a link between a psychedelic state and being connected to “some other universal cosmic something.” She then mentioned ibogaine, a hallucinogen being promoted as a treatment for addictions. The interviewer asked if ibogaine would be the next big thing she would read about on Goop, and Gwyneth back-pedaled, saying she didn’t know. Then “The Healing Trip,” appeared as the first episode for the Netflix series, The Goop Lab, where several Goop employees went to Jamaica to ingest magic mushrooms.

The New York Times referred to this as “Goop-ification,” when Gwyneth Paltrow’s health and beauty company, Goop, regularly wrote articles on the health benefits of hallucinogens. The Times article highlighted three authors. Michael Pollan, who wrote the best selling How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression and Transcendence, chronicled the history of psychedelic drugs, including his own personal use of psychedelics. There was a memoir, A Really Good Day, written by Aylet Waldman, and a novel about Timothy Leary, Outside Looking In, by T.C. Boyle.

Psychedelics have entered into mainstream conversations, with psychedelics being touted for wellness, lifehacking, therapy and self-care. The Milken Conference, a business event, had a panel called “Psychedelics: Mind-Enhancing Methods to Well-Being.” Silicon Valley entrepreneurs are using Ecstasy, LSD, and magic mushrooms. “A booming—and unregulated—shaman market has emerged.” Ironically, Pollan and Waldman, who published books on the benefits of psychedelics “worry about the ayahuasca retreat gentrification even as they usher more people in the door.” The promises made for what psychedelics can do for you harken back to the days of patent medicines.

But Pollan cautioned against legalizing psychedelics: “Psilocybin has a lot of potential as medicine, but we don’t know enough about it yet to legalize it.” Someone, he feared, could commit suicide while they were coming off of SSRIs in conjunction to their hallucinogenic therapy. “I do think we could have another backlash.” Goop urged caution as well:

If we’ve learned anything from interviewing psychiatrists and psychedelic researchers over the past few years, it’s two things: 1) Psychedelics have incredible potential as therapeutic agents, and 2) they are not something you should approach lightly—they require a great deal of care and expertise and support to have those desired therapeutic effects. They can leave you vulnerable and have the potential for serious (and in rare cases fatal) harm. If you’re considering any experimental healing experience, you should consult your own medical team and understand the risks before proceeding. And for anything involving psychedelics, verify the legal status, as psychedelics are illegal in many countries and unregulated in others.

This psychedelic “renaissance” was explored by Michael Pollan in his 2018 book, How to Change Your Mind. Pollan noted how Western science and modern drug testing depended on the ability to isolate one single variable. Yet it is not clear how the effects of a psychedelic drug can ever be isolated as a single variable from the context in which it is administered—the presence of the therapists involved, or the expectations of the person ingesting the psychedelic. “Any of these factors can muddy the waters of causality.” He then asked how was Western medicine to evaluate a psychiatric drug that appears to work by administering a certain kind of experience in the minds of the person, and not strictly by means of any pharmacological effect?

This is why it is important to understand that “psychedelic therapy” is not simply treatment with a psychedelic drug but rather a form of “psychedelic-assisted therapy,” as many of the researchers take pains to emphasize.

One of those researchers is Dr. Kenneth Alper, who has coauthored multiple papers with Howard Lotsof (See Part 1 for more about Howard Lotsof) and is the first editor of an English language text on ibogaine.  In “Ibogaine: A review,” an article in The Alkaloids Chemistry and Biology, February 2001, he said there were “stages” or phases to the subjective experience of ibogaine. He said ibogaine was typically given in a nonhospital setting as a single dose in the morning. Vomiting is common, as it seems to be with the ingestion of ayahuasca, another psychedelic alleged to be helpful in treating addictions. Patients generally lie still in a quiet, darkened room throughout their treatment.

The subjective effects of the Acute phase appear to have common elements described by individuals treated with ibogaine. The onset of the acute phase occurs within 1 to 3 hours of ingesting ibogaine and lasts about 4 to 8 hours. The predominant experiences reported seem to involve “visions” or “waking dreams” of long-term memories. Descriptions from individuals in this state are more consistent with an experience of dreams, rather than hallucinations. Subjects also emphasize their experience of being placed in, or entering/exiting visual landscapes, rather than an intrusive visual or auditory hallucination.

Ibogaine-related visual experiences are reported to be strongly associated with eye closure and suppressed by eye opening. The term “oneiric” (Greek, oneiros, dream) has been preferred to the term “hallucinogenic” in describing the subjective experience of the acute state. Not all subjects experience visual phenomena from ibogaine, which may be related to dose, bioavailability, and interindividual variation.

