Initially posted October 17, 2022. Updated Nov. 1, 2022. We thank Prof. Thomas Schoenemann for his comments and suggestions regarding our post.
I. Introduction
Psychedelic drugs are making a comeback. In this post we will deal with research on effects of the two so-called classic psychedelics, LSD and psilocybin (the main active ingredient in “magic mushrooms”). Although these two drugs have distinct origins, they both became popular in the 1960s, when anecdotal reports also indicated that they might be of use in treating some psychiatric disorders. People who ingested these drugs generally reported intense experiences characterized by heightened, if unrealistic, sensory perceptions, hallucinations, a sense of “mind alteration” or “mind expansion,” and loss of a sense of boundaries between the self and the external world. Most users saw these experiences as euphoric and mystical or spiritual. However, there were also occasional “bad LSD trips,” in which unsupervised users suffered severe panic attacks or injuries associated with the perceived absence of physical boundaries. The bad reports led most industrialized countries to ban the drugs by 1970 or so. In the U.S., for example, LSD and psilocybin are among the drugs classified since 1970 as Schedule I, i.e., drugs with high potential for abuse and no currently accepted medical uses, despite early hints of medical uses and no indications that these drugs are addictive.
The experiences reported by subjects who have ingested the drugs suggest that the psychedelics affect brain function profoundly. If we understood in detail the nature of these alterations, it could help to sharpen our understanding of human brain function and possibly point the way to the clinical use of psychedelics in addressing various abnormal psychiatric disorders. The technology certainly exists today to image brain activity and connectedness for human subjects on and off psychedelics. Techniques such as functional magnetic resonance imaging (fMRI), electro-encephalography (EEG), and magnetoencephalography (MEG) are readily available to scan brain activity in volunteer subjects. fMRI is most sensitive to changes in blood flow within the brain, while EEG and MEG measure electric and magnetic (caused by electrical currents) activity in the brain, respectively. The three techniques provide complementary signals of brain activity.
However, the poorly justified schedule classification of these drugs has long impeded research on either brain imaging or potential therapeutic uses, making it difficult to get approval or government funding for research that might provide a more compelling basis for controlled clinical studies of the drugs’ positive and negative impacts. As a result, until very recently there have been only a few groups worldwide doing rigorous scientific research on how psychedelics affect the human brain. One prominent group has been at Imperial College London, led by neuroscientists Robin Carhart-Harris and Karl Friston and neuropsychopharmacologist David Nutt. Other UK groups at the University of Sussex, the University of Bristol and the Cardiff University Brain Research Imaging Centre in Wales have also contributed to the research. Most of the funding for this research has come from the private Beckley Foundation, established in Oxford by Amanda Feilding, precisely to advance research on psychedelics. A second center of psychedelics research is in Zurich, Switzerland at the University Hospital for Psychiatry, led by Katrin Preller, and the University of Zurich, led by Franz Vollenweider.
Results obtained over the past decade by these two groups have illuminated the effects of psychedelics on the human brain sufficiently to spur an ongoing worldwide revival of interest in clinical trials to examine the drugs’ efficacy in treating depression, anxiety, addiction and other mental disorders. Carhart-Harris’ recent move to direct a psychedelic research division at the University of California at San Francisco is a signal that a few U.S. institutions are now beginning to take up the challenge of both neurological research and therapeutic trials of psychedelics in understanding and treating psychiatric disorders.
Although such research is still at an early stage involving limited subject samples, there are already highly instructive results that inform connections between measured neurological impacts of psychedelics and the anecdotal self-reporting of people who experience the drugs’ effects. And early clinical trials have provided sufficiently encouraging results that the U.S. Food and Drug Administration has recently designated psilocybin as a “breakthrough therapy” for the treatment of severe (so-called treatment-resistant) depression, facilitating more extensive clinical trials. Nonetheless, Amanda Feilding has pointed out that the bureaucratic and financial obstacles imposed by the continuing Schedule I classification of LSD and psilocybin in the U.S. and U.K. still make research on psychedelics cost five to ten times as much as research on Schedule II drugs, such as cocaine, fentanyl, and oxycodone.
In Sections II and III of this post we discuss the early history of the discovery, usage, and subsequent banning of psilocybin and LSD, respectively, and their qualitative impacts reported by subjects and users. Part II of this post contains Sections IV, V and VI. In Section IV, we review what is currently known about the quite similar neurochemistry of the two drugs and how they establish unusual connectivity among brain networks, accounting for the reported qualitative impacts. In Section V, we review clinical results currently available and plans for follow-up clinical trials of the drugs’ use for treating various psychiatric conditions. Section VI contains a summary and consideration of avenues for further research. Our descriptions rely heavily, among many other sources, on two talks given by Robin Carhart-Harris and on the book How to Change Your Mind by Michael Pollan.
II. History of Psilocybin Usage
Psilocybin is a natural psychoactive substance. It is found in mushrooms that grow in areas around the world. Figure II.1 shows a collection of psychedelic mushrooms. Figure II.2 shows the distribution of psychoactive psilocybe mushrooms around the world. As can be seen, these mushrooms are widely found in many different countries, including those in North, Central and South America.
Figure II.1: A collection of psilocybin mushrooms. Ingesting these substances can produce hallucinations and can alter the interpretation of sensory information.
Figure II.2: Worldwide distribution of psychoactive psilocybin mushrooms. As shown in the figure, these fungi grow in many areas of the world, particularly in the Americas and Western Europe.
Evidence from prehistoric murals and rock paintings in Spain and Algeria suggests that psilocybe mushrooms may have been consumed in ancient European societies. After the Spanish “discovery” of the New World, Spanish chroniclers reported that the psilocybe mushrooms had been used in ceremonies by the native populations. In particular, the Franciscan friar Bernadrino de Sahagun described the use of mushrooms for entheogenic purposes (i.e., using psychoactive substances in religious or spiritual activities) in his Florentine Codex (1545 – 1590 AD; it is called the Florentine Codex because the best-preserved manuscript is housed in the Laurentian Library in Florence, Italy). A page from this manuscript is shown in Fig. II.3. The Spanish forbade the use of these fungi in an effort to stamp out “pagan” practices; however, various Mesoamerican Indian populations continued the use of these mushrooms in secret.
