As an undergraduate, many years ago when I was young and daring, I volunteered to take part in a psychological test. “Volunteered” may not be the correct term, since the deal was that I would get paid ten bucks for about two hours of my time, which was a princely wage when most jobs that students could pick up paid no more than a buck an hour. In any case, I “volunteered” with alacrity, and one grey wintry afternoon I reported to the test site, prepared for whatever and eager to collect my reward.

I was seated at a table, fitted with headphones, and told that I would listen to a narrative which would last perhaps four or five minutes, and then answer a few questions about the narrative. This would be repeated several times during the course of one hour, after which I would be tested and examined. I was given a little device which would supposedly allow me to adjust the volume of the narrative in my headphones.

It all sounded okay.

Then the actual test began. The narrative, spoken by a male with a whiny voice, seemed to be about trying to find a parking spot in Cambridge around Kendall Square. It was far from clear. The volume of the speaker would change without my having done anything with my device. But when I tried to readjust the volume with my device, the effect was completely erratic. I was a bit confused at first – I thought that I had the direction backward. Turning the knob clockwise was supposed to raise the volume, I thought. But that seemed to lower the volume. Then the volume would increase drastically, and I would turn the knob, first counterclockwise, then clockwise, in a totally futile effort to turn the volume down.

Meantime, the whiny voice continued to meander about his search for a parking spot. Delivery trucks kept getting in the way. The guy would say which street he was on, and at which corner he turned, and then the name of the street he had turned onto, and then another street name, and then the same truck was in the way again, blocking a potential parking spot. As he wandered about, mentioning the occasional landmark I knew about (a pizza parlor called Regina), his speech would get very, very slow. And then it would speed up. And then it would get very quiet, and my little device would do nothing useful.

After a few minutes of this, I got fed up. I took off my headphones, pushed back my chair, stood up, and walked to the door of the little room in which I had been sequestered. To hell with my ten bucks, I thought. I’ll pick up a few bucks helping out at a faculty member’s cocktail party – way more agreeable!

When I emerged from my cell, the two men who were running the test were smiling. “You didn’t last long,” one of them said.

“Was that supposed to be a test of my endurance?” said I.

No answer. I was prepared to leave, but I was not quite done. The two guys performed some simple tests on me. And they took a blood sample. And, even though I had obviously not gone the distance, they paid me my ten dollars. One of the men mumbled something about trying to measure the physical consequences of psychological frustration. The frustration was evidently intentional.

I later learned that the guiding light behind my frustrating experience was Richard Alpert, a faculty member in the psychology department. Alpert was focused on the interactions between mental states and physiology. In the experiment in which I was a subject, Albert was attempting to create an alternate reality in order to investigate the effects of that experience on my physiologic response. This was not quite a psychedelic experience, but it was tending in that direction.

Alpert came into prominence a few years later when he teamed up with Timothy Leary, and the two of them began to promote psychedelics essentially as a pathway to an alternate experience, and perhaps also to a richer, better, fuller consciousness and life.

Leary, Alpert, and LSD

The psychedelic agent promoted by Leary and Alpert was LSD – lysergic acid diethylamide. LSD was first isolated in 1938 by a Swiss chemist, Albert Hoffman, who was working for Sandoz at the time. The source of LSD is a fungus called ergot, which affects a number of related grain crops, principally rye, but also other grains. Eating grain affected by this fungus can cause a very wide range of physical as well as mental symptoms. Ergot causes vasoconstriction, which can lead to a variety of symptoms, from shooting pains in the fingers and toes all the way to gangrene and amputation of limbs. Psychological symptoms may cause hallucinations, convulsions, and even death.

However, the harmful properties of ergot do not seem to persist when LSD is extracted from ergot, and LSD can be synthesized from elementary components without relying on ergot as a source.

In the presence of some of his associates, Hoffman ingested a very small quantity of LSD, which led to remarkable visual and perceptual changes. This led to speculation that LSD might be valuable in the treatment of psychotic disorders and also possibly addiction. Scientists at Sandoz and also at the National Institutes of Health were examining LSD as a serious treatment option. However, in the sixties, the patent life for LSD expired, and Sandoz stopped making it.

