A (Not So) Brief History of Psychedelic Science

Psychedelics* (i.e. chemicals that reliably produce altered states of consciousness characterized by sensory distortion and changes in cognition) have been subject to human ritualistic, therapeutic, and recreational use for millennia.  Their profound perceptual effects have the potential to elucidate countless mysteries of human neurobiology, illuminating the sensitivity of our conscious experience to stereotyped, chemically-induced changes.  Nonetheless, our understanding of these compounds is remarkably limited.

Yeah, it’s kinda like that

Presently, the lion’s share of psychedelic substances are classified by the Controlled Substances Act as Schedule I, implying (1) a lack of currently accepted medical use in the United States, (2) a lack of safety of use under medical supervision, and (3) a high “potential for abuse.”  This distinction presents an immense obstacle to the study of these compounds, stifling scientific advancement toward understanding their nature and clinical value (for more on why this humble author believes widespread study of psychedelics is a necessary scientific endeavor, stay tuned for a veritable diatribe in the future).  An overwhelming preponderance of scientific evidence directly contradicts the verisimilitude of this classification; existing research shows documented psychotherapeutic utility (re: medical use, safety), minimal toxicity (re: safety), and a lack of self-administration in animals (re: abuse potential).  Why, then, is our legal designation of psychedelics in direct contrast to scientific knowledge?  In a highly-regarded scientific review on hallucinogens*, renowned medicinal chemist Dr. David Nichols argues:

What is it, exactly, that makes these pharmacological curiosities so fearsome? The answer lies, in large measure, beyond hard science and within a complex sociological and political agenda that surround psychedelics….[A discussion] of the history and background of these unique substances is warranted to provide a little insight into how this situation arose.

Before diving into the systemic problems precluding exploration of an invaluable scientific avenue (i.e. aforementioned future diatribe), let’s honor Old Man Nichols and take a brief trip (pun only kind of intended) through the fascinating history of psychedelic science.

Ancient Use: What a long, strange trip it’s been…

Although (to our knowledge) systematic scientific investigation of psychedelics didn’t begin until the late 1800s, their widespread human exploration can be traced back over 5,000 years!  Mescaline-containing buttons of the peyote cactus collected by Native Americans have been carbon dated to between 3780-3660 BCE, and are still used ceremonially by the descendents of these natives to this day.

Mescaline-containing buttons of the peyote cactus

Furthermore, indigenous cultures in Mexico and Guatemala produced rock paintings and sculptures of mushrooms (many of which resemble hallucinogenic species) and constructed temples dedicated to “mushroom deities” that date back to approximately 1000 BCE.  Fittingly, Aztec shamans, deriving much influence from their colocalized cultural ancestors, refer to psilocybin-containing mushrooms (AKA “magic mushrooms”) as teonanácatl, meaning “flesh of the gods.”  Indigenous Amazonian consumption of the psychedelic brew ayuhuasca, which contains a synergistic hodgepodge of psychoactive alkaloids (e.g. DMT, 5-MeO-DMT, harmine, harmaline) is also thought to date back several millennia.

Mushroom stone effigies found in Guatemala, dated to approximately 1000 BCE

Ancient ritualistic use of psychedelics doesn’t appear to be isolated to the Americas, either.  Sacred texts arising from the ancient Indus River Valley make frequent reference to soma, a ritually-consumed drink ascribed divine properties.  Recorded references to soma date back to approximately 1700 BCE, but it is widely believed that its consumption may have significantly preceded written record, with hypothetical use as early as 3000 BCE.  While the identity of this sacramental substance is still subject to speculation, many leading candidates proposed by experts are psychedelic in nature.  For instance, Terence McKenna, an ethnobotanist specializing in the study of psychedelics, suggests that soma may have been a tea brewed from psilocybe mushrooms.  Because these mushrooms grow readily in cow dung, McKenna speculates that their entheogenic properties may have thus played a role in the sanctification of the cow in Hindu culture.

Psilocybin-containing “magic” mushrooms growing in cow dung

Similarly, the Eleusians of ancient Greece practiced a highly secretive annual ceremony (for any Greek citizen not convicted of murder) that involved consumption of a drink called κψκεον, which has been speculated to be derived from psychedelic ingredients.  This practice may have started as early as 1700 BCE, and was described as “both the most awesome and the most luminous [of all the divine things that exist among men].”  Despite such pervasive use, however, systematic scientific study of psychedelics didn’t arise until just over 100 years ago, when Western scientists became interested in the powerful psychotropic properties attributed to these ceremonial staples.

The Birth of Psychedelic Science: Mexican mescaline and Hofmann’s happy little accident

In 1888, German toxicologist Dr. Louis Lewin became interested in the presumed psychotropic properties of the peyote cactus after learning of its ritual use by indigenous Mexicans.  Over the course of the next decade, Lewin and his colleague, Dr. Arthur Heffter, performed numerous self-experiments with peyote, resulting in the first recorded reports of its psychological effects.  The duo isolated mescaline as a primary active compound in the cactus, and, twenty years later, mescaline was successfully synthesized by Dr. Ernst Späth.  The ability to synthesize mescaline dramatically increased its availability and facilitated standardization of dosage, effectively opening the door for systematic research and report on the qualitative nature of the psychedelic experience.

Dramatization of Louis Lewin’s early peyote experiments

Descriptive and clinical studies on mescaline comprised the landscape of psychedelic research for another two decades until 1938, when a young chemist working at the Sandoz pharmaceutical company in Switzerland made an unexpected discovery.  Dr. Albert Hofmann was exploring the medicinal properties of alkaloids derived from the ergot fungus, a somewhat dangerous oxytocic used by midwives to promote labor, with the goal of finding a safe, effective alternative for the induction of uterine contractions.  Since many of the alkaloids contained in the fungus are peptide derivatives of lysergic acid, Hofmann made a number of modifications to this structure with varied results, including an unpromising attempt known as LSD-25.  Nonetheless, Hofmann couldn’t shake the sense that there was more to this compound, and, after five years hiatus, returned to its study.  One fateful Friday, while working on a recrystallization of LSD-25, Hofmann found himself unusually dizzy and restless and returned home, where he  “sank into a not unpleasant intoxicated-like condition…in a dreamlike state, with eyes closed…[and] perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.”

Albert Hofmann, pictured holding a structural model of his “problem child,” LSD

Hofmann made the correct assumption that this odd state had resulted from the absorption of LSD-25 through his skin.  The following Monday, Hofmann (as any good scientist would) measured out and ingested 0.25 mg of LSD-25, the smallest amount he could possibly imagine having a discernible effect (n.b. a common recreational dose of LSD is ~0.1mg), and had planned to increase the dose until an effect was noticed.  Within half an hour, the symptoms of the previous Friday had returned, and Hofmann returned home on his bicycle along with his assistant.  On that bicycle trip and the hours following, Hofmann became acutely aware of the pseudohallucinations, perceptual distortions, and cognitive alterations we know to be characteristic of the LSD-induced state.  Hofmann had just discovered the most potent psychoactive compound to date, entirely by accident!  After a bit more personal testing among the staff at Sandoz and some preliminary psychiatric studies, the drug was released under the trade name Delysid for use as a psychotherapeutic aid and as an agent for familiarizing psychiatrists with the ideas and sensations of psychotic patients.

LSD-treated blotter paper commemorating Hofmann’s historic bicycle ride

From Psychiatry’s Tool to Society’s Fool

Between 1950 and the mid-1960s, more than a thousand clinical papers and several dozen books were published on psychedelic drug therapy.  Clinicians found significant utility for psychedelics for the treatment of alcoholism, end-of-life anxiety, “uncovering the unconscious roots of neuroses (i.e. psycholytic therapy),” inducing “overwhelming [psychiatric] healing experiences (i.e. psychedelic therapy),” and facilitating mystical or religious experiences (for a fascinating example of this, look up Walter Pahnke’s “Miracle of Marsh Chapel” experiment at the Harvard Divinity School, which I’d go into more detail on if I had the space…).  Concurrently, Dr. Alexander “Sasha” Shulgin, a chemist working (initially) for Dow Pharmaceuticals, began exploring the neuropsychological effects of structural manipulations on known psychedelics.  Shulgin synthesized and consumed hundreds of novel psychedelics, documenting active doses, routes of administration, and qualitative comments regarding their subjective effects.  In doing so, Shulgin dramatically expanded the existing library of psychedelic compounds, and compiled the largest and most comprehensive qualitative database on human structure-activity relationships to date, furthering the field of neuropsychopharmacology by leaps and bounds.

Psychedelic scientist Alexander “Sasha” Shulgin, being a stud

But clinicians and chemists weren’t the only ones interested in these powerful substances.  Beginning in the early 1950s, the CIA began a program codenamed MKULTRA, which sought the “research and development of chemical, biological, and radiological materials capable of employment in clandestine operations to control human behavior.”  One MKULTRA document summarized the goals of the program as follows (n.b. abridged to save space and preserve relevance):

  • Substances which will promote illogical thinking and impulsiveness to the point where the recipient would be discredited in public.

  • Substances which increase the efficiency of mentation and perception.

  • Materials which will cause temporary/permanent brain damage and loss of memory.

  • Physical methods of producing shock and confusion over extended periods of time and capable of surreptitious use.

  • Substances which alter personality structure in such a way that the tendency of the recipient to become dependent upon another person is enhanced.

  • A material which will cause mental confusion of such a type that the individual under its influence will find it difficult to maintain a fabrication under questioning.

  • Substances which will lower the ambition and general working efficiency of men when administered in undetectable amounts.

  • Substances which promote weakness or distortion of the eyesight or hearing faculties, preferably without permanent effects.

  • A material which can be surreptitiously administered by the above routes and which in very small amounts will make it impossible for a person to perform physical activity.

Given that LSD is remarkably potent and virtually undetectable, it provided an outstanding candidate for these goals, and was prominently featured in a number of experiments.  Many of these experiments involved the unwitting (and thus nonconsensual) administration of LSD in massive quantities to American and Canadian citizens, often in conjunction with various forms of torture and abuse.  Experiments halted in 1973, however, when, in the wake of the Watergate scandal, concern over revelation resulted in the immediate termination of the MKULTRA program.  Nonetheless, revelation of many disturbing details of the program over the course of the mid- to late-1970s helped frame a brutal public legacy for psychedelics as possible psychological weapons, facilitating their impending social, legal, and academic marginalization.

Schematic representation of Project MKULTRA

During the height of psychedelic research, an eccentric Harvard psychology professor, Dr. Timothy Leary, began experimenting, both personally and professionally, with the behavioral effects and therapeutic potential of psilocybin and LSD.  However, after many of Leary’s informal academic group sessions with LSD devolved (at least in the perception of the institution) into chaotic drug parties, the university began proceedings to dismiss Leary.  Following his dismissal in 1963, Leary became a prominent countercultural icon by advocating for widespread use of psychedelics and encouraging his generation to “turn on, tune in, and drop out.”

Psychedelic proponent and counter-cultural icon Timothy Leary, casting aside “parochial social insanities”

While Leary’s request through the Harvard University Department of Social Relations for 100 g of LSD and 25 kg of psilocybin – enough for 1 million doses of LSD and 2.5 million doses of psilocybin – was declined by Sandoz due to his impending dismissal, the purchase and open distribution of 43 Sandoz-supplied cases of LSD by Al Hubbard, a millionaire uranium mogul, and the legal availability of lysergic acid for facile conversion to LSD, made street supplies plentiful.  Before long, psychedelic use became ubiquitous, and was synonymous with a pervasive countercultural movement formed from growing sociopolitical discontent.  To quote Dr. Daniel M. Perrine, author of The Chemistry of Mind Altering Drugs:

LSD was intersecting with several powerful social forces in American culture: the leaden proprieties of the conformist ‘50s, Leary’s “parochial social insanities,” were being cast aside to the magical music of the Beatles; the presumptive authorities of church and state were being revealed as the corrupt proponents of an immoral war; and the ugly gangrene of American racism was being exposed by the civil rights movement.

Countercultural associations cast psychedelics in a negative light to the American government and the more traditional segments of American society, catalyzed by the fear of the unknown and the ontological burden of a malleable consciousness.  With such widespread public use, backlash was inevitable.  By late 1965, Sandoz had all but halted distribution of LSD and psilocybin, and researchers were required to return their existing supplies of these substances to the company.  Psychedelic scientists were forced to reapply to the FDA for Investigational New Drug (IND) permits, and very few were granted.  The Controlled Substances Act of 1970 categorized all psychedelics with a known recreational presence as Schedule 1, hampering further acquisition and testing.  The last grant for use of LSD on human subjects was terminated in 1974, ushering in a two-decade-long de facto moratorium on human psychedelic research.

Yeah, it was kinda like that

Drug Wars Episode IV: A New Hope

Fortunately, in 1994, the FDA cautiously changed its course with respect to permitting human psychedelic research, granting approval for a study on the effects N,N-dimethyltryptamine (DMT) in humans to be conducted by Dr. Rick Strassman at the University of New Mexico.  With that precedent, a glimmer of hope for human psychedelic research has returned.  Since then, a small but promising set of studies, largely recapitulating clinical potential elucidated in the 50s and 60s, have been carried out using human subjects.  The success of these studies promotes optimism about the future of psychedelic research, particularly alongside a liberalizing sociopolitical climate toward therapeutic applications for “drugs of abuse.”  Still, for a field with such a controversial and dynamic history, the future is anything but certain.  Administrative roadblocks and social stigma still plague the progress of psychedelic science, and a complete overhaul of American drug policy will likely be necessary for it to fully recover.  Psychedelics, if nothing else, exist as a tool for addressing fundamental questions underlying the nature of consciousness, and perhaps the answers must wait until the world is ready…


Landon Klein is a third-year Ph.D. student in the UCSD Neurosciences Graduate Program.  Working in the translational neuropsychopharmacology lab of Dr. Mark Geyer, Landon studies the neural mechanisms underlying the effects of psychedelics.  Landon hopes that such insight will improve our understanding of the pharmacological and molecular correlates of human consciousness, and enhance his own understanding of his often-illogical subjective reality.  When he’s not trip-sitting mice, Landon spends his days playing music, eating until he is uncomfortable, and contemplating the hypothetical victor of unlikely fights between historical figures.


*What’s in a name?

As you may have gathered by now, psychedelia, both in the scientific community and in society at large, is a highly controversial topic.  For a microcosm of this controversy, one need look no further than the intense discourse over what these compounds should even be called.  The term psychedelic, from the Greek roots for “mind manifesting,” was coined by Humphry Osmond, a Canadian psychiatrist who employed mescaline and LSD extensively in psychotherapy, in 1957.  Osmond’s coinage was a response to perceived insufficiencies in the existing nomenclature, namely hallucinogens and psychotomimetics.  Phenomenological studies have verified that these substances rarely produce true hallucinations (i.e. “perceptions in the absence of external stimulus [with the] qualities of real perception”; vis-à-vis hallucinogens), but are more prone to pseudohallucinations (i.e. hallucination-like perceptions that are recognized by the observer to be occurring in absence of external stimulus) or perceptual distortions, and possess limited potential for mimicking psychosis (vis-à-vis psychotomimetics).

While the usage of psychotomimetic has declined, significant debate remains as to the proper nomenclature, and the appropriateness of interchangeable use.  Despite its insufficiencies, hallucinogen is currently the most common designation in scientific literature, as psychedelic has been suggested to connote a positive valence, while the latter is more common in popular media.  Recently, the term entheogen (meaning “generating the god within”) has increased in popularity among non-scientific circles, due to the ability of these substances to promote mystical and religious experiences.  The jury is still out on the most accurate, connotation-free term for this class of substances.  I have elected here to use the term psychedelic; read into it what you will.


References

Dyck, E. (2006). “Hitting Highs at Rock Bottom”: LSD Treatment for Alcoholism, 1950-1970. Social History of Medicine, 19(2), 313–329. doi:10.1093/shm/hkl039

Gouzoulis-Mayfrank, E., Hermle, L., Thelen, B., & Sass, H. (1998). History, rationale and potential of human experimental hallucinogenic drug research in psychiatry. Pharmacopsychiatry, 31 Suppl 2, 63–8. doi:10.1055/s-2007-979348

Nichols, D. E. (2004). Hallucinogens. Pharmacology & Therapeutics, 101(2), 131–81. doi:10.1016/j.pharmthera.2003.11.002

Perrine, D. M. (1996). The Chemistry of Mind-altering Drugs: History, Pharmacology, and Cultural Context (p. 480). American Chemical Society. Retrieved from https://books.google.com/books?id=vFcQAQAAMAAJ&pgis=1

Project MKULTRA, The CIA’s Program Of Research In Behavioral Modification. (1977). Washington, DC. Retrieved from http://web.archive.org/web/20071128230208/http://www.arts.rpi.edu/~pellr/lansberry/mkultra.pdf

Sandison, R. A., Spencer, A. M., & Whitelaw, J. D. A. (1954). The Therapeutic Value of Lysergic Acid Diethylamide in Mental Illness. The British Journal of Psychiatry, 100(419), 491–507. doi:10.1192/bjp.100.419.491

Shulgin, A., & Shulgin, A. (1995). Pihkal: A Chemical Love Story (p. 978). Transform Press. Retrieved from https://books.google.com/books?id=O8AdHBGybpcC&pgis=1

Shulgin, A., & Shulgin, A. (1997). Tihkal: The Continuation (p. 804). Transform Press. Retrieved from https://books.google.com/books?id=jl_ik66IumUC&pgis=1

Tanne, J. H. (2004, March 20). Humphry Osmond. BMJ : British Medical Journal. BMJ Group. Retrieved from /pmc/articles/PMC381240/?report=abstract

The Medical History of Psychedelic Drugs. (2007). University of Cambridge. Retrieved from http://psychedelic.nfshost.com/history_of_psychedelics.pdf

Vollenweider, F. X., & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews. Neuroscience, 11(9), 642–51. doi:10.1038/nrn2884

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