Figure II.3: Page 51 from Book IX of the Florentine Codex, by Franciscan friar Bernardino de Sahagun. He worked on this manuscript from 1545 to his death in 1590. The Codex describes the culture and practices of Aztec society in 12 books comprising 2,400 pages, with illustrations provided by natives who were his students. The book was written in the Nahuatl language and was not translated into English until 2002.
Despite the fact that psilocybe mushrooms are rather common in western Europe, in modern times there was very little evidence of the use of these substances for spiritual or recreational purposes. This changed after the publication of an article in 1957 by R. Gordon Wasson and his wife Valentina that described their studies of psilocybe mushroom use by natives in the Mexican village of Huaulta de Jimenez. The Wassons participated in the use of these substances, and Gordon’s article for Life magazine was called “Seeking the Magic Mushroom.” Wasson’s article and the description of his own experience with these drugs caused a sudden interest in these mushrooms and their qualities. Wasson coined the phrase “magic mushroom,” which has become a commonly used term to describe the psilocybe mushrooms.
In 1958 Wasson sent a sample of Psilocybe mexicana mushrooms to the pharmacologist Albert Hoffman at the Swiss company Sandoz. As we will see in our Section III discussion of LSD, Hoffman was the same scientist who first produced LSD. Hoffman’s research team managed to isolate and identify psilocybin from these samples. They further showed that although psilocybin itself was an inactive compound, when ingested it was converted to psilocin, which is a psychoactive molecule. Hoffman and his team then synthesized a number of compounds that were closely related to naturally occurring psilocybin. Specifically, they synthesized 4-phosphoryloxy-N,N-diethyltryptamine, which they named CEY-19, and 4-hydroxy-N,N-diethyltryptamine, which was called CZ-74. Sandoz then marketed pure psilocybin, which they called Indocybin, and sent it to clinics that might want to perform research with this substance.
The distribution by Sandoz, coupled with Gordon Wasson’s Life magazine article, created a great fascination with psilocybin and its properties. There was particular interest shown by a research group at Harvard led by psychologist Timothy Leary and his colleagues Richard Alpert and Ralph Metzner. Leary traveled to Mexico where he ingested magic mushrooms. As a result of his experiences there, he founded the Harvard Psilocybin Project in 1960. Leary and his associates performed several experiments. Two of the most famous were the Concord Prison Experiment and the Marsh Chapel Experiment.
Figure II.4: Harvard psychologist Timothy Leary. Leary was the founder of the Harvard Psilocybin Project and was the director of this group from 1960 to 1962. However, in 1963 Leary was fired by Harvard, after it was alleged that he was pressuring students at Harvard to take psilocybin or LSD, and that he was distributing LSD to people who were taking it for recreational purposes rather than for clinical research trials. Media guru Marshall McLuhan advised Leary that he would be more effective and memorable if he was photographed smiling. Leary took this advice to heart.
The Concord Prison Experiment took place from 1961 to 1963. It involved 32 prisoners at the Concord, Massachusetts maximum-security prison for young offenders. They took part in a group psychotherapy trial where they were administered psilocybin that had been manufactured by Sandoz. Results for the inmates taking part in this study were compared to those from the general Concord prison population. The researchers reported that 64% of Concord inmates returned to prison within 6 months of their release on parole. However, they claimed that only 25% of the participants in the Concord trials returned to prison within six months. Furthermore, the Concord study participants were given a battery of psychological tests before and after their treatment. It was claimed that the inmates showed dramatic improvement from their pre-treatment to post-treatment scores.
However, a follow-up study obtained quite different results from the original. The authors of the follow-up study claimed that the original researchers used different criteria in evaluating the participants and the general prison population. Furthermore, the original authors had not differentiated between new crimes and parole violations in evaluating return to prison. The follow-up study found a very small difference between the prisoners in the psilocybin program and those in the general prison population. The follow-up authors recommended that a larger and better-designed program be developed to determine the degree to which psychedelic-drug programs were effective for incarcerated citizens.
The second major study from the Harvard Psilocybin Project was the Marsh Chapel Experiment, which is also known colloquially as the Good Friday Experiment (from the date of that trial). This study was carried out in 1962 by Harvard Divinity School graduate student Walter Pahnke, who was working under the guidance of Timothy Leary and Richard Alpert. In this study, twenty grad students at the Harvard Divinity School were given either psilocybin or (as an active placebo) niacin. Nearly all of the participants who received psilocybin reported that they had a profound spiritual experience.
The Marsh Chapel Experiment was criticized by researcher Rick Doblin, the founder and director of the Multidisciplinary Association for Psychedelic Studies. First, he stated that niacin was not really a “control” drug, since it was fairly easy for the researchers to ascertain who had received psilocybin and who got niacin; hence, this could not be called a “double-blind” experiment. Second, Doblin claimed that Walter Pahnke failed to mention that a few of the participants had experienced extreme anxiety during this test; in fact, one participant had to be restrained and treated with Thorazine. Nevertheless, there was general agreement that the Concord Prison and Marsh Chapel experiments showed that the effects produced by ingesting psilocybin were similar to spiritual encounters described by mystics.
Timothy Leary was fired by Harvard because he allowed his enthusiasm for the power of LSD and psilocybin to interfere with his professional ethics (the official Harvard explanation was that Leary had failed to show up to teach his classes). Leary subsequently became the public face of LSD, and he became infamous for his advice to youth: “Turn on, Tune in, Drop out.” For the remainder of his life, Leary was a hero to the counterculture and a target of investigation by the authorities. As will be described in detail in the section on LSD, the association of LSD and psilocybin with Timothy Leary led to their banning in a 1966 U.S. Congressional law that prohibited the production, sale or use of hallucinogenic drugs. In 1970, this prohibition was expanded under the Controlled Substances Act. This law placed psychoactive drugs into categories based on their potential for harm, and their potential medical uses. Both psilocybin and LSD were listed as Schedule I drugs; this meant that they were judged to have a high potential for harm and/or abuse, and no known potential for medical applications. We know of no serious scientific investigations of the effects of psilocybin that led to its being declared a Schedule I drug.
Until that point, psychedelic drugs had been used to treat a number of conditions, including “alcoholism, depression, obsessive-compulsive disorder, and anxiety at the end of life.” However, these were not clinical studies conducted with rigor, and “some of them were compromised by the enthusiasm of the researchers involved.” For the past 50 years, medical research on psilocybin has been difficult, because it is illegal to possess this substance. The scientific community generally blames Leary for making it impossible to continue with research on psychedelics that had begun in the 1950s.