But LSD turned out to be fairly easy to make, and, out of curiosity, people started making LSD in home laboratories and experimenting with small doses to test out what those experiences might be like.

The word “psychedelic” dates from 1957, according to my Oxford English Dictionary, which defines it as follows: “Of a drug producing an expansion of consciousness through greater awareness of the senses and emotional feelings and the revealing of unconscious motivations.”

The word was coined by H. Osmond, a member of the American Academy of Sciences, who was quoted in the OED as follows: “I have tried to find an appropriate name for the agents under discussion: a name that will include the concept of enriching the mind and enlarging the vision.”

The word combines psyche, from the Greek, meaning breath, but also the life-animating principle in man and other living creatures, and delos, to make manifest or reveal. Thus, psychedelic agents might be said to help us perceive and understand what is truly essential and valuable in our existence, and help us rid our minds of what is trivial, annoying, disquieting, upsetting.

As I said earlier, LSD does not possess any of the dangerous qualities of its original source, ergot. Dr Jerrold Rosenbaum, who is the director of Massachusetts General Hospital’s Center for the Neuroscience of Psychedelics, has this to say about LSD’s safety: “You should know these drugs are remarkably safe in the sense that they’re not addictive. What they do is offer you an experience that you might prefer to the experience you have in daily life. So people may have used them in protest or used them as escape, but they’re remarkably safe as far as drugs that are in the pharmacopoeia, or accessible to people over the counter. Their ability to harm oneself or harm others is remarkably low. Nonetheless, despite their therapeutic potential that was being explored and their recreational use, they became viewed as a threat to government at that point in time. Indeed, there probably were some individuals that had bad experiences and were damaged in some ways by those experiences, but the vast majority of use was pretty benign.”

About psychedelic drugs, Rosenbaum said, “Psychedelic drugs alter for a period of time, depending on the duration of their efficacy, your visual, cognitive, and perceptual reality. You may have hallucinations, visions, meaningful spiritual experiences. People feel they’ve seen God or they’ve lost their sense of self or their identity for a period of time and have merged with the universe, and often return from that experience feeling changed in some way, usually with a greater sense of peace or a greater sense of connectedness to nature and the world, or a sense that there’s another reality out there that makes our lonely individual lives more endurable.”

LSD got to be fairly widely known in the late 1950s. During that period, quite a few eminent persons experimented with LSD, perhaps genuinely seeking that otherworldly experience, or perhaps just out of curiosity. Just this past week a new musical, Flying Over Sunset, that opened on Broadway tells the story of three well-known individuals who embarked on LSD trips in the 50s – Aldous Huxley, Cary Grant, and Clare Booth Luce.

Huxley we know mostly as the author of Brave New World. If you have read that novel, which is science-fiction with a serious social slant, you will not be surprised to learn that Huxley tried LSD in the late 1950s. Cary Grant evidently talked his wife’s psychiatrist into prescribing LSD for him, so he could give it a try. And Claire Booth Luce took an LSD trip shortly after being named Ambassador to Brazil in 1959.

From what I can tell from the reviews, the show is interested not so much in the effect of the LSD trips on those three individuals; rather the show uses the trips as a justification for creating dazzling visual representations of those hallucinatory experiences.

And yet, the mere fact that three really big names sought psychedelic experiences tells us a good deal about how LSD was viewed in those times.

Timothy Leary began promoting psychedelics in the 1960s, espousing the view that the alternative experience provided by LSD was preferable to day-to-day reality. He encouraged people to “tune-in, turn-on, and drop out.” This was thought to be strange and disconcerting, coming from a Harvard faculty member.

A considerable number of people, mostly young, followed Leary’s lead and experimented with LSD, which was fairly easy to obtain, since synthesizing this agent could be done simply in a home laboratory.