The Evaluative phase comes about 4 to 8 hours after ingestion, and lasts 8 to 20 hours. The volume of material recalled in the waking visions slows. The emotional tone is described as neutral or reflective. Attention still has an inner subjective focus directed at evaluating the experiences of the Acute phase, rather than the external environment. “Patients in this and the acute phase above are apparently easily distracted and annoyed by ambient environmental stimuli and prefer as little environmental sensory stimulation as possible in order to maintain an attentional focus on inner experience.”

Twelve to 24 hours after ingestion of ibogaine marks the beginning of the Residual Stimulation phase. It lasts somewhere between 24 and 72 hours; maybe longer. There is a return to normal attention to the person’s external environment. “The intensity of the subjective psychoactive experience lessens, with mild residual subjective arousal or vigilance.” Some people report a reduced need for sleep for several days up to a few weeks following treatment. In summary, Alper concluded:

The available evidence suggests that ibogaine and the iboga alkaloids may have efficacy in addiction on the basis of mechanisms that are not yet known and which can possibly be dissociated from toxic effects, and may present significant promise as a paradigm for the study and development of pharmacotherapy for addiction.

Despite the carefully described observations noted here, Pollan still urged caution with psychedelic therapy: “None of these psychedelic therapies have yet proven themselves to work in large populations; what successes have been reported should be taken as promising signals standing out from the noise of data, rather than definitive proofs of cure.” But he didn’t stop there with his investigation into psychedelic therapies.

He turned to the work of Robin Carhart-Harris and his theory of the entropic brain. He said it represented a first stab at a unified theory of mental illness and helped explain several psychiatric disorders. According to Pollan, Carhart-Harris believes that “depression, anxiety, obsession, and the cravings of addiction are how it feels to have a brain that has become excessively rigid or fixed in its pathways and linkages.” These disorders are manifested in a brain with more order than is good for it. “On the spectrum he lays out (in his entropic article) ranging from excessive order to excessive entropy, depression, addiction, and disorders of obsession all fall on the too-much-order end.”

In “The entropic brain” article, Robin Carhart-Harris et al proposed a theory of consciousness they called the entropic brain hypothesis. This hypothesis proposes that the quality of any conscious state depends on the system’s entropy measured vie key parameters of brain function. Increased subjective uncertainty accompanies states of increased system entropy. Psychedelics work therapeutically “by dismantling reinforced patterns of negative thought and behavior by breaking down the stable spatiotemporal patterns of brain activity upon which they rest.” Pollan thought this effect, which he called “the dissolution of the ego,” was the most important and therapeutic of all the phenomenological effects people who are on psychedelics report. See the graphic below from “The entropic brain.”

In particular, the changes in activity and connectivity in the default mode network on psychedelics suggest it may be possible to link the felt experience of certain types of mental suffering with something observable—and alterable—in the brain. If the default mode network does what neuroscientists think it does, then an intervention that targets that network has the potential to help relieve several forms of mental illness, including the handful of disorders psychedelic researchers have trialed so far.

Pollan said the default mode network (DMN) is a set of interacting brain structures first described by the Washington University neuroscientist Marcus Raichle. It is most active when the brain is in a resting state, linking parts of the cerebral cortex with deeper, older structures of the brain involved in memory and emotion. “Its key structures include, and link, the posterior cingulate cortex, the medial prefrontal cortex, and the hippocampus.”

Neuroimaging studies suggest that the DMN is involved in such higher-order “metacognitive” activities as self-reflection, mental projection, time travel, and theory of mind—the ability to attribute mental states to others. Activity in the DMN falls during the psychedelic experiences, and when it falls most precipitously volunteers often report a dissolution of their sense of self.

The approval of psychedelic therapy with ibogaine has some serious concerns to overcome, but there is enough evidence available to support doing further research and for the FDA to provide the funds for it. However, Michael Pollan may have the right of it in saying, “it isn’t clear that the effects of a psychedelic drug can ever be isolated … from the context in which it is administered.” Deborah Mash’s attempts to somehow separate the drug effect from the set and setting of the dream-like experience of ibogaine may radically, and negatively, effect its efficacy. Her efforts points to the limitations of scientific inquiry into the healing properties of hallucinogens. The Dalai Lama said: “The view that all mental processes are necessarily physical processes is a metaphysical assumption, not a scientific fact. I feel that, in the spirit of scientific inquiry, it is critical that we allow the question to remain open, and not conflate our assumptions with empirical fact.” In closing, Robin Carhart-Harris’s thoughts on the unique scientific value of psychedelics have relevance:

The unique scientific value of psychedelics rests in their capacity to make consciously accessible that which is latent in the mind. This paper takes the position that mainstream psychology and psychiatry have underappreciated the depth of the human mind by neglecting schools of thought that posit the existence an unconscious mind. Indeed, psychedelics’ greatest value may be as a remedy for ignorance of the unconscious mind.