Regardless of his sloppy research and his advocacy for people to “drop acid,” Leary’s research with psilocybin did produce a number of insights regarding this and other psychedelic drugs. First, Leary and his collaborators showed that the effects of psilocybin were highly variable. In one of their experiments, they tried to control for the environment in which the drug was administered, and the expectations of those ingesting the drug. They showed that both the environment and the state of mind of the participants played a significant role in determining the effect of the drug – these are now called the “set and setting” for the psychedelic experience. Here, “set” refers to a person’s state of mind, their previous experience with psychedelic drugs, and their expectations for the encounter. “Setting” is the environment in which the drug is ingested. Outcomes are more positive if the environment is familiar or comfortable, if it is taken indoors, if music is playing and if the lighting is pleasing. Leary and members of the Harvard Psilocybin Project administered psilocybin to 175 volunteers. The rooms for this project were designed to look like a “comfortable living room.” Also, the researchers piped in music, and attempted to correlate the psychedelic experience with the type of music the volunteers were exposed to. In addition, they attempted to create a calm, quiet and relaxed environment; subjects reported these conditions led to more positive experiences than when taken in noisy and/or crowded conditions.
The Harvard researchers determined that the size of the dose was crucial in determining the outcome of the experience. Very small doses of psilocybin produced relatively small effects (although hallucinations could sometimes be induced with very small doses), while with large doses of psilocybin subjects had roughly a one in three chance of feeling significant fear and 17% of the subjects experienced transient paranoia. The size of the group was also important in determining the outcome. Members of groups with more than eight people found the experience less pleasant, while people in groups of six or fewer rated their drug experiences as more meaningful. Leary and collaborators suggested that psilocybin made individuals more susceptible to environmental stimuli and more receptive to interactions with the researchers in the experiment.
In several of the Harvard experiments, the researchers took psilocybin along with the subjects. Many members of the research community strongly objected to this practice and criticized the Harvard Psilocybin Project for this behavior. This appears to be one of the reasons that Harvard shut down the project and fired some of the researchers, including Timothy Leary.
Qualitative Experiences with Psilocybin:
People taking psilocybin report a wide range of effects. Many report feelings of disorientation, lethargy, giddiness, euphoria, joy and depression. Most subjects report that the effects they experienced were totally new and hence ineffable (difficult or incapable of being described in words). As we have mentioned, the effects experienced from ingesting psilocybin appear to be indistinguishable from mystical experiences obtained by other means, such as meditation or specialized breathing techniques.
It is also the case that subjects on psilocybin report that the boundaries between “self” and “the world” tend to loosen or disappear. One subject reported experiencing a “total dissolving of ego boundaries,” while another said they were no longer able to discern “where I end, and where my surroundings begin.” Many subjects report a dramatic increase in “magical thinking” after they have taken psilocybin. In Section IV of this report we will summarize what has been learned from neurochemical studies of the brains of people who have been injected with psilocybin.
Figure II.5 lists a number of subjective experiences reported by 15 subjects who had been injected either with a placebo (red) or with psilocybin (blue). Note that subjects with psilocybin reported a wide range of mental effects. Many noted distortions in their sense of space and time; several also experienced “disintegration of self” or “merging with surroundings;” and some reported the psychedelic experience had a strong spiritual quality. A smaller number of subjects also reported either paranoia or fear.
Figure II.5: Subjective experiences reported by patients in fMRI experiments conducted by Carhart-Harris et al. Fifteen subjects were first given a placebo and subjected to an fMRI scan for 18 minutes. These subjects were then injected with psilocybin and the fMRI scan was repeated. The subjects were asked to rate the existence and strength of various reactions; red denotes the reactions to the placebo while blue gives the reactions on psilocybin.
Scientists have differed over the years in their interpretation of the effects of psilocybin on subjects. Paul McHugh, the former director of the Dept. of Psychiatry and Behavioral Science at Johns Hopkins, stated that “The unmentioned fact in [the book]The Harvard Psychedelic Club is that LSD, psilocybin, mescaline and the like produce not a “higher consciousness” but rather a particular kind of “lower consciousness” known well to psychiatrists and neurologists – namely, toxic delirium.” On the other hand, Johns Hopkins medical researcher Roland Griffiths carried out a controlled double-blind study on 36 volunteers who had never before experienced psilocybin. Two months after taking the drug, 79% of the participants reported moderately to greatly increased life satisfaction and sense of well-being. Although 36% of the volunteers experienced strong to extreme dysphoria at some point during the session, the negative effects were reported to be easily managed by the researchers.
In a follow-up study 14 months after the psilocybin experience, two-thirds of the participants listed this as one of the five most spiritually significant events in their life; and one-third of the participants rated it as the single most meaningful event of their lives. Two-thirds of these participants claimed that the psilocybin experience increased their sense of satisfaction with life. Dr. Griffiths claimed that these relatively long-term effects on subjects’ well-being were very different from the transient toxic delirium experienced by mental patients.
Adverse Effects and Relative Risks of Psilocybin:
A number of scholarly studies have demonstrated that the Schedule I classification of psilocybin and LSD is unjustified by the facts. We will review the potential therapeutic uses of these drugs in Section V of this post. We discuss the potential for abuse of these drugs here in association with Figs. II.6 and II.7.
Figure II.6 shows that psilocybin and LSD are the least harmful of 16 drugs involved in a UK study of the relative harm of several substances. The figure shows the dependence potential (the risk of addiction) on the y-axis vs. the ratio of the active dose to the lethal dose on the x-axis. A commonly used terminology is the therapeutic index, the ratio of the lethal dose to the active dose of a substance. The higher the therapeutic index, the smaller the danger of an overdose from a normal active dose of a substance. Note that the therapeutic index is the inverse of the quantity plotted on the x-axis of Fig. II.6; thus, a very high therapeutic index corresponds to a very low value in that figure. The therapeutic index for psilocybin is estimated to be 641, based on extrapolation from experiments with mice. The extrapolation from mouse experiments was used because, as of 2011, there were almost no known cases of human death from ingesting ‘magic mushrooms.’ There were only two known cases, and both of those involved several potentially confounding circumstances. For comparison, the therapeutic indices of aspirin, nicotine, and alcohol are 199, 21, and 10, respectively. A 60-kg human would have to consume 1.7 kg of dried magic mushrooms or 17 kg of fresh mushrooms to reach this estimated lethal dose of psilocybin. Furthermore, the dependence potential of both psilocybin and LSD are extremely low — they are the lowest of the 16 substances compared in Figure II.6 – indicating that neither drug appears to be addictive. In addition, the ratio of active dose to lethal dose is also the smallest of the 16 substances that were tested.