In that period, from about 1960 to 1980, “tripping” on LSD became common and popular in that segment of the population that proudly defined itself as “countercultural.” Several issues brought them together, especially the movement against the war in Vietnam. It seems likely that LSD use was more of a sign of protest than a philosophical exploration of an otherworldly experience.

In the 1960s, LSD and other psychedelics were taken up emphatically by the counterculture movement and brandished as a sign of their protest against the existing status quo, in particular American foreign policy. As a result, LSD came to be viewed as a direct cultural threat to American values. It was designated as a Schedule 1 substance in the US in 1968 and currently has no approved medical use. The UN listed LSD as a Schedule 1 controlled substance in 1971.

Leary continued to advocate LSD as a way of experiencing an alternate reality. According to Leary, that experience would free people from the limiting and depressing constraints of their day-to-day lives. Harvard evidently took exception to having a faculty member openly urge people, including his own students, to indulge in an experience through drug use. In many people’s minds, LSD was not categorically different from opiates, and so Leary was seen as behaving like a dope pusher. Harvard gave Leary his walking papers in 1963.

As for Alpert, the author of my frustrating little test, he travelled to India, had a “mystical experience,” and continued his life in India as a spiritual leader, under the name Ram Dass.

What does LSD actually do?

If LSD takes people on a trip to an alternate reality, how does accomplish this feat?

For a start, LSD binds both to dopamine and serotonin receptors. Specifically, LSD is an agonist of a specific subtype of the dopamine receptor, labeled 5-HD_2A receptor. (By “agonist” we mean that LSD turns on and excites that receptor; if it turned off the 5-HD_2A receptor, we would call it an “antagonist.”) That particular dopamine receptor has also been found to be the one through which a number of antipsychotic drugs exert their effects, which is one reason why there is a great deal of interest in LSD as a treatment mode for some psychological conditions. Also because it is a dopamine agonist, the effects of LSD are more energetic and fast-paced as compared to some other psychedelic agents.

The specific ways in which LSD affects that dopamine receptor have as yet not been totally determined, but one of the effects is to increase global functional connectivity, meaning that different parts of the brain are more interconnected. And LSD also increases transmission between neurons by way of glutamate. To put this information in somewhat less technical terms, LSD seems to connect and speed up different areas of brain function, and at the same time erase the distinctions between these functions – i.e., the visual and the auditory overlap, and the difference between the perceived and the imagined may be blurred. A person under the influence of LSD may form realistic images in response to music and hear sounds emanating from a visual image. And these imagined sights and sounds may not be distinguishable from reality.

LSD’s activity as a serotonin receptor agonist is the likely reason that people who have taken LSD mostly have a good time on the “trip” – the serotonin receptor is the “feel good” button, activated not only by LSD but by a number of drugs, including drugs of abuse.

However, all the evidence about LSD thus far confirms that it has a very low potential for abuse. Attempts to train laboratory animals to self-administer LSD have repeatedly failed. It doesn’t appear to be habit-forming. However, some adverse psychological reactions have been observed, such as anxiety, paranoia, and delusions – persons who have experienced hallucinations while on an LSD trip, return from the trip convinced that what they saw/heard/felt on LSD was real, and in some cases threatening. This has been labeled as “hallucinogen persisting perception disorder.”

The assertion that LSD is entirely safe needs to be taken with a bit of skepticism. While LSD is not addicting and LSD overdosing does not appear to result in harmful physical symptoms, persons “under the influence” of LSD may experience accidents leading to serious injury or death. It is probably not a good idea to be driving a car while on an LSD trip.

LSD is by no means the only psychedelic agent

Psilocybin

There are quite a number of substances that induce experiences similar to LSD. The best known of these is psilocybin. This is a compound derived from certain types of dried or fresh hallucinogenic mushrooms found in Mexico, South America and the southern and northwest regions of the United States. Mushrooms with these hallucinogenic properties are commonly called “magic mushrooms.” Psilocybin is what is called a “pro-drug,” meaning that it is converted to the active compound only after being ingested. The active compound is psilocin.

There are over 180 species of hallucinogenic mushrooms that contain the chemicals psilocybin/psilocin. These mushrooms have been used in native or religious rites for centuries. Psilocybin/ psilocin can also be produced synthetically in the lab.

These “magic mushrooms” look very much like ordinary run-of-the-mill mushrooms. In some cases, they closely resemble poisonous mushrooms. A person looking for a magic mushroom in order to embark on a hallucinogenic trip can easily pick the wrong king of mushroom and wind up quite sick, or even dead. There have also been reports that psilocybin bought on the streets can actually be other species of mushrooms laced with LSD.

Genuine magic mushrooms can be eaten raw, cooked, or brewed into a tea. They can also be dried, formulated in capsules, or smoked along with cannabis or tobacco. Synthetic psilocybin can be packaged in tablets or capsules or dissolved in water

Other names for these mushrooms are “shrooms,” “mushies,” “blue meanies,” “golden tops,” “liberty caps.”

Psilocybin is currently being studied by a team of investigators at the University of Washington in Seattle. The plan is to enroll a group of healthcare workers who are under stress because of the COVID-19 pandemic, and to administer 25 mg doses of synthesized psilocybin, followed by several therapy sessions. The team is working with a Canadian biopharmaceutical company, Cybin, which is also conducting a psychedelic-assisted therapy program entitled EMBARK. Cybin is co-funding the University of Washington project.

Peyote / mescaline

Peyote is a small cactus without needles or spines, shaped more or less like a small pumpkin. It grows commonly in the southwestern part of the US and parts of Mexico and some countries in South America. It has been used in religious ceremonies by natives of those parts of the Americas for close to 6,000 years. The active ingredient in peyote is the psychoactive compound mescaline, which, like many psychedelics, can be synthesized easily.

Ceremonial and religious use of peyote has been recognized as a part of the practice of the Native American Church and has been legal for that purpose since 1920. The objective in using peyote is fundamentally different from the usual purpose in taking LSD, which is to have a transcendent experience mostly for pleasure and to escape from humdrum day-to-day existence. Peyote is considered to be an entheogen, essentially a substance that brings the user closer to the God within ourselves. Entheogens induce alterations in perception, mood, consciousness, or behavior in order to enhance spiritual development. These substances supposedly help users achieve a number of spiritual objectives, including divination, meditation, sensory deprivation, asceticism, trance, ritual, ecstatic dance, and others.

In traditional peyote preparations, the top of the cactus is cut off, leaving the large tap root along with a ring of green photosynthesizing area to grow new heads. These heads are then dried to make disc-shaped buttons, which can be chewed to produce the desired effects, or soaked in water to drink. However, the taste is very bitter, so these days users will often grind it into a powder and form capsules to avoid having to taste it. The concentration of mescaline in peyote is rather low, so a user would have to chew more than ten of these peyote buttons to achieve the psychedelic effect.

Mescaline has a number of possible medical benefits including treatment of alcoholism and depression, both of which are associated with serotonin deficiencies. However, because it is defined as a Schedule I controlled substance, it is not generally available to researchers, so there have been very few studies of its potential therapeutic benefits.

Ayahuasca

Ayahuasca is a concentrated brew made by boiling certain plants that grow in the Amazon region. It is used both socially and as a ceremonial spiritual medicine by the indigenous residents of the Amazon basin. Drinking this brew produces an altered state of consciousness including hallucinations. A similar concoction can be made in the laboratory using fairly common ingredients, in particular N, N-dimethyltryptamine also known as DMT. Several psychedelics are based on DMT or related tryptamines.

Ibogaine

Ibogaine is found in plants growing in central Africa, in particular the root bark of the iboga tree. Its psychoactivity was discovered by the Pygmy and Bwiti tribes. The French learned of it and brought it back to Europe, where it was marketed as a stimulant under the trade name “Lambarène.” Like other psychedelics, ibogaine can be used to facilitate introspection and spiritual exploration.

Its use has been associated with serious side effects and death. Between the years 1990 and 2008, a total of 19 fatalities linked with ibogaine were reported. Six persons died of acute heart failure or cardiopulmonary arrest. It is not known how many people have used ibogaine without adverse effects.