Figure II.6: Results of a UK study of the relative harm of 16 substances, including psychoactive drugs, narcotics, caffeine and nicotine. The vertical axis measures the potential to develop dependence, ranging from very low to very high. The horizontal axis plots the ratio of the active dose to the lethal dose of that substance. This ratio is the inverse of the therapeutic index, the ratio of a lethal dose to the active dose. Note that the hallucinogenics psilocybin and LSD have both the lowest dependence potential, and also the highest therapeutic index.
Figure II.7 shows a different UK ranking of the harm from a number of drugs. This 2010 study, by D.J. Nutt, et al. in The Lancet, ranked drugs according to several different criteria. First, they listed harm to users, including health damage and mental impairment, mortality, and loss of tangibles and relationships. They also considered harm to others, including economic and environmental costs to the community, crime, and family adversities. In this assessment of 14 different substances alcohol, heroin and crack cocaine were clearly the most harmful substances, while LSD and psychoactive mushrooms came out lowest (13 and 14, respectively) of all substances in the study. In this ranking of relative harm, mushrooms had an overall harm rating of 6, compared with 72 for alcohol and 27 for tobacco.
Figure II.7: The results of a 2010 U.K. study of the relative harm of 14 different drugs. This study analyzed both the harm to users and the harm to others from these substances. Of the 14 different substances studied, LSD and psychoactive mushrooms were the least harmful, with overall harm scores of 7 and 6 respectively, while alcohol was by far the most harmful drug with a score of 72.
The Lancet study is a stark reminder of the discrepancy in how hallucinogenic substances such as LSD and psilocybin have been treated, relative to the legal drugs alcohol (overall harm score 72) and tobacco (overall score 27).
Classic addiction experiments demonstrated that if rats were placed in a cage with a supply of an addictive drug such as heroin or cocaine that they could access by striking a bar, they would continue to strike the bar, neglecting even basic needs such as food or sleep. However, if the same experiments were repeated by substituting hallucinogenics such as LSD or psilocybin, the rats would avoid self-administering the substances after a single dose.
Even though psilocybin has very low dependence potential and very low ratio of active dose to lethal dose compared with other psychoactive substances, that does not mean that psilocybin is free from adverse effects. The most common cause of hospital admissions from the use of psilocybin is panic reactions, where subjects become scared and extremely agitated. These psychotic states can result in self-harm or suicide attempts. It is reported that when psilocybin is taken under the guidance of trained counselors, subjects can relatively easily be ‘talked down’ when they experience a panic attack. Studies of hospital records of people admitted after taking psilocybin have found extremely high levels of phenethylamine (PEA). It is possible that the presence of PEA may accentuate adverse effects of psilocybin. Subjects that are prone to psychotic episodes should not take psilocybin, as the drug could trigger psychosis or a psychotic episode.
III. History of LSD Usage
LSD is short for the psychedelic substance lysergic acid diethylamide. LSD was first synthesized in 1938 by Swiss chemist Albert Hoffman. As was mentioned in our preceding section, Hoffman was also the first person to synthesize psilocybin. Hoffman was experimenting with ergotamine, an alkaloid found in ergot, a fungus that attacks grain. His goal was to create a substance that would stimulate the central nervous system, and potentially have medical applications. Hoffman’s initial terminology was LSD-25, since this was the 25th substance he had synthesized from lysergic acid.
In 1943, Hoffman accidentally discovered that LSD had psychedelic properties. It is believed that he might have absorbed some LSD through his skin while he was working with it. Hoffman was struck by the intensely powerful feelings that were activated by LSD. He also realized that even tiny amounts of LSD, such as 20 µg (20 micrograms, where a microgram is one millionth of a gram), could produce its effects. Figure III.1 shows some of the reported physical effects of LSD on humans. These include: increased temperature and profuse sweating; dilated pupils; elevated blood pressure and heart rate; and numbness, weakness and tremors of muscles.
Figure III.1: Possible physical effects of LSD on humans. These include increased body temperature, blood pressure and heart rate; profuse sweating; dilated pupils; and numbness, weakness and tremors of muscles.
The neurological effects of LSD are very similar to the effects of psilocybin. Frequent users of LSD generally develop a tolerance for the drug; this means that over time, increasing doses of LSD are necessary to achieve the same effect. However, as far as is known LSD is not addictive. In the early history of LSD, it was known as a psychomimetic; that is, the qualitative effects of LSD appeared similar to the experiences of a person suffering a psychotic episode. When people were given psychiatric tests while they were on LSD, the results were similar to those of people with schizophrenia, or who were experiencing a temporary psychotic episode. A common topic among early scientific researchers was to see if the administration of LSD could shed light on psychotic reactions. These researchers focused on symptoms such as hallucinations, extreme anxiety or paranoia, loss of “ego boundaries,” and distortion of the sense of time. In 1951 the Canadian magazine McLean’s reported a journalist’s experiences on LSD in an article titled “My 12 Hours as a Madman.”
However, researchers soon learned that there were significant differences between psychosis and LSD. In addition to the negative symptoms, subjects who had taken LSD also reported experiencing some very positive sensations. Several subjects reported feeling “being united with the world;” they also reported profound revelations in the areas of religion or philosophy, and greater sensitivity to the feelings of others. Many subjects reported their LSD “trip” as being one of the greatest spiritual experiences in their lifetime. These positive subjective experiences on LSD seemed to be radically different from the negative reactions to a psychotic episode.
Eventually, researchers understood the importance of “set” and “setting” in the outcomes of subjects on psychedelics. People who began such experiences with the expectation that they would have negative effects tended to report negative experiences, while those who were conditioned to expect positive spiritual experiences tended to report those. Also, the results of psychedelic experiments were strongly dependent on the advisors who accompanied the subjects and also on conditions such as the music and lighting, the location (indoors or outdoors) and the testing rooms (clinical and sterile, or homey and comfortable). Subjects seemed to be more receptive to suggestions during psychedelic experiences. In fact, there are anecdotal reports that for applications of LSD in psychotherapy, “patients working with Freudian therapists returned with Freudian insights, … while patients working with Jungian therapists returned with vivid archetypes from the attic of the collective unconscious, and Rankians with recovered memories of their birth traumas.” West Coast LSD researcher Sidney Cohen summarized these results by stating that “Under LSD the fondest theories of the therapist are confirmed by his patient.” We now understand that these findings reflect the fact that patients using LSD or other psychedelics are highly susceptible to the expectations of those guiding them through the experience.
The Sandoz pharmaceutical firm, where Albert Hoffman worked, was interested in finding clinical applications for LSD. As a result, they trademarked the name Delysid for the drug, and offered it free to researchers. In the 1950s and early 1960s, there was considerable interest in LSD by medical researchers. Psychiatrist Humphry Osmond used LSD as a complement to psychotherapy. Osmond reported that in a few cases, alcoholics who were given a single dose of LSD stopped drinking, at least temporarily. In 1957 Osmond also coined the term psychedelic (meaning “mind manifesting”) for LSD and similar hallucinogenic compounds. The work of Osmond and others led to LSD being used to treat thousands of alcoholics in the US and Canada.
A fascinating revelation from Michael Pollan’s book is the role that psychedelic drugs played in the development of the Alcoholics Anonymous movement. Bill Wilson, the founder of AA, had been treated in hospital with belladonna, an alkaloid substance with psychoactive properties. Wilson attributed his own sobriety to the spiritual experience he had with this drug. AA encourages alcoholics to submit to a “higher power;” although it is generally assumed that the higher power of AA is the Christian God, Pollan speculates that perhaps Wilson intended this to refer to his own mystical experience on psychedelics. In fact, when he learned about research using LSD to treat medical issues, Wilson was administered acid by researchers, and became convinced that the drug might produce a spiritual experience comparable to his own. He proposed to his board that they consider adding psychedelic drug treatments to fight alcohol addiction; however, his board strongly disagreed and felt that any links between AA and psychoactive drugs would be disastrous for that organization.
In the 50s and early 60s, LSD was used to treat conditions such as “addiction, depression, obsessive-compulsive disorder, schizophrenia, autism and anxiety for patients with life-threatening conditions.” As many as 40,000 subjects participated in research trials that utilized LSD, and between 1950 and 1965 there were six international scientific conferences that featured potential medical applications of LSD. A 1967 review article covering treatment with psychedelic drugs reported success in “70 percent of cases of anxiety neurosis, 62 percent for depression, and 42 percent for obsessive-compulsive disorder.” But beginning in 1968, LSD became illegal in the U.S. In almost every case, scientific research on LSD in America ceased at that time. And when research and clinical trials finally restarted in the late 1990s, scientists at that time remembered almost nothing from what were considered promising applications of LSD before its ban.
In 1970, LSD was declared a Schedule I drug in the U.S. This means that it had a very high danger of abuse and risk, and that it had no legitimate medical applications. Figure III.2 shows a “radar plot” where the harm of 20 different recreational drugs were compared. A group of addiction specialists in psychiatry, chemistry, pharmacology, epidemiology and the police ranked these substances in different categories. The relative risk is zero at the center of the circle and increases with the radius. Red denotes the relative social harm of each substance; green denotes the risk of dependence; and blue shows the relative physical harm. LSD is notable in that it has relatively low risks in all three of the ranking categories. It is ranked 14th in dependence, 15th in physical harm, and 13th in social harm. In addition, Figs. II.6 and II.7 show that LSD is not known to be addictive, and that it has a very low ratio of active dose to lethal dose. This is a radically different perspective than the hysterical response that led to LSD being classified a Schedule I drug.
Figure III.2: Ranking of 20 recreational drugs by a panel of addiction experts. Red denotes the social harm of each substance; green the risk of dependence of that substance; and blue the relative physical harm. LSD ranked 14th in dependence, 15th in physical harm, and 13th in social harm.
Project MKUltra:
A particularly bizarre chapter in the history of LSD was Project MKUltra. This was a secret program developed by the U.S. Central Intelligence Agency (CIA). MKUltra was illegal, because the CIA charter prohibited it from engaging in domestic activities involving American citizens. The project began in 1953 and ran until 1973. One potential motivation was a response to concerns about “brainwashing” and mind-control that was supposedly carried out by North Korean and Soviet agents on U.S. prisoners of war in the Korean War. The CIA was also concerned that the Soviets could produce a “Manchurian candidate:” a person who had been brainwashed, and then returned to American society where they would remain under the control of foreign agents. The MKUltra program was designed to see if a “truth serum” could be developed that could be used to unmask suspected Russian spies. In addition, the program attempted to control the minds of subjects. Alternatively, they looked for substances that could render its agents impervious to tactics such as torture and deprivation, if they were captured by the enemy.
In setting up the MKUltra program, the CIA demonstrated its complete lack of a moral compass when they attempted to utilize coercive methods that had been employed by the Japanese and Nazis in their prison camps. In fact, the CIA secretly recruited former Nazi torturers to advise them on methods they had developed in Nazi prison camps. From CIA documents, we know that the agency was particularly focused on the use of chemical, biological and radiological substances that could be used for mind-control purposes.
The CIA quickly focused on the use of LSD. They knew that it was active in exceptionally small doses; furthermore, they noted that subjects on LSD were unusually receptive to suggestions. They also knew that subjects on LSD were essentially incapacitated, as they experienced hallucinations and distortions of time and space. The CIA carried out numerous experiments to test the effects of LSD on human behavior. At the same time, they funneled millions of dollars in grants to support academic research on LSD. Some of the administrators of these grants realized that they were being bankrolled by the CIA, while other researchers were completely in the dark as to the source of their funding. For example, Gordon Wasson’s 1955 trip to Mexico, described in the preceding section, where he experienced psilocybin and wrote up his experiences for Life magazine, was underwritten by the CIA’s MKUltra program without Wasson’s knowledge.
Early experiments with LSD were conducted on mental patients, prisoners, drug addicts and prostitutes; these were people over whom the agency had some leverage. One of us (TL) had a family member who consented to be given LSD in return for dropping a felony charge against him. Many of the CIA experiments were conducted on subjects without their knowledge or consent; this was a clear violation of the Nuremberg Code (this stated that “the voluntary consent of the human subject is absolutely essential … to satisfy moral, ethical and legal concepts.”) Although the CIA focused on the use of chemical, biological or radiological techniques for interrogating captured enemy agents (or ensuring that their own agents were impervious to attempts to interrogate them), they were also interested in using these substances for “harassment, discrediting or disabling purposes.” The CIA was particularly interested in trying to drug Cuban leader Fidel Castro. In fact, they spent a great deal of time and money trying to develop a cigar loaded with drugs that might be given to Castro.
In one especially troubling experiment, called Operation Midnight Climax, the CIA set up brothels within their safehouses in San Francisco. Men who frequented the brothels were dosed with LSD without their knowledge; the CIA would then film the men through one-way mirrors and later study their behavior while on acid. In another experiment, heroin users were provided with supplies of heroin in return for participating in LSD studies. Many tests involved giving LSD to unwitting CIA staff or to civilians, and clandestinely observing their behavior. Apparently several of these subjects experienced serious adverse reactions, and there were at least a few deaths. Perhaps the most infamous case was that of Frank Olson, an Army chemist who was covertly dosed by his CIA supervisor. Nine days later, Olson died after falling out of a 13th-story hotel room in New York City. Stephen Kinzer, author of the book Poisoner in Chief: Sidney Gottlieb and the CIA Search for Mind Control (Dr. Sidney Gottlieb was the Director of the CIA MKUltra program), claims that Olson was killed a few days after he requested to be transferred from MKUltra because of his concerns about the morality of the project.
As Director of the MKUltra program, Dr. Sidney Gottlieb pioneered the use of “black sites,” locations outside the U.S. where people could be taken, interrogated and also tortured. For example, Stephen Kinzer reports that in 1952 Gottlieb led a team of scientists to a CIA black site in Munich, Germany. Here, “prisoners of war were pumped full of drugs, interrogated and then allowed to die.” Such experiments were greatly expanded when the MKUltra program was created one year later. These CIA practices became highly publicized when U.S. intelligence agencies used black sites to interrogate prisoners who had been involved in the 9/11 attack on the World Trade Center, or prisoners who were captured during the Iraq Wars at locations such as the Abu Ghraib prison. At Abu Ghraib, the CIA and U.S. Army committed serious human rights violations of prisoners that included “physical and sexual abuse, torture, rape and the killing of [a prisoner] Manadel Al-Jamadi.”) In Sharon Weinberger’s review of Kinzer’s book in the New York Times she states that “Gottlieb has previously been treated as a historical footnote, but Kinzer elevates him to his proper place as one of the CIA’s most influential and despicable characters.”
The MKUltra program never succeeded in developing a “truth serum,” chemicals that wipe away details from an agent’s mind, or pills that could create a “Manchurian Candidate.” They did, however, establish a pattern of illegal and immoral activities that would later culminate in the torture revelations at Abu Ghraib in Iraq. MKUltra was closed down in 1973. In Dec. 1974, the New York Times published an article by Seymour Hersh claiming that “the CIA had conducted illegal domestic activities, including experiments on U.S. citizens, during the 1960s.” Although Hersh’s article referred to CIA actions against antiwar activists such as Daniel Ellsberg and Jane Fonda, the fact that the agency had violated its prohibition against conducting operations against American citizens led to scrutiny of additional domestic CIA operations.
This led to the creation of a Senate committee chaired by Frank Church, and a presidential Rockefeller Commission to investigate the domestic practices of the U.S. intelligence community. The two committees released reports in the summer of 1975 that detailed how Project MKUltra had violated the law and had conducted experiments in the U.S. that used hallucinogenics such as LSD and mescaline on American citizens. Although these reports first revealed to the American public the existence of programs such as MKUltra, the committees were hampered by the fact that in 1973, following the revelations about the Watergate break-in, CIA Director Richard Helms had ordered the destruction of all documents relating to MKUltra.
Figure III.3: The final report of the Church Committee on domestic activities of the CIA. This report was issued in 1975, and described CIA activities involving U.S. citizens in the MKUltra program. By law, the CIA was prohibited from activities involving domestic citizens.
The original Church Committee report had access to very little information about MKUltra. However, in 1977 a cache of MKUltra documents was discovered; they had been mis-filed and hence escaped the destruction of other CIA documents. These documents were used in a series of 1977 Congressional hearings. Still, even in 1977 the information available to the Church Committee was fragmentary and lacking in specific detail. The former Director of MKUltra, Dr. Sidney Gottlieb, testified before the Senate Committee, but Dr. Gottlieb essentially refused to answer questions that were directed to him, or claimed ignorance of details about the program.
Although the MKUltra activities were curtailed and the Church Committee report blasted the CIA for violating its charter, none of the individuals in charge of the program were ever fired, indicted, or jailed. “Mad scientist” Dr. Sidney Gottlieb retired, and although he was subject to several lawsuits from among the thousands of people who were drugged and studied by MKUltra staff, he otherwise continued without taking any responsibility for this massive, illegal, and mainly useless program.
Timothy Leary and the Banning of LSD:
Prior to 1959, Timothy Leary had been a promising young psychologist. He had conducted an experiment to test the effectiveness of psychotherapy. At Oakland, California’s Kaiser Hospital, Leary and a collaborator divided psychotherapy patients into two groups. The first group received standard psychiatric treatment. The second group were placed on a waiting list and received no treatment at all. After one year, they assessed all of the people in both groups. One-third of the patients had improved, one-third had regressed, and one-third saw no change. But this was true of patients in both groups. This experiment raised considerable doubt regarding the efficacy of psychotherapy. When he was hired at Harvard’s Department of Social Relations, Leary was ready to consider something new.
Leary first experienced psilocybin during a trip to Mexico in 1960. He then returned to Harvard and recruited a young faculty colleague Richard Alpert. The two of them founded the Harvard Psilocybin Project, which we reviewed in Section II. As we have mentioned, the Harvard Psilocybin Project carried out two large experiments, the Concord Prison Experiment and the Good Friday Experiment, also known as the Marsh Chapel Experiment. Both of these experiments reported dramatic effects on the participants. However, the work of the Harvard Psilocybin Project is now infamous for the sloppiness of its research methods. This was possibly the result of Leary’s own personality. As a cynic he believed that scientific research was a game, and he seems to have felt justified in stretching the rules to justify his conclusions. The second aspect is that Leary became obsessed with the mind-altering properties of psychedelic drugs.
Leary outlined his messianic feelings in a 1968 memoir called High Priest (see Fig. III.4). In this book he summarized his desire to turn everyone on to psychedelic trips. “Wake up! You are God! You have the Divine plan engraved in cellular script within you. Listen! Take this sacrament! You’ll see! You’ll get the revelation! It will change your life!” During the early 60s, Leary moved from what he called the “psychology game” to the “guru game.” In his new role, Leary believed that he had been called upon to spread the word about psychedelics to the general public. This began with a Harvard graduate class developed by Leary called “Experimental Expansion of Consciousness,” which advertised that students “will participate in experiments with consciousness expanding methods.” The course was wildly popular; however, the chair of Leary’s department David McClelland criticized the researchers with pressuring students to take psychedelic drugs and with using slipshod methods to justify their results, saying that “The data are simply used to support what you already know to be true.”
Figure III.4: The cover of Timothy Leary’s 1968 memoir High Priest. In this book Leary recounts his experiences with LSD and his highly publicized crusade to turn Americans on to LSD and other psychedelic drugs.
In 1962, responding to a complaint from colleague Herb Kelman, the Dept. of Social Relations held a faculty meeting to discuss allegations that Leary and Alpert were putting pressure on graduate students to take drugs, and that these “consciousness expanding” psychedelic drug sessions had an “emphasis on pure experience, not on verbalizing findings.” The meeting ended with an agreement that Leary and Alpert would modify their seminar to put more emphasis on controlled scientific studies of these substances; furthermore, they agreed to put their supply of psilocybin under the control of Harvard Health Services. However, one of the attendees at this meeting was a reporter for the Harvard Crimson, who published an article the following day titled “Psychologists Disagree on Psilocybin Research.” This article was then taken up by the popular press, and Timothy Leary began his new career as an apostle of mind-expanding drugs. For example, Leary was quoted as saying “Psychedelic drugs cause panic and temporary insanity among those who have not taken them.”
In 1962, the Harvard Psilocybin Project was shut down by the university. By 1963, Leary and Alpert had formed the International Federation for Internal Freedom (IFIF) and announced that future research with psychedelics would be conducted by that organization and not Harvard University. The manifesto for IFIF announced “If you want to research your own nervous system, expand your consciousness, who is to decide that you can’t and why?” In 1963, another article in the Harvard Crimson reported that Leary and Alpert had been giving mescaline to undergraduates, in violation of their agreement to restrict access to psychedelics to graduate students. As a result, Leary and Alpert were fired by Harvard. They then took their show on the road.
In the mid-1960s, one of us (TL) was an undergraduate at the University of Rochester. In fall 1963 one of Timothy Leary’s former psychology associates at Harvard arrived on our campus. It was not long before psychedelic drugs, particularly LSD, began appearing at fraternity parties and other campus social events. It seemed clear that a few recent arrivals on campus were handing out samples of drugs to interested students (probably also to graduate students and faculty). The University of Rochester was unusual in that marijuana was not widely available to students until 1964, while LSD had been circulating on campus for nearly a year.
Timothy Leary proceeded to become the high priest of psychedelic drugs. He was eminently quotable, so he was constantly sought out by journalists and TV reporters. His new mantra to the emerging social class of “hippies” was “Turn on, Tune in, Drop out.” The proliferation of illegal drugs, particularly marijuana and the psychedelics, became an important element of a new American counter-culture movement. Leary’s exhortation for Americans to tune in and drop out was directly connected with a growing anti-Vietnam War ethos among American youth. Leary announced that “The kids who take LSD aren’t going to fight your wars. They aren’t going to join your corporations.” This was a direct challenge to conventional American society, and a threat that was taken very seriously by the Establishment.
One of the first major psychedelic drug initiatives from the American counter-culture was led by Ken Kesey, author of the novel One Flew Over the Cuckoo’s Nest, who had homes in California and Oregon. A number of his friends, who called themselves the Merry Pranksters, lived communally on Kesey’s properties. In the summer of 1964, the Merry Pranksters purchased a school bus that they decorated with psychedelic symbols and called Furthur (see Fig. III.5). In August 1964 a group of the Pranksters embarked on a road trip from California to the 1964 World’s Fair in New York. Along the way they stopped at towns across the country and would present events for the locals. The Merry Pranksters traveled with massive amounts of LSD and amphetamines, which they took themselves and also distributed to their audiences. On some of Kesey’s road trips, the Grateful Dead (then known as The Warlocks) traveled with the Pranksters and would perform live impromptu concerts. There would be poetry readings and other activities that Kesey called “hallucinogenic-inspired spontaneity.” In 1968 Tom Wolfe’s book The Electric Kool-Aid Acid Test described a 1966 road trip of the Merry Pranksters from Mexico to Houston.
Figure III.5: The former school bus Furthur, decorated with psychedelic symbols, used by Ken Kesey and his Merry Pranksters in road trips across the U.S.
The Merry Prankster trip was arguably one of the first public events that centered around the distribution of drugs, particularly LSD. This movement was strong on the West Coast and centered in San Francisco. In August 1965, under considerable pressure from the U.S. government, the Sandoz company stopped supplying American groups with LSD. With Timothy Leary serving as a public-relations ambassador for LSD, starting in September 1965 various groups began to synthesize and distribute LSD. Owsley Stanley, the sound engineer for the Grateful Dead band (see Fig. III.6), was the unofficial supplier of LSD for much of the acid that was distributed in San Francisco and elsewhere. Stanley has stated that he manufactured enough LSD in the mid-60s to account for 5 million doses. And “Owsley Acid” became infamous at a number of public events on the West Coast called the “Acid Tests.” These events featured light shows and psychedelic-inspired rock music, while accompanied by wholesale distribution of drugs.
Figure III.6: Owsley Stanley (left) with Jerry Garcia, the lead guitarist of the Grateful Dead. Stanley, the first known private individual to produce LSD, produced and distributed as many as 5 million doses of LSD in the mid-60s.
Figure III.7: Much LSD was produced on squares of paper called blotter. The paper was often decorated with designs or artwork, perforated, then soaked in a liquid solution of LSD and dried. One square of blotter contained a single dose of LSD. This “blotter acid” could be swallowed or placed on the tongue. Shown is a sample of blotter acid; each square represents a single dose.
The Grateful Dead lived communally in a large ramshackle house in the Haight-Ashbury district of San Francisco. Haight-Ashbury soon became the epicenter of hippie culture. In January 1966, a store called the Psychedelic Shop opened. It featured LSD, which was still legal in California at the time, and the store promoted the safe use of LSD. But on October 6, 1966 California banned LSD, and the Psychedelic Shop closed its doors. However, advocates of LSD held a Love Pageant rally on that date in the section of Golden Gate Park adjoining Haight-Ashbury. This became a symbol of hippie culture, as participants were urged to bring “children, flowers, flutes, drums, feathers, bands, beads … incense, chimes, gongs, cymbals, symbols, costumes and joy.” A free concert featured the Grateful Dead and Janis Joplin. Ken Kesey and his Merry Pranksters brought their bus Furthur to the event. After a “declaration of independence” was read aloud, thousands of participants simultaneously swallowed a tab of acid (see Fig. III.7).
The Love Pageant was followed in January 1967 by the Human Be-In, also at Golden Gate Park. This event attracted some 30,000 people, many of whom were there to experience a free concert featuring San Francisco bands Grateful Dead, Big Brother and the Holding Company, and Jefferson Airplane. For the event, Owsley Stanley distributed copious amounts of his “White Lightning” LSD. Keynote speaker Timothy Leary (see Fig. III.8) unveiled his mantra “Turn On, Tune In, Drop Out,” Allen Ginsberg and Lawrence Ferlinghetti read poetry, and Dick Gregory and Jerry Rubin made political remarks. The success of the Human Be-In was a major factor in the Summer of Love that took place a few months later. These events, and the 1969 Woodstock concert that attracted 400,000 people, arguably marked the high point of the hippie counter-culture movement.
Figure III.8: Timothy Leary addressing the crowd of 30,000 at the January 1967 Human Be-In held at San Francisco’s Golden Gate Park.
While Timothy Leary and others were touting the amazing mind-expanding qualities of psychedelic drugs, a powerful backlash was mounted against these substances. The press was bombarded with stories of adverse effects of psychedelic drugs, particularly LSD. It was reported that people who had taken large amounts of LSD were sometimes subject to “flashbacks,” hallucinatory effects that occurred long after ingesting the drugs. Panic reactions among LSD users were fairly common, and people who had schizophrenia or had psychotic tendencies could experience serious psychotic episodes after taking psychedelic drugs. A particularly effective story was that of media personality Art Linkletter’s daughter Diane, who died after she fell or jumped out of a window. Linkletter stated that his daughter had experienced a “bad trip” after taking LSD; he insisted that Diane’s death was a suicide that was directly connected to her drug use.
A media blitz ensued, where the press painted a picture of extreme danger from psychedelic drugs. Some of these horror stories were true but misleading; although panic reactions are not uncommon among users of psychedelics, they are usually easily handled if experienced guides are present. Negative reactions to LSD do occur, but mostly among unsupervised users; but according to a 1960 survey by psychiatrist Sidney Cohen, people taking psychedelics administered by qualified therapists generally gave very favorable reports of their experience. Cohen found “no evidence of serious prolonged physical side effects” from this group – complications were “surprisingly infrequent” and both LSD and mescaline were “safe.”
But Cohen’s 1960 conclusions were generally ignored amidst a flurry of articles claiming that psychedelics posed extreme danger to the public. In fact, Cohen himself contributed to the negative publicity. In 1962, he published an article pointing out that when psychedelics were taken by groups or individuals with no professional guidance, they could experience “serious complications” and “the dangers of suicide, prolonged psychotic reactions and antisocial acting out behavior exist.”
Among the negative revelations were stories that turned out to be completely bogus. The claim by a researcher that LSD could damage chromosomes and cause birth defects was widely touted, while the refutation of this falsehood received little publicity. In 1967, Newsweek reported that six students who were tripping on LSD had gone blind after staring directly into the Sun; once again this completely fraudulent tale received a tremendous amount of publicity. A Life magazine article in 1966 titled “LSD: the Exploding Threat of the Mind Drug that Got Out of Control” claimed that an LSD trip “could be a one-way trip to an asylum, a prison or a grave.” This article summarized the establishment’s contention that consumption of LSD was dangerous and potentially fatal. This echoes almost precisely the hysteria about marijuana that was promulgated in the “Reefer Madness” days.
Media attention to the dangers of psychedelic drugs culminated in March 1966 with Senate hearings on LSD. Senator Robert F. Kennedy defended the use of LSD in research, stating “Perhaps we have lost sight of the fact that it can be very, very helpful in our society if used properly.” However, his fellow Senators had indeed lost sight of that fact, and Kennedy was a lone figure defending research on LSD. In October 1966, the FDA ordered researchers working with LSD to discontinue their work. And in October 1968, the possession of LSD was made a crime in the U.S. In 1970 Congress passed the Controlled Substances Act and LSD was designated a Schedule I drug, meaning that it was a substance of high danger for abuse, and with no legitimate medical applications. From Fig. II.6, we see that LSD actually has an extremely low danger of dependence; as far as we know it is not addictive. And in Section V we point out that LSD appears to have a reasonably high potential for medical applications. This means that labeling LSD a Schedule I drug has greatly impeded legitimate scientific research on this substance in the U.S. for the past 55 years. In 1971, the United Nations, strongly influenced by the situation in the U.S., labeled LSD a Schedule I Controlled Substance.
Many scientists believe that Timothy Leary was personally responsible for shutting down a rather extensive number of research programs on the neurochemical effects of mind-altering drugs. Leary’s controversial statements urging American youth to “turn on” to psychedelic drugs created a fierce backlash. In the process, substances that may have useful medical applications were demonized and then banned as Schedule I drugs. Would the establishment crusade against psychedelic drugs have been as sweeping and draconian without Timothy Leary? This is a question that invites speculation; but the reality is that the American ban on psychedelic drugs has cost us 50 years of time when we could have answered many of the scientific questions involving these complicated and powerful substances. In Part II of this post, we survey the more recent scientific research that has sprung up in this century, despite the continuing Schedule I designation, mainly with private funding.
— Continued in Part II —
Debunking Denial 