Ibogaine is used as an alternative medicine treatment for drug addiction in some countries. However, because of the serious adverse effects, its use is prohibited in several countries, including the US. This has delayed scientific research.

5-MeO-M-DMT (usually shortened to DMT)

This psychedelic of the tryptamine class is known as “Five-methoxy” or “Toad venom.” It is found in many plant species and in at least one species of toad. In parts of South America it is used to enable communication with the gods. Research on DMT is currently being conducted by the Canadian company, Small Pharma.

MDMA

MDMA’s common name is “ecstasy.” The chemical name (seldom used, as you will quickly see), is methylenedioxymethamphetamine. It is classed as an “empathogen,” meaning that it increases a person’s feeling of empathy towards others. Besides ecstasy, it is sometimes called pingers, bikkies, flippers, molly, and M&Ms.

Some pills sold as ecstasy may have a very small amount of MDMA or none at all; these pills may contain other drugs, including methamphetamine (meth), which presents a clear danger to users.

MDMA is thought to have potential for clinical use in the treatment of a number of disorders, including post-traumatic stress disorder (PTSD), alcohol and substance abuse, and perhaps childhood trauma. MDMA is currently being studied by the Multidisciplinary Association for Psychedelic Studies (MAPS) for those uses.

Ketamine

The only reason I mention ketamine is that an article in Psychology Today, (to which I was pointed by a Gumshoe regular) described the work of a psychotherapist who stated that she uses psychedelics in her treatment of patients, especially those who are depressed. The substance she mentioned as a psychedelic was ketamine. However, ketamine is not generally considered to be a psychedelic. Doc Gumshoe posted a piece about ketamine just about three years ago, (21 January 2019, “Ketamine: Menace or Miracle” ) Here’s a bit of what I said about ketamine in that piece:

“What prompted me to look at ketamine a bit more closely was a densely-written paper in The American Journal of Medicine entitled “Nonanaesthetic Effects of Ketamine: A Review Article,” by a group of physicians at the University of Montreal (Eldufani J. Am J Med 2018;131:1418-1424). What first caught my attention was a box listing the highlights of the paper, which I reproduce here:

CLINICAL SIGNIFICANCE

Ketamine has a variety of pharmacologic effects including sedation, analgesia, bronchodilation, and nervous system stimulation.

It is used as an active adjutant that prolongs the duration of analgesic effects of painkillers in pain management.

Ketamine is used in clinical practice to manage major resistant depression, enhance memory function in Alzheimer’s patients, and reduce brain damage after stroke.

Ketamine is clinically used for managing cognitive dysfunction and immune system disorders.

As I looked through the review article, I was especially struck by the characteristics of this drug when used as an anaesthetic. What most anaesthetics do along with suppressing pain responses and inducing loss of consciousness is to slow respiratory function and heartbeat. This is true of opiates, whether taken purely for pain management or for other purposes. What kills people who overdose on opiates is, pure and simple, that they quit breathing. And anaesthesiologists are extremely scrupulous about monitoring their patients’ breathing and heart rate. They want to make absolutely sure that their patients don’t quietly drift off into permanent oblivion. But when ketamine is used as an anaesthetic, depressed respiratory function simply is not a problem. And, as the title of that review article implies, anaesthesia was the initial medical use of ketamine. Because it preserved respiratory function, it was used as a battle-field anaesthetic during the Vietnam War, and medics in the US military always have it at the ready.”

Ketamine is related to a substance called phencyclidine, which was originally used as an anaesthetic but discontinued as a number of adverse effects emerged. However, it was adopted as a recreational drug because of some of those neurotoxic side effects such as delusions and hallucinations. Phencyclidine is sometimes called “angel dust” by its fans.

What’s happening on the psychedelic front these days?

For a start, a couple of large organizations are involved in psychedelic research. The pre-eminent one is Massachusetts General Hospital’s Center for Neuroscience of Psychedelics, which was launched in February of 2021. The objective of this organization, according to their statement, is to understand how psychedelics enhance the brain’s capacity for change, to optimize current treatments and create new treatments for mental illness and to render the term “treatment resistant” obsolete. Dr Sharmin Ghaznavi, the Associate Director, said, “In the last couple decades, the possibility of using psychedelics for treatment of psychiatric illness has seen a renaissance, and the evidence so far is compelling enough to warrant investigation of their potential and their effects on the brain.”

Another large non-profit organization is the Multidisciplinary Association for Psychedelic Studies (MAPS), which was founded in 1986 just as the US Drug Enforcement Administration (DEA) was moving to criminalize psychedelic substances which had been the subject of considerable research by psychologists. MAPS tried without success to dissuade the DEA from making that move. MAPS continues to provide funding in support of research on such psychedelics as MDMA.
MAPS is the sponsor of 37 of the 353 clinical trials involving psychedelics currently listed in Clinical Trials.gov.

Other organizations doing research on psychedelics include such institutions as M. D. Anderson; John Hopkins University; NYU Langone Health; the Universities of Alabama, Arizona, Washington, Wisconsin, Utah; Yale University; King’s College, London; and the John Wayne Cancer Center.

Psychedelics do not present a tempting opportunity for pharmaceutical companies, for the obvious reason that it would be nearly impossible to get a patent on most psychedelic substances. The essential psychedelic molecule in most psychedelic organisms has been identified and synthesized, frequently by scientists working on their own.

An exception is the Canadian pharmaceutical company Cybin, which, according to their online statement, “is focused on progressing Psychedelics to Therapeutics by engineering proprietary drug discovery platforms, innovative drug delivery systems, novel formulation approaches and treatment regimens for mental health disorders.”

As noted earlier, Cybin is working with the University of Washington on a study of stressed health-care workers and the effects psilocybin on their levels of stress. In their online information, Cybin asserts that they are investigating the effects of synthesized psilocybin on a number of disorders. Clinical Trials.gov lists no trials sponsored by Cybin, either recruiting or underway. However, Cybin reports that they have completed 90 preclinical studies and have three active drug programs.

Some major pharmaceutical outfits such as AstraZeneca have at least a toe in the water, and I would surmise that many others, major and minor, are keeping an eye on the psychedelics area for opportunities.

My personal guess is that most of the research into the potential benefits of treatment with psychedelics will come from the not-for-profit institutions such as Massachusetts General Hospital’s Center for Neuroscience of Psychedelics and MAPS, and also from academic centers.

But Doc Gumshoe will keep his eyes peeled and his ear to the ground as more information comes trickling out, and he will do his best to keep Gumshoe readers informed.

* * * * * * *

You will have noticed that there has not been one syllable so far in this installment about COVID-19 or the Omicron variant. I’m sure that all of us are drowning in “news” on that topic, and I don’t want any drowning victims on my conscience. But as I try to keep my head above the rising tide of news releases, I do notice some details that are worth thinking about. I’ll include some of these in the next Doc Gumshoe disquisition; however, most of it will be about something else which may be of longer-term significance to most of us.

Thanks for all the comments – keep ’em coming! Stay well, best to all, Michael Jorrin (aka Doc Gumshoe)

P.S. Travis here, jumping in with a note that although there is not a lot of action from “big pharma” in the psychedelics space, investment pundits do get enthralled with the potential of the pscyhedelics to create something like the “marijuana boom” that cannabis investors enjoyed a few years ago. Cybin (CYBN) is one of those companies that has been teased a few times, with Compass Pathways (CMPS), Atai Life Sciences (ATAI) and MindMed (MNMD) probably the other ones that are most frequently mentioned, and that bubble of speculative enthusiasm, though it has now deflated quite a bit (MNMD was once among the best-performing teased stocks of 2020, but is down 75% since then), led to the creation of a few ETFs, including Defiance Altered Experience (PSY) and AdvisorShares Psychedelics (PSIL), both of which have also been terrible performers since they were introduced last year. I last covered a psychedelics “next marijuana!” teaser pitch back in September.

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers a couple times a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions]