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Psychedelics and Other Drug States

The adjective psychedelic in psychedelic drugs comes from the Greek words psyche ("mind") and delos ("clear, manifest, revealing").  The word was coined in 1956 by Humphry Osmond, a psychiatrist who was interested in hallucinogenic drugs as laboratory models of schizophrenia.  Osmond also co-authored Models of Madness, Models of Medicine (1966, with Miriam Siegler), whose sociological interpretation of the "medical model" of psychopathology I teach in my introductory courseLegal restrictions on the availability of psychedelic drugs to researchers, as well ethical and legal restrictions on researchers, have effectively prevented much research on these "consciousness altering" substances from being conducted.  Moreover, the environment in which such research has been conducted has been distorted by the "recreational" use of many of these substances, such as marijuana and LSD.  Because most of the available research on the mental (as opposed to physiological) effects of psychedelic drugs is impressionistic and anecdotal, they did not get much attention in this course.  But in the 2010s, with the trend toward legalization of marijuana and other psychedelic drugs for medical and recreational use picking up steam, it seemed that some actual research might get conducted, and so it seemed appropriate to fill out the story.


Classification of Psychoactive Drugs

William Farthing, whose Psychology of Consciousness (1992) offers as good a summary of research on psychedelics, up to its publication date (and there hasn't much after that, until lately), as can be found anywhere, offers a useful classification of psychoactive drugs.  There have been lots more added since 1992, which is a tribute, I guess, to the genius of the recreational drug industry -- especially with the increasing legalization of marijuana.  I don't intend to provide comprehensive coverage of al of these drugs.  This isn't a course on biochemistry or pharmacology.  If you're really interested in the full range of psychoactive drugs, and how they work in the nervous system, I highly recommend "Drugs and the Brain" (Molecular & Cell Biology 62, cross-listed as Psychology 119 and Letters & Science 30) taught by UCB's Dr. David Presti -- one of Berkeley's most popular and distinguished teachers.

The distinction between "major" and "minor" psychedelics was introduced by Charles Tart (1972), based the degree to which the subjective effects of the drug are under volitional control.  on the amount ofvolitional control which

If you want more detailed information, especially on the physiology and pharmacology of these drugs, see:

 

Pre-Scientific History

The modern history of consciousness-altering drugs properly begins with Humphrey Davy, the English chemist who, as discussed in the lectures on Anesthesia and Coma, experimented with nitrous oxide (NO2) in the late 18th century.  Davy did not pursue the anesthetic effects of nitrous, but he certainly appreciated its effects on consciousness:

"a thrilling all over me most exquisitely pleasurable....  The objects around me became dazzling, and my hearing more acute".

Davy's enthusiasm was infectious, as it were, and pretty soon the English "smart set" was holding regular nitrous oxide parties in which people -- for want of a better term -- got high.  Later, after Morton's introduction of ether as a surgical anesthetic, ether parties were added to the social calendar.  

NO2-LaughingGas_Caricature.jpg (1105311 bytes)The story of Davy's adventures with nitrous oxide are detailed by Richard Holmes in The Age of Wonder: How the Romantic Generation Discovered the Beauty and Terror of Science (2009), a history of the "second scientific revolution", of the late 18th and early 19th centuries.  another view of Davy and the second scientific revolution is provided by Mike Jay in The Atmosphere of Heaven: The Unnatural Experiments of Dr. Beddoes and His Sons of Genius (also 2009).

 

But consciousness-altering drugs have a more extended history than that.  In fact, they go back to the beginnings of Western civilization, with the Oracle at Delphi, and her sister soothsayers (at left, image from an cup, c. 440 BCE, showing King Aegeus of Athens and Themis, the first Pythia, the earliest surviving image of the Oracle of Delphi; at right, a modern representation by John Collier, 1850-1934, an English member of the "Pre-Raphaelite" art movement).  The Oracle held court in the adyton, or forbidden inner sanctum, of the Temple of Apollo (the Greek god of prophecy) at Delphi, giving advice to private and public figures.  It was she, according to myth, who prophesied that Oedipus would kill his father and marry his mother.  And it was she who told Croesis, King of Lydia, that if he went to war with Cyrus, King of the Persians, he would "destroy a great empire" -- which he promptly did (his own).  According to legend (including Plutarch's Moralia, c. 100 CE), the Oracle entered a trance by breathing the vapors arising in the adyton from a chasm in the earth, filtered through water from a sacred spring.  However, archaeological excavations at Delphi conducted around the turn of the century uncovered no such chasm, or any evidence of a natural gas that could produce an intoxicated state.  Later geological analysis confirmed that Delphi was not situated in the kind of volcanic area that could produce such gases.  In the 1980s, however, Jelle Zeilinga de Boer, a geologist at Wesleyan University, and his colleagues, participating in a new geological survey, discovered two fault lines that intersected on Mount Parnassus, beneath the Temple of Apollo -- right at the site of the adyton.  One of the faults was marked by a series of springs. Sampling the water, they discovered traces of ethylene, a gas with a sweet odor that is a known anesthetic agent.  In lighter doses, however, ethylene can induce a trance-like state of delirium characterized by euphoria, out-of-body feelings, and amnesia. 

For more detail on the Oracle at Delphi, see "Questioning the Delphic Oracle" by John R. Hale, de Boer, and others, Scientific American, 8/2003.

For a discussion of ancient divination in general, including dream analysis and animal sacrifice as well as oracular pronouncements, see Divination and Human Nature: A Cognitive History of Intuition in Classical Antiquity (2016) by Peter Struck.  Struck argues that ancient divination, in al its forms, more closely resembled what we would now call intuition, or maybe "gut instinct", as opposed to superstition and charlatanism.

A little later, according to Michael Pollan (in The Botany of Desire: A Plant's-Eye View of the World (2001), the Rig Veda, one of the earliest known religious texts (dating from c. 1700-1100 BCE), took soma, an intoxicant probably related to the mushroom Amanita muscaria, in order to obtain knowledge of the divine. 

Also according to Pollan, who read it in Herodotus, the Scithyans, nomads living north of the Black Sea in the 8th century BCE, built inhalers to trap the fumes of burning cannabis buds, after which they would "rise up to dance and betake themselves of singing". 

And finally, again according to Pollan, Socrates, and Plato, among other ancient Greek philosophers, all participated in the Mysteries of Eleusis, in which they consumed a potion made of ergot, which has a chemical structure resembling that of LSD.  Pollan speculates that Plato's "supernatural metaphysics", in which the ideal forms of things exist in a world existing beyond our senses, might have had its origins in ergot intoxication -- though this doesn't explain Aristotle's insistence that the only reality is the one we know directly, through our senses.  (Plato's the one pointing up, in this segment of Raphael's painting, The School of Athens; Aristotle is the one pointing down; Socrates is in the painting, too, though not in this portion of it.)

Fast-forward to the 19th century, hallucinogenic drugs were a staple of the Romantic movement.  And not just Humphrey Davies's nitrous-oxide parties, either.  Napoleon's army discovered hashish during the conquest of Egypt (which may explain why they shot the nose off the Sphinx), and brought it back to France.  Baudelaire wrote an entire book, Artificial Paradises (1860) retailing his own experiences with the drug. 

And, of course, the British got opium from India .  The English romantics, for their part, consumed their share of opium, and some literary critics have suggested that it played no small role in their movement.  Samuel Taylor Coleridge became addicted to opium (taken in the form of laudanum, an infusion of opium and brandy), and it's been suggested that he wrote his famous poem, "Kubla Kahn -- or, a Vision in a Dream: A Fragment", under its influence.  It's also been suggested that his idea of "willing suspension of disbelief) was opium-inspired.  Shelley and Byron also used opium, though not Wordsworth.

The prime user of opium among British Romantics was Thomas De Quincey, a onetime friend of Wordsworth, Coleridge, and other English Lake Poets, whose Confessions of an Opium-Eater (1869) documented his (and their) quaffing of laudanum, and argued that opium-induced brain changes spurred his (and their) creativityDon't try this at home!  De Quincey became addicted to both opium and alcohol, and died a broken man (for a recent biography of de Quincey, see Guilty Thing: A Life of Thomas De Quincey by Frances Wilson, 2016; also; also Thomas De Quincey and the Cognitive Unconscious by Markus Iseli, 2015) .  Here's an extract (sorry) in which De Quincey describes the effects of the drug (punctuation original):


Heavens!...  [W]hat an upheaving, from its lowest depths, of the inner spirit!... Here was a panacea... for all human woes: here was the secret of happiness, about which philosophers had disputed for so many ages, at once discovered: happiness might now be bought for a penny, and carried in the waistcoat pocket: portable ecstasies might be corked up in a pint bottle: and peace of mind could be sent down in gallons by the mail coach.

Fast forward again 100 years, and Aldous Huxley, the author of Brave New World and other novels, not to mention the visionary Perennial Philosophy, consumes 400 milligrams of mescalin dissolved in a glass of water and reports the results in The Doors of Perception:




From what I had read of the mescalin experience I was convinced in advance that the drug would admit me, at least for a few hours, into the kind of inner world described by Blake and AE. But what I had expected did not happen. I had expected to lie with my eyes shut, looking at visions of manycolored geometries, of animated architectures, rich with gems and fabulously lovely, of landscapes with heroic figures, of symbolic dramas trembling perpetually on the verge of the ultimate revelation. But I had not reckoned, it was evident, with the idiosyncrasies of my mental make-up, the facts of my temperament, training and habits....

The change which actually took place in that world was in no sense revolutionary. Half an hour after  swallowing the drug I became aware of a slow dance of golden lights. A little later there were sumptuous red surfaces swelling and expanding from bright nodes of energy that vibrated with a continuously changing, patterned life. At another time the closing of my eyes revealed a complex of gray structures, within which pale bluish spheres kept emerging into intense solidity and, having emerged, would slide noiselessly upwards, out of sight. But at no time were there faces or forms of men or animals. I saw no landscapes, no enormous spaces, no magical growth and metamorphosis of buildings, nothing remotely like a drama or a parable. The other world to which mescalin admitted me was not the world of visions; it existed out there, in what I could see with my eyes open. The great change was in the realm of objective fact. What had happened to my subjective universe was relatively unimportant.  I took my pill at eleven. An hour and a half later, I was sitting in my study, looking intently at a small glass vase. The vase contained only three flowers-a full-blown Belie of Portugal rose, shell pink with a hint at every petal's base of a hotter, flamier hue; a large magenta and cream-colored carnation; and, pale purple at the end of its broken stalk, the bold heraldic blossom of an iris. Fortuitous and provisional, the little nosegay broke all the rules of traditional good taste. At breakfast that morning I had been struck by the lively dissonance of its colors. But that was no longer the point. I was not looking now at an unusual flower arrangement. I was seeing what Adam had seen on the morning of his creation-the miracle, moment by moment, of naked existence.

"Is it agreeable?" somebody asked. (During this Part of the experiment, all conversations were recorded on a dictating machine, and it has been possible for me to refresh my memory of what was said.)

"Neither agreeable nor disagreeable," I answered. "it just is."

***

Reflecting on my experience, I find myself agreeing ...  with Broad "that the function of the brain and nervous system and sense organs is in the main eliminative and not productive. Each person is at each moment capable of remembering all that has ever happened to him and of perceiving everything that is happening everywhere in the universe. The function of the brain and nervous system is to protect us from being overwhelmed and confused by this mass of largely useless and irrelevant knowledge, by shutting out most of what we should otherwise perceive or remember at any moment, and leaving only that very small and special selection which is likely to be practically useful." According to such a theory, each one of us is potentially Mind at Large.... To make biological survival possible, Mind at Large has to be funneled through the reducing valve of the brain and nervous system. What comes out at the other end is a measly trickle of the kind of consciousness which will help us to stay alive on the surface of this Particular planet....  Most people, most of the time, know only what comes through the reducing valve and is consecrated as genuinely real by the local language. Certain persons, however, seem to be born with a kind of by-pass that circumvents the reducing valve. In others temporary by-passes may be acquired either spontaneously, or as the result of deliberate "spiritual exercises," or through hypnosis, or by means of drugs. Through these permanent or temporary by-passes there flows, not indeed the perception "of everything that is happening everywhere in the universe" (for the by-pass does not abolish the reducing valve, which still excludes the total content of Mind at Large), but something more than, and above all something different from, the carefully selected utilitarian material which our narrowed, individual minds regard as a complete, or at least sufficient, picture of reality.

The brain is provided with a number of enzyme systems which serve to co-ordinate its workings. Some of these enzymes regulate the supply of glucose to the brain cells. Mescalin inhibits the production of these enzymes and thus lowers the amount of glucose available to an organ that is in constant need of sugar. When mescalin reduces the brain's normal ration of sugar what happens? Too few cases have been observed, and therefore a comprehensive answer cannot yet be given. But what happens to the majority of the few who have taken mescalin under supervision can be summarized as follows.

  1. The ability to remember and to "think straight" is little if at all reduced. (Listening to the recordings of my conversation under the influence of the drug, I cannot discover that I was then any stupider than I am at ordinary times.)

  2. Visual impressions are greatly intensified and the eye recovers some of the perceptual innocence of childhood, when the sensum was not immediately and automatically subordinated to the concept.  Interest in space is diminished and interest in time falls almost to zero. 

  3. Though the intellect remains unimpaired and though perception is enormously improved, the will suffers a profound change for the worse. The mescalin taker sees no reason for doing anything in particular and finds most of the causes for which, at ordinary times, he was prepared to act and suffer, profoundly uninteresting. He can't be bothered with them, for the good reason that he has better things to think about.

  4. These better things may be experienced (as I experienced them) "out there," or "in here," or in both worlds, the inner and the outer, simultaneously or successively. That they are better seems to be self-evident to all mescalin takers who come to the drug with a sound liver and an untroubled mind.

These effects of mescalin are the sort of effects you could expect to follow the administration of a drug having the power to impair the efficiency of the cerebral reducing valve. When the brain runs out of sugar, the undernourished ego grows weak, can't be bothered to undertake the necessary chores, and loses all interest in those spatial and temporal relationships which mean so much to an organism bent on getting on in the world. As Mind at Large seeps past the no longer watertight valve, all kinds of biologically useless things start to happen. In some cases there may be extra-sensory perceptions. Other persons discover a world of visionary beauty. To others again is revealed the glory, the infinite value and meaningfulness of naked existence, of the given, unconceptualized event. In the final stage of egolessness there is an "obscure knowledge" that All is in all - that All is actually each. This is as near, I take it, as a finite mind can ever come to "perceiving everything that is happening everywhere in the universe."

And a little later to the era of modern jazz and Beat poetry, here's Allen Ginsberg writing in the Atlantic Monthly (August 1966), in favor of the decriminalization of marijuana:



How much there is to be revealed about marijuana in this decade in America for the general public! The actual experience of the smoked herb has been clouded by a fog of dirty language perpetrated by a crowd of fakers who have not had the experience and yet insist on downgrading it. The paradoxical key to this bizarre impasse of awareness is precisely that the marijuana consciousness is one that, ever so gently, shifts the center of attention from habitual shallow, purely verbal guidelines and repetitive secondhand ideological interpretations of experience to more direct, slower, absorbing, occasionally microscopically minute engagement with sensing phenomena.

A few people don't like the experience and report back to the language world that it's a drag. But the vast majority all over the world who have smoked the several breaths necessary to feel the effect, adjust to the strangely familiar sensation of Time slow-down, and explore this new space thru natural curiosity, report that it's a useful area of mind-consciousness to be familiar with. Marijuana is a metaphysical herb less habituating than tobacco, whose smoke is no more disruptive than Insight.

And here's Ginsberg again, from an interview in the Paris Review (1965):

I smoked a lot of marijuana and went to the basement of the Museum of Modern Art in New York and looked at his water colors and that's where I began really turning on to space in Cezanne and the way he built it up... . I suddenly got a strange shuddering impression looking at his canvases, partly the effect when someone pulls a Venetian blind, reverses the Venetian -- there's a sudden shift, a flashing that you see in Cezanne canvases. Partly it's when the canvas opens up into three dimensions and looks like wooden objects, like solid-space objects, in three dimensions rather than flat. Partly it's the enormous spaces that open up in Cezanne's landscapes. And it's partly that mysterious quality around his figures.... They look like great huge 3-D wooden dolls, sometimes. Very uncanny thing, like a very mysterious thing -- in other words, there's a strange sensation that one gets, looking at his canvases, which I began to associate with the extraordinary sensation -- cosmic sensation, in fact -- that I had experienced catalyzed by Blake's "Sun-flower” and "Sick Rose” and a few other poems.... he produced a solid two-dimensional surface which when you looked into it, maybe from a slight distance with your eyes either unfocused or your eyelids lowered slightly, you could see a great three-dimensional opening, mysterious, stereoscopic, like going into a stereopticon.... Particularly there's one of rocks, I guess "Rocks at Garonne,” and you look at them for a while, and after a while they seem like they're rocks, just the rock parts, you don't know where they are, whether they're on the ground or in the air or on top of a cliff, but then they seem to be floating in space like clouds, and then they seem to be also a bit like they're amorphous, like kneecaps or cockheads or faces without eyes. And it has a very mysterious impression. Well, that may have been the result of the pot. But it's a definite thing that I got from that.

And finally, here's Carl Sagan, the astronomer and science-popularizer, writing as "Mr. X" in Lester Grinspoon's anthology, Marijuana Reconsidered (1969):




It all began about ten years ago. I had reached a considerably more relaxed period in my life -- a time when I had come to feel that there was more to living than science, a time of awakening of my social consciousness and amiability, a time when I was open to new experiences. I had become friendly with a group of people who occasionally smoked cannabis, irregularly, but with evident pleasure. Initially I was unwilling to partake, but the apparent euphoria that cannabis produced and the fact that there was no physiological addiction to the plant eventually persuaded me to try. My initial experiences were entirely disappointing; there was no effect at all, and I began to entertain a variety of hypotheses about cannabis being a placebo which worked by expectation and hyperventilation rather than by chemistry. After about five or six unsuccessful attempts, however, it happened. I was lying on my back in a friend's living room idly examining the pattern of shadows on the ceiling cast by a potted plant (not cannabis!). I suddenly realized that I was examining an intricately detailed miniature Volkswagen, distinctly outlined by the shadows. I was very skeptical at this perception, and tried to find inconsistencies between Volkswagens and what I viewed on the ceiling. But it was all there, down to hubcaps, license plate, chrome, and even the small handle used for opening the trunk. When I closed my eyes, I was stunned to find that there was a movie going on the inside of my eyelids. Flash... a simple country scene with red farmhouse, a blue sky, white clouds, yellow path meandering over green hills to the horizon. . . Flash... same scene, orange house, brown sky, red clouds, yellow path, violet fields... Flash... Flash... Flash. The flashes came about once a heartbeat. Each flash brought the same simple scene into view, but each time with a different set of colors... exquisitely deep hues, and astonishingly harmonious in their juxtaposition. Since then I have smoked occasionally and enjoyed it thoroughly. It amplifies torpid sensibilities and produces what to me are even more interesting effects.....

I can remember another early visual experience with cannabis, in which I viewed a candle flame and discovered in the heart of the flame, standing with magnificent indifference, the black-hatted and -cloaked Spanish gentleman who appears on the label of the Sandeman sherry bottle. Looking at fires when high, by the way, especially through one of those prism kaleidoscopes which image their surroundings, is an extraordinarily moving and beautiful experience.

I want to explain that at no time did I think these things 'really' were out there. I knew there was no Volkswagen on the ceiling and there was no Sandeman salamander man in the flame. I don't feel any contradiction in these experiences. There's a part of me making, creating the perceptions which in everyday life would be bizarre; there's another part of me which is a kind of observer. About half of the pleasure comes from the observer-part appreciating the work of the creator-part. I smile, or sometimes even laugh out loud at the pictures on the insides of my eyelids. In this sense, I suppose cannabis is psychotomimetic, but I find none of the panic or terror that accompanies some psychoses. Possibly this is because I know it's my own trip, and that I can come down rapidly any time I want to.

Given these kinds of reports, you would think that when the consciousness revolution hit in the 1960s, and again later in the 1980s, that the effects of marijuana, LSD, and other psychedelic drugs would have been the subject of intense research activity.  But it was not to be.  In the first place, as with Humphrey Davy's experience with nitrous oxide, people -- including researchers, like Timothy Leary and Richard Alpert -- were more interested in taking these drugs than in studying their effects.  But second, and most important, government drug policy got in the way.  In the Controlled Substances Act of 1970, both marijuana and LSD, along with MDMA ("Ecstasy") and Psilocybin ("magic mushrooms") were put on "Schedule I", subject to the most stringent regulations by the Drug Enforcement Administration (DEA), as drugs with the highest potential for abuse and "no currently accepted medical use".  This effectively drove the drugs underground, and effectively precluded any basic or clinical research on their effects.  And so the situation remains today -- at least so far as federal policy is concerned.

Most recently, however, state-level movements toward legalization, first in Colorado and Washington State, legalized the use of marijuana for either medical or recreational use.  California already permits medical marijuana, and Proposition 64, legalizing recreational marijuana, was put on the ballot in 2016.  For the record, I haven't smoked marijuana, or done anything else with it, for more than 35 years, and even then, like Bill Clinton, I didn't inhale (no wonder it had little effect on me!).  I support legalization in principle -- recreational marijuana strikes me as no different from recreational alcohol -- but voted against Prop 64 because there are as yet no established standards for "driving under the influence" of the drug.

Which brings me to the subject of Maureen Dowd, an Op-Ed columnist for the New York Times, who sampled a little too much marijuana-laced candy which she bought at a Colorado dispensary after the state legalized the sale of the drug for recreational purposes (link to the article from the Times. 06/03/2014):

For an hour, I felt nothing. I figured I’d order dinner from room service and return to my more mundane drugs of choice, chardonnay and mediocre-movies-on-demand.

But then I felt a scary shudder go through my body and brain. I barely made it from the desk to the bed, where I lay curled up in a hallucinatory state for the next eight hours. I was thirsty but couldn’t move to get water. Or even turn off the lights. I was panting and paranoid, sure that when the room-service waiter knocked and I didn’t answer, he’d call the police and have me arrested for being unable to handle my candy.

I strained to remember where I was or even what I was wearing, touching my green corduroy jeans and staring at the exposed-brick wall. As my paranoia deepened, I became convinced that I had died and no one was telling me.

It took all night before it began to wear off, distressingly slowly. The next day, a medical consultant at an edibles plant where I was conducting an interview mentioned that candy bars like that are supposed to be cut into 16 pieces for novices; but that recommendation hadn’t been on the label.

The availability of private research funding, through such organizations as the Multidisciplinary Association for Psychedelic Studies, has allowed some research to go forward, but the federal restrictions still hamper the publication of this research and its translation into therapeutic uses.  Anyway, almost all of this research is directed toward clinical applications, such as the use of marijuana or LSD in the treatment of anxiety or PTSD, or the relief of pain in chronically or terminally ill patients -- not on the alterations in consciousness that are the principal topic of this course.


State-Dependent Memory

Moving into the modern era of drug research, we begin with a number of drug-induced states that have been subject to careful experimental research.  While not "psychedelic" in nature, these drugs do have effects on consciousness -- especially conscious memory.  Much of this literature has its origins in the study of state-dependent learning (SDL) or state-dependent memory (SDM), an experimental paradigm in which an animal or human subject learns while under the influence of a drug (or not), and then is tested for retention of that learning while under the influence of a drug (or not). When learning condition (drug vs. no drug) is crossed with test condition (drug vs. no drug), the typical finding is of a statistical interaction: retention is best when the condition of test is the same as the condition of learning:  drug-drug (D-D) or no-drug-no-drug (ND-ND)). Typically, there are also main effects, such that the drug impairs learning and retrieval. Typically, retention is best when both learning and test take place in the no-drug state.

The design for a basic SDL experiment takes the form of a 2x2 table:

Learning Trials

Test Trials

No Drug

Drug

No Drug

+++

-

Drug

-

++

Learning is best when both the acquisition and test trials take place in the non-drugged state.  This is because SDL is induced by psychoactive drugs and, as a rule, psychoactive drugs tend to impair performance at both the encoding and retrieval stages of learning and memory (the stimulant Ritalin is an exception, but only in subjects with attention-deficit hyperactivity disorder).  But otherwise, memory is actually best when the animal's physiological state at the time of test matches its state at the time of learning.  The advantage of congruent over incongruent trials is the essence of state-dependent learning.

 

Animal Studies

SDL was first noted by Girden and Culler (1937), in experiments on dogs who had been temporarily paralyzed by curare.  These experiments were originally intended to examine the role of behavioral response in classical conditioning -- paralyzed animals can't make behavioral responses, so if they are capable of learning, they must be learning something other than the association of an environmental stimulus with a behavioral response.  Of course, they're still able to make autonomic responses, such as heart-rate acceleration in response to a shock CS.  Girden and Culler found that classical conditioning could be obtained in curarized dogs, but that the conditioned responses were stronger when the animals were still under the influence of the drug, and diminished after the drugs wore off.  So, conditioned responses were, in some sense, conditional on the physiological state of the animal.  

The first controlled studies of SDL were by Overton (1964), who studied rats trained to escape shock in a T maze.  This research, done as Overton's doctoral dissertation, is now a classic of the animal-learning literature: the individual studies are masterpieces of experimental design.  In his research, Overton trained rats to escape shock in a T-maze.  During the acquisition phase, the animals were trained to turn left, or right, at the choice point in order to escape the shock (of course, the direction was counterbalanced across subjects).  Then, learning was tested in a maze where escape was possible in either direction.  Before training or testing, half the animals were given a (just barely) sub-anesthetic dose (amounting to 25 mg/kg) of sodium pentobarbital, a barbiturate sedative; training or testing took place after the animals had recovered somewhat from the initial dose, so that they were able to actually move through the maze!
Taken together, Overton's experiments provide evidence of state-dependent learning.  Conditioning did not generalize across the drug states, and the animals performed the CR only when in the same state in which that CR had been acquired. Overton concluded that SDL can produce a complete dissociation of learning.  He discovered that animals can make discriminations based on certain internal state cues, and concluded that SDL was not based on the usual sorts of sensory cue changes.  

Overton did his research in the heyday of Skinnerian functional behaviorism, and so we was loathe to talk about his animals' internal states.  Accordingly, he referred to his finding as a case of drug discrimination learning (DDL).  That is, he considered the drug to be a discriminative stimulus, essentially controlling the animal's response.  These days, we might say that the drug state signaled whether a left or right turn would be reinforced -- but even that is too mentalistic for some Skinnerians.  Still, he argued that the total SDL observed in his experiments was simply an extreme form of drug discrimination learning.

The really interesting question, though, concerns conscious accessibility.  Behind the notion of state-dependent learning is that the knowledge (e.g., about the maze and the contingencies of reinforcement) acquired during the drugged state is not consciously accessible during the non-drugged state, and vice-versa.  This stance is compatible with the view of this course, which is that consciousness and conscious accessibility are issues to be taken seriously.  But the whole question is anathema to a strict behaviorist, because mental states cannot enter into an explanation of behavior.  

Since 1964 SDL (also known as drug discrimination learning) has been documented in a wide variety of nonhuman animal species, using a wide variety of drugs.

Typically, SDL is studied in the milder form of drug discrimination learning.  The higher doses of barbiturate that produce very dramatic SDL are potentially lethal -- and even when they're not, it's not a pleasant thing, for an experimenter to watch an animal stumble through a maze (and think what it's like for the animal).  The lower doses employed in DDL have correspondingly less deleterious effects on the acquisition phase (remember, as a rule, psychoactive drugs impair both memory encoding and retrieval).  Still, the assumption is that SDL and DDK represent different points on a single continuum of drug effects on memory.  

Interestingly, SDL and DDL, viewed as "behavioral" preparations, have the usual pharmacological properties of the drugs that induce them:

 

Human Studies

Evidence of SDL is not restricted to dogs, rats, and other nonhuman animals.  Human studies of state-dependent memory (SDM), paralleling animal studies of SDL, commonly make use of typical verbal-learning paradigms.  In a typical experiment, a subject will study a word list in the D or ND state, and then attempt to remember that list in the same or opposite state.  The general finding is that retention, typically measured by free recall, is best when there is a match between the conditions of encoding and retrieval.  However, it should be noted that human studies typically do not yield the complete dissociations between D and ND states obtained in Overton's classic studies.  Most likely, this is because ethical considerations preclude the use with humans of the very high, barely sub-lethal doses of anesthetics that Overton used with his rats.  (And before you say anything, ethical considerations generally preclude the wanton use of such high doses with nonhuman animals as well -- which is why it's important that Overton's studies were so well controlled, so that they didn't have to be repeated unnecessarily to clean them up.

An early study by Swanson and Kinsbourne (1976) nicely illustrates the application of the SDM paradigm in humans.  The subjects were "hyperactive" children, diagnosed with what we would now call attention deficit hyperactivity disorder (ADHD), who were being treated with the amphetamine Ritalin, a CNS stimulant that, paradoxically, has a beneficial effect in such patients (and is, essentially, the only exception t the general rule that psychoactive drugs impair cognitive performance).  The children in the patient group were administered Ritalin either before breakfast or before lunch.  At the doses employed, the drug takes effect in about 30 minutes, and lasts about 4 hours, permitting the children to be in the D and ND over the course of a single day.  There was also a control group of children who had not been diagnosed with ADHD, but who, for the purposes of this experiment, were also run in the D and ND states.  During the acquisition phase, the children performed a zoo location" task, essentially paired-associate learning, in which they were to assign each of 48 animal pictures to one of 4 cities.  

On Day 1, the children learned 24 pairs in the D state, and 24 in ND.  Errors in initial learning were reduced for the ADHD children who had received Ritalin; but performance was worse for the non-ADHD controls.

On Day 2, they relearned the same list, 12 D and 12 ND items from Day 1 in the D state, the remainder in ND, achieving the traditional 2x2 design.  Errors in relearning were also reduced for the ADHD children, but increased for the normal controls.  Most important, for the ADHD children, there was a symmetrical SDM effect.  The ADHD children made more errors when the learning and relearning states were congruent.  And the biggest effect was obtained in children for whom initial learning was helped by the drug.  

A review by Eich (1980) documented SDM in humans with a wide variety of psychoactive drugs, especially anesthetic agents, amphetamine, alcohol, and marijuana.  Apparently, any drug that acts on the central nervous system has the capacity to produce SDM in humans.

Eich's review also revealed some interesting differences between the human and animal studies.

Perhaps most important, Eich also concluded that SDM was "cue-dependent", in that it was most likely to occur with free recall tests (in which retrieval cues provided to the subject are relatively vague and fragmentary), and not with cued recall or recognition tests (in which the retrieval cues are more powerful). In the typical experiment involving humans, apparently, external cues supplied by the experimenter are more powerful, and thus "outshine", the internal cues created by the drug-induced physiological state.

 

State-Dependency and Encoding Specificity

Drug-induced SDM illustrates the encoding specificity principle in memory (ESP; Tulving & Thomson, 1973): memory is best when the cues provided at retrieval match those provided at the time of encoding. It also illustrates the effects of context on memory.  The ESP is sometimes referred to as the principle of transfer-appropriate processing.

Encoding specificity, in turn, is a variant on the cue-dependency principle (Tulving, 1974).  Although some memories occur to us spontaneously, in general memory retrieval is prompted by cues of various sorts, which contain information about the target item to be remembered.  The principle of cue-dependency says simply that retrieval is best when these cues are highly informative.

But it turns out that retrieval is not merely a function of the sheer quantity of cue information: the quality of the cues is also critical.  In particular, retrieval is best when the cues processed at the time of retrieval match the cues that were processed at the time of encoding.  Or, put another way, retrieval is best when the conditions of retrieval match those which prevailed at the time of encoding.  Apparently, these conditions of learning and performance, of encoding and retrieval, extend to the subject's physiological state -- conditions that can be altered by psychoactive drugs.   While physiological state is one component of internal context, there are other contextual manipulations that have similar effects on memory.

 

Alcoholic Blackout

Mild to moderate doses of alcohol can lead to state-dependent memory, reflecting a change in consciousness between encoding and retrieval.  But larger doses of alcohol can produce a lapse in consciousness itself.

In alcoholic blackout, a person carries out normal activities while intoxicated, but has no memory of them after sobering up.  Blackout was authoritatively defined by Jellineck (1952), but it probably has been known to alcoholics since the beginning of alcoholism.  It has also been formally recognized by the medical profession -- as in Bonhoeffer's reference to alcoholic palimpsests: a palimpsest being writing material, such as a piece of paper, from which previous writing has been erased.  Goodwin et al. (1969) suggest that the term blackout is actually a corruption of blankout, an old printer's term for "pulling a blank", when a proof sheet comes out blank because of a failure to properly ink the galleys.

The occurrence of blackout marks the heightened sensitivity of the person to the effects of alcohol -- it occurs to non-alcoholics who have ingested very large amounts of alcohol, but it occurs to alcoholics even when they are only moderately intoxicated.

Ryback (1970) performed an in vivo study of blackouts with a group of inpatient alcoholics who, for research purposes, were housed in a special ward permitting controlled access to alcoholic beverages.  After 1 week of enforced abstinence, they were permitted to drink at will for 1 week.  Each morning, the patients were questioned about their memory for salient events of the previous day, and also about their experience of blackouts.  Blackouts tended to occur following sudden, dramatic changes in blood alcohol levels.

There appear to be two kinds of blackout.

Along these lines, Washburne (1958) has noted two broad theoretical approaches to alcoholic blackout.

Obviously, both theories could be right, but apply to blackouts at different stages of alcoholism.  Most experimental evidence supports the characterization of blackout as reflecting encoding failure, or a failure to consolidate memory traces.

045HiddenBottle.jpg (35893 bytes)Lisman (1974) conducted a formal test of the state-dependency hypothesis.  Employing en in vivo setup like Ryback's, he put four chronic alcoholics, each with a history of blackouts, through two cycles of 5 "dry" days followed by 7 "wet" days.  Every afternoon he conducted a series of memory tests, including recall of the previous day's events, recognition of cards from Holtzman's version of Rorschach's inkblot test, and paired-associate learning (a Chinese ideograph paired with a color swatch).  He also showed each patient a picture of a room in the ward indicating the location of a hidden bottle of alcohol.  The results yielded no evidence of state-dependency, even on the hidden-bottle task.  Generally, though, the experiment provided good evidence of the encoding-failure hypothesis.  The patients had very poor memory for the stimulus materials even after a 20-minute retention interval, and memory after 20 minutes was a good predictor of memory 24 hours later.

While clinical lore has suggested that blackout might be a form of SDM, experimental studies suggest that the relevant memories are not accessible when the person becomes intoxicated again later. Rather, blackout appears to reflect a permanent encoding deficit, not unlike the anterograde the amnesia associated with bilateral damage to the medial temporal lobe memory system. This encoding deficit appears to be caused by rapidly rising levels of blood alcohol.  All the evidence to date suggests that alcoholic blackout is an instance of anterograde amnesia.  By virtue of a failure to properly encode memories, traces of experience are simply unavailable for retrieval.  

However, it should be noted that almost all research on alcoholic blackout involves tests of explicit memory.  It is possible that, like the amnesic syndrome, blackout impairs explicit memory but spares implicit memory.  To date, however, there have been no studies testing for dissociations between explicit and implicit memory in alcoholic blackout.  (Hint, hint.....)

 

Conscious Sedation

A medically induced state resembling alcoholic blackout is conscious sedation, produced by various tranquilizing drugs:

As with general anesthesia, the mechanisms by which these drugs work is not well understood.  However, their effects on memory are well known.  All of these drugs can induce a dense anterograde amnesia covering the period during which the patient was sedated.  As with the amnesic syndrome and alcoholic blackout, however, the patient remains conscious -- which is why it's called conscious sedation.  

026Propofol.jpg
                (54218 bytes) This anterograde amnesia dissociates explicit and implicit memory, impairing recall and recognition, but spares priming.  This may be illustrated with a study by Cork et al. involving patients who underwent outpatient surgery under conscious sedation with propofol (trade name, Diprivan), a barbiturate-like synthetic compound that is "unrelated to any other drug or class of drugs".  Introduced in 1985, propofol is widely used for conscious sedation, and was the drug that, in overdose, killed Michael Jackson, the "King of Pop".  Following the same sorts of procedures used to study implicit memory in general anesthesia, Cork et al. employed a tape-recording consisting of paired associates of the form ocean-water.  The tape was played continuously throughout the surgery, from the first incision to the last stitch; another, matched set of paired-associates served as a control.  Memory was then tested in the recovery unit.
So, conscious sedation impairs recall and recognition, but spares priming effects.  As with general anesthesia, studies employing the process-dissociation procedure confirm that the spared priming is mediated by automatic rather than controlled processes.  priming effects.  Note, however, that, technically, the priming in this instance is properly classified as repetition priming: although the cue (ocean) and target (water) are semantically related, both were presented at the time of encoding, so that presentation of the cue at the time of test constitutes a partial repetition of the original stimulus.

In the case of general anesthesia, spared priming counts as evidence of implicit perception, not just implicit memory, because adequately anesthetized patients have no conscious perceptual awareness of surgical events at the time they occur.  In the case of conscious sedation, however, the patients are perceptually aware of the pairs as they were presented on the tape.  They just forgot them later.  Therefore, spared priming in conscious sedation counts as evidence of implicit perception.

In any event, it's now clear that both the major and the minor tranquilizers can impair consciousness.  Patients have no conscious recollection of events that occurred during sedation, even though they retained "on line" conscious perception of those same events.  But the memory impairment is not total: perceptual processing does leave some trace of the event in memory, and those implicit memories can still influence the patient's subsequent experience, thought, and action -- albeit outside awareness.

 

Narcosynthesis and "Truth Serum"

Interestingly, clinical lore holds that the same sedative drugs which produce amnesia in conscious sedation can also permit the recovery of memories which have been repressed or dissociated due to traumatic stress. Although this technique, known as narcosynthesis  was popular during and after World War II, and remains in use even today, there is surprisingly little evidence that it actually works -- and, given is amnesic capacities, no reason to suppose it does.  Mostly, though, the technique hasn't been subject to experimental study at all.

The use of barbiturates to recover traumatic memories was clearly influenced by Freud's psychodynamic theory -- though, in truth, it was Breuer and Freud's (1883-1885) pre-psychoanalytic hypothesis that "hysterics suffer from reminiscences" that really lies at the root of this practice.  As recounted in the lectures on "'Hysteria' and Hypnosis", Breuer and Freud proposed that traumatic memories were repressed, and blocked from conscious awareness, but that hysterical symptoms symbolically represented the traumatic experience.  Thus, they function as implicit memories of the repressed trauma.  For Freud, at least in this early incarnation, the goal of treatment was to achieve abreaction, or conscious recall of the traumatic event, along with its accompanying emotion; and then catharsis, or a "purification" of the mind, leading to the restoration of mental health.

Of course, Freud had no evidence for this other than his own case studies.  Nevertheless, this general therapeutic strategy of abreaction and catharsis was applied to the treatment of "war neurosis" (sometimes called "shell shock") during World War I.  The general idea was that the traumatic experience of war caused amnesia by virtue of "psychogenic" processes of repression and dissociation, and that the unconscious traumatic memory caused the patient's symptoms -- of "hysterical" paralysis or whatever.

The only problem is that psychoanalysis takes a long time.  In a military situation, it's necessary to achieve abreaction and catharsis quickly, so that the soldier can be returned to duty or discharged.  For this purpose, Hadfield (1920) introduced hypnoanalysis, in which Freudian psychoanalysis was carried out while the patient was hypnotized.  The general idea was that hypnosis was itself a form of regression, in which the patient had an "infantile" relationship with the hypnotist, and relied on a predominance of "primary process" thought.  This characterization of hypnosis was wrong, but psychiatrists didn't know (or appreciate) that fact at the time.  So, hypnoanalysis became quite popular, both in military medicine and in civilian clinics, for the treatment of hysterical patients who were, it was presumed, suffering from repressed "reminiscences" of past trauma.

But if psychoanalysis takes a long time, not every patient is hypnotizable, and so military and civilian psychiatrists sought a more reliable technique for speeding up psychoanalytic treatment.  The answer was soon found in a new class of psychoactive drugs: the barbiturates, which had been first synthesized by a German researcher, Adolf von Bayer, in 1864 (he went on to found the pharmaceutical company that produces Bayer aspirin).  Barbiturates, of course, depress cortical activity, and induce a sleep-like state of drowsiness -- which is pretty much what physicians thought hypnosis was at the time.  Interestingly, the first psychological studies of the barbiturates by Lindemann (1932), found that they increased self-disclosure on the part of the subjects, who were apparently unable to resist answering even very personal questions.  This observation is the origin of the label "truth serum" given to this class of drugs.

So it was only a short leap to the hypothesis that injecting a patient with barbiturates would enhance the psychoanalytic processes of abreaction and catharsis.  And indeed, in short order Horseley (1936) developed "narco-hypnosis", and then "narco-analysis" for the purpose of facilitating the recovery of repressed traumas and forgotten childhood events.  

Grinker and Spiegel (1943, 1945), still operating under the influence of Freudian psychodynamic theory, promoted the widespread use of barbiturates for the treatment of war neurosis (sometimes called "battle fatigue") in World War II.  Patients would be given low dose via intravenous administration, and then receive suggestions that they relive whatever trauma they had experienced.  They also introduced the term "narco-synthesis".  In their psychoanalytically influenced view, it was not enough for the patient to relive his traumatic experience under the influence of the drug.  It was also important that he transfer this memory to the non-drugged state, and integrate the experience, now accessible to conscious recollection, into his personality structure.   

Grinker and Spiegel's use of narco-synthesis in the treatment of war neurosis is documented in "Let There Be Light", a propaganda film produced by John Ford, the famous Hollywood director.  The film, once embargoed out of a fear that the public would turn against the war if they saw its psychological consequences for soldiers, has now been released on home video.  

Grinker and Spiegel's apparent success in the treatment of war neurosis led to the widespread use of barbiturates in civilian psychiatry, as well.  But it is important to understand that their "success" was only apparent.  Rarely did they make any attempt to verify the memories recovered under the influence of the drug.  Rather, they simply assumed that the recollections were valid.  After all, they were vivid, detailed, and emotionally powerful; the memories made sense in the context of the patient's war experiences; and their drug-facilitated recovery led to symptom relief.  

In fact, there has never been any controlled experimental or clinical study of "truth serum", with independent corroboration of the memories recovered thereby.   There isn't even any study so simple as one that asks subjects to study a list of words, and after a delay long enough to induce forgetting, tests recall with and without administration of the drug.  There's no question, as Lindemann originally observed, that sedated patients become more talkative - -that is, before they fall asleep.  But this doesn't mean that their memories have improved.

A similar point can be made about the use of hypnotic suggestions for hypermnesia to recover repressed or dissociated - -or just plain forgotten -- memories.  For details, see the lectures on "'Hysteria' and Hypnosis".

Nevertheless, the idea that "truth serum" (and, for that matter, hypnosis) works is very widespread.  It is part of the clinical folklore shared by many psychotherapists and patients alike.  And both techniques have been revived in contemporary practice, for the treatment of patients with post-traumatic stress disorder (PTSD).  For example, barbiturates were used in the famous "Ramona" case in California, where a young woman recovered apparently false memories of childhood sexual abuse at the hands of her father -- leading to a huge and ugly lawsuit that shed light on the dangers of this practice.  The practice of using drugs or hypnosis to recover ostensibly repressed or dissociated traumatic memories lacks any evidentiary basis.  No scientific study backs the claims of practitioners who use these techniques.  

In the absence of independent corroboration, no particular credence should be given to any memory recovered through the use of "truth serum", hypnotic hypermnesia, or any similar techniques.


Hallucinations

One of the major features of psychedelic states are hallucinations --false sensory/perceptual experiences that occur in the absence of an adequate stimulus.  Hallucinations are similar to mental images, except that images are usually experienced as voluntarily generated.  Hallucinations, by contrast, appear to occur involuntarily, much like sensations and perceptions derived from external stimuli.  Hallucinations, of course, are characteristic features of "psychotic" forms of mental illness, such as schizophrenia.  Therefore, it is commonly assumed that psychedelic states might serve as laboratory models for understanding psychosis.

Perhaps the single most important clinical study of hallucinations, at least in the modern era, is Hallucinations by -- who else? --Oliver Sacks (2013; reviewed by Michael Greenberg in "The Hallucinators Among Us", New York Review of Books, 04/04/2013). Sacks himself suffers from migraine headaches (the subject of his first book, Migraine, originally published in 1970), whose auras include hallucinations; and, as he confesses in his book, he also experimented (a little) with psychedelic drugs as a medical student. So his study has the benefit of a first-person perspective on the subject. In his book, Sacks focuses on hallucinations that occur in the context of palpable brain insult, injury, or disease -- including, but not limited to, the temporary brain injury caused by the ingestion of psychedelic drugs. But he does not discuss the hallucinations associated with functional psychosis, such as schizophrenia or affective disorder. Sacks notes that psychotic hallucinations are dynamic, in that they address the patient (schizophrenic hallucinations are typically auditory, while the hallucinations associated with brain damage are typically visual), and the patient converses with the voices. In some way, psychotic hallucinations are related to the patient's personality and social circumstances; "organic" hallucinations are more impersonal and unemotional.

The "organic" hallucinations, including those produced by psychedelic drugs, are in some sense autonomous products of alternations in brain chemistry or activity. They also appear to be universal, in that their content seems not to vary by time, place, or person. Sacks and other neuroscientists sometimes call them proto-images, because they seem to consist of the building-blocks of more complex, personally significant images (think, perhaps, of Biederman's geons). As Sacks writes, "Such activity operates at a basic cellular level, are beneath the level of personal experience, The hallucinatory forms are, in this way, physiological universals of human experience".

Sacks asserts that more complex hallucinations emerge from higher levels of the visual system, including the temporal and parietal lobes, and are in some sense more specific and less universal -- tied to the patient's individual knowledge and memory. Possibly, these are the kinds of hallucinations noted by Wilder Penfield when he electrically stimulated various portions of the cortex prior to neurosurgery..

According to Sacks, synesthesia and phantom limbs also qualify as hallucinations.


Placebo Effects in Antidepressant Medications

Here there will be a summary of the controversy surrounding Irving Kirsch's work, and his claim that placebo effects overwhelmingly account for the effects of antidepressant drugs (Kirsch, 1998, 2002). 

Whenever the effects of drugs on anything, including consciousness, are discussed, it's important to also discuss placebo effects.  Every treatment -- not just drugs, but also psychotherapy and even surgery has a placebo component to it, meaning that psychosocial factors, including "set and setting" -- the context in which the treatment is delivered and the subject's expectancies concerning the procedure, will affect the outcome of the treatment. 

I've already discussed placebo effects on "The Mysterious Leap from the Mind to the Body".  In the standard definition (Shapiro & Shapiro, 1997),

In clinical trials, placebos are typically used as controls to reveal whether new pharmacological agents actually have any specific effects on medical outcomes.  In order to be approved by the US Food and Drug Administration, new drugs must be shown to be safe and effective -- the latter usually by comparison of the active drug to an inert placebo (the new treatment can also be compared to the current "standard of care".  For more information, see "Understanding Clinical Trials" by Justin A. Zivin, Scientific American, 04/2000).

In the earlier lectures, I discounted placebo effects on purely subjective states as irrelevant to my analysis of the four problems of mind and body.  There, I was interested in the effects of beliefs, expectations, and the like on "bodily" states, such as heart rate and blood pressure. (I had to discuss placebos for pain because that's where most of the placebo literature is; to illustrate the issues involved).  But because the psychedelic states are induced by drugs, and all drugs are assumed to have placebo components to them, placebo effects on subjective mental states become relevant.  Unfortunately, there are relatively few studies comparing psychedelic drugs to placebos, and placebo controls in psychedelic drug research are problematic anyway, for reasons I'll discuss later. 

For the purposes of illustrating some of the issues, let's consider depression to be an altered state of consciousness -- which it is, once you think about it, even if we hardly ever think about that way.

In a provocative series of studies, Irving Kirsch and his associates (Kirsch & Sapirstein, 1998; Kirsch et al., 2002) have claimed that placebo effects accounted for as much as 75% of the effects of antidepressant drugs.

In a provocative article entitled "Listening to Prozac But Hearing Placebo", Kirsch & Sapirstein (Prevention & Treatment,1998) conducted a meta-analysis of 19 published studies in which an antidepressant medication (such as Prozac) was compared to placebo. 

On the basis of these results, K&S concluded that the active ingredients in antidepressant medications accounted for about 25% of the outcome in the drug treatment of depression; spontaneous remission (natural history) accounted for another 24%, and placebo accounted for approximately 51%.

As you might imagine, this claim drove psychiatrists, who generally favor drugs over psychotherapy, and even some psychologists (who sometimes envy psychiatrists' ability to prescribe drugs; ), quite crazy.  Kirsch's title was, in fact, a deliberate play on Listening to Prozac (1993), a pean to the drug by psychiatrist Peter D. Kramer.

In response, Kirsch (Prevention & Treatment, 1998a, 199b) compared the K&S meta-analysis to two others, published at about the same time, which used somewhat different methods. 

Kirsch concluded that "Inert placebos produce a powerful effect on depression", and "Antidepresant drugs enhance that effect to a relatively modest degree".

Still, there was the possibility that the published studies were somehow unrepresentative of all the studies conducted comparing antidepressants and placebo.  Frankly, that possibility always seemed unlikely, because you'd think that, with the file-drawer problem and all, the published studies would be the best ones available.  But, in fact, there were lots of unpublished studies lying around.  This is because the Food and Drug Administration, as part of its protocol for approving new drugs, requires only two independent trials showing that the investigational new drug is significantly better than placebo.  In principle, drug companies could run dozens or hundreds of trials, and pick the two best to submit for FDA approval.  But even those trials have to be registered with the FDA in advance.  Accordingly, Kirsch et al. (Prevention & Treatment, 2002) made a Freedom of Information Act to the FDA and obtained the results of 47 randomized placebo-controlled trials for 6 different antidepressants (38 of these trials had data suitable for their analysis).  Overall, patients in the drug group improved by 10.01 points on the Hamilton Rating Scale for Depression (HAM_D), a commonly used endpoint in treatment studies; the comparable figure for the patients receiving placebo was 7.82; put another way, on average, 79% of the drug response was duplicated by placebo (unweighted means from Table 2).  That's a significant difference, which is why the drugs in question received FDA approval, For the drug group.  But Kirsch et al., applying the FDA's own standards for evaluating new drugs, concluded that "18% of the drug response is due to the pharmacological effects of the medication".

This study, entitled "The Emperor's New Drugs", also drove the promoters of antidepressant medication crazy, all the more so because Kirsch followed up with a book, The Emperor's New Drugs: Exploding the Antidepressant Myth (2011).  In response, Kramer recently published a new book, Ordinarily Well: The Case for Antidepressants (2016), which conceded that antidepressant medication works best for the most severely depressed patients, but argued that a combination of medication and psychotherapy is good for everyone.

The point of all this is not to diminish the value of antidepressants.   Kirsch's data is convincing, but Kramer's response is probably correct: when people are depressed, the combination of drugs and psychotherapy can be very helpful.  The point is that even powerful psychoactive drugs have substantial placebo components, and this is likely to be true for the major and minor psychedelics as well.  As Kirsch et al. (2002) point out, "Placebo alcohol produces effects that are not observed when alcohol is administered surreptitiously...". 

The "Gold Standard" for Drug Trials

In principle, assessing the effects of psychedelic drugs on consciousness is no different from assessing drug effects anywhere else in science or medicine.  There are standards, and these are embodied in the procedure for a randomized, double-blind, placebo-controlled drug trial.  Unpack this phrase, and you've got the whole methodology.

  1. You've got to have random assignment of subjects to conditions.  In this case, one group receives the active drug -- marijuana, LSD, or whatever -- and the other group receives a placebo.
  2. Neither the subject receiving the drug (or placebo), nor the experimenter administering it, can know who is getting what.
  3. The placebo is, theoretically, an inert substance -- that is, it does not contain the active ingredient hypothesized to be responsible for the drug's effects.  This is often referred to as a "sugar pill" (unless, of course, the "drug" is itself sugar!).
  4. However, the placebo should not be entirely inert.  It should be an active placebo, which has some kind of effect that will disguise the fact that it's a placebo.  In the case of psychedelic drug research, for example, the placebo has to have some physiological effects, so that subjects -- and, for that matter, experimenters -- don't quickly realize that they've been assigned to the control group.
  5. In fact, the best placebo design is the balanced placebo design frequently used in alcohol research (e.g., Rohsenow & Marlatt, 1981).  In the balanced placebo design, there are actually four groups:
    1. Subjects who receive the active agent and are told they are getting it.  This is the standard experimental group.
    2. Subjects who are told they are getting the active drug but get placebo instead.  This is the standard placebo-control group.
    3. Subjects who receive the placebo and are told they are getting the placebo.  Amazingly, some subjects who are told they're getting the placebo show the effects of the active drug!  Perhaps they don't believe it.  Perhaps that just shows the power of "the mind over the body".
    4. Subjects who receive the active agent but are told they are getting the placebo.  This is the real innovation in the balanced-placebo design.


Actual Treatment


Expected Treatment

Drug

Placebo

Drug

Vodka and Tonic

Vodka and Tonic

Placebo

Tonic Only

Tonic Only

A major problem common among studies using the balanced placebo design is that investigators often collapse across conditions.  For example, they analyze pre-post changes in performance for subjects who were told they were receiving THC, even though half of them actually received placebo.  And they analyze pre-post changes in performance for subjects who received THC, even though half of them were told they would receive placebo.  While this design allows investigators to analyze the main effects of drug and expectancy, what we really want to see are the interactions.  For example, what changes occurred in subjects who received the drug, but were told they were receiving the placebo; and in the subjects who were told they were receiving placebo, but who actually received the drug.  This way, we can learn how positive and negative expectancies may moderate the effects of the drug. 

And speaking of "telling", another feature of many alcohol studies is surreptitious delivery, so that subjects get alcohol but aren't told that's what they're drinking.  Supposedly, this removes the "placebo" component of alcohol intoxication entirely.  But it's going to be difficult getting approval from a "human subjects" committee.


Minor Psychedelics

The term "minor psychedelics" refers mostly to marijuana and its derivatives, such as hashish, whose active ingredient is  delta-9-tetrahydro-cannabinoid (THC), found in the hemp plant cannabis sativa).  Marijuana and hashish were introduced to Europe from Asia, Africa, and the Middle East, where it had both medicinal and recreational uses.  Marijuana, came to the US via Mexican guest workers, and it 1937 it was outlawed in the Marijuana Tax Act, and again in the Controlled Substances Act of 1970 (which also outlawed the major psychedelics, sucu as LSD and psilocybin).

In addition to "natural" marijuana, there is also a synthetic marijuana, often blended with various herbs and sold as K2.  Although it is typically marketed as incense, apparently everyone who wants to know already knows that it's smokeable -- although nobody knows precisely what hazards may be associated with its use.  Parents are largely ignorant of it, and it doesn't show up in conventional urine tests.  The active ingredients in K2 are synthetic cannabinoids, first developed for research use by John W. Huffman, a chemist at Clemson University, that mimic some of the psychedelic effects of tetrahydrocannabinol (THC).  Despite its apparent availability at head shops everywhere, Huffman never intended these synthetic cannabinoids for non-research use, and as of 2010 their effects -- psychedelic and toxic -- have not been studied formally.  Nevertheless, K2 users show up in emergency rooms with some frequency, complaining of negative effects such as elevated physiological arousal and attacks of paranoia.  For this reason -- and also, let's face it, because it's synthetic marijuana, some states have banned K2 and similar drugs, although as of 2010 it isn't (yet) listed on the DEA's schedule of controlled substances.  


Marijuana

For all the use it gets, and for all the attention paid to it in the legal and policy domains, there has been surprisingly little research on the psychological effects of marijuana.  In his comprehensive survey, LSD, Marijuana, Yoga, and Hypnosis, Barber (1970) covered only three studies.

In the 1930s, New York's Mayor Fiorello LaGuardia commissioned a study of the drug, including a survey of its use and an experiment to document its effects (Mayor's committee, 1944).  The report was published in 1944.  The experiments were conducted with inmates of the city's jails, most of whom were already experienced users of marijuana.famous Riker's Island Prison.  Unusually for the time, the experiment used a placebo control, but the study was not conducted double-blind, and the placebo was pretty transparent.  In addition to documenting the subjective effects of smoking marijuana, the research found that even a relatively high dose of had little effect on simple mental functions, like simple reaction time.  However, even a moderate dose had effects on complex functions, like complex reaction time.  Whatever the effects, they were most obvious in subjects who had no previous experience with marijuana.

More than 20 years later, a study by Clark & Nakashima (1968) confirmed many of these findings with oral ingestion of marijuana.

Weil and his colleagues (Weil, Zinberg, & Nelsen, 1968; Weil & Zinberg, 1969) employed a true double-blind procedure.  Chronic and inexperienced college students smoked 2 cigarettes containing a low or high dose of THC (the chronic users were tested only with the high dose, because they experienced no subjective changes with the low dose).  Again, there were dose-related decrements in performance on some psychomotor tasks, especially those of some complexity such as digit-symbol substitution and pursuit-rotor learning; but most of these effects were confined to the inexperienced subjects.


The chief problem with the Weil study, however,  is that the double-blind placebo control failed.  Only 15 minutes after smoking the joints, the subjects were clearly able to recognize whether they had been given the placebo or the drug. 




This is a problem that will crop up later in studies of the major psychedelics, such as LS and psilocybin, and it may be insurmountable.  The whole point of a double-blind placebo control is that neither the researchers nor the subjects can tell who has received the placebo.  That works fine on the researchers' side: an independent pharmacist can pack capsules the drug or placebo, so that the researchers do not know which is which.  And most drugs that have been subjected to double-blind placebo trials do not have immediate psychoactive effects (cancer drugs, for example, don't have any psychoactive effects; and antidepressants take a while to take effect); but psychedelic drugs have their effects on consciousness almost immediately.  So subjects don't stay blind very long!  In the case of psychedelics, as will be seen, researchers try to administer an "active" placebo, which mimics at least some of the psychological effects of the drug -- like nicotinic acid, which -- because it is the active ingredient of nicotine -- acts as a CNS stimulant.  But even so, once subjects start hallucinating (because they've taken LSD) or fail to start hallucinating (because they've taken placebo), it's pretty easy to tell who's in which group. 

A study by Crancer et al. (1969; see also Crancer, 1969; Kalant, 1969) compared the effects of marijuana (1.7 grams) and alcohol (a 0.1 blood alcohol level) on performance on a driving simulator over a period of 4-1/2 hours.  The subjects had prior experience with both marijuana and alcohol.  Alcohol impaired driving performance, compared to a no-treatment control group, but marijuana did not.  



This is not to say that it's OK to drive after smoking marijuana.  It probably isn't -- not least because, following legalization, the California Highway Patrol and other police agencies have announced that they will test suspicious drivers for THC, just as they now test subjects for blood-alcohol levels.  Whether you're actually impaired or not, if you have high levels of THC or alcohol in your body, you're going to be in trouble.

As of 2016, only one study of marijuana, by Matrik et al. (2012), has used the balanced placebo design with college students who already had some experience with marijuana.  Recall that in this design, some subjects are told they are getting the placebo, when they really are getting the active drugThis condition ostensibly "balances" the usual placebo condition, in which subjects are led to expect they are getting the drug, but are getting only an inert substance.  This is also one of the few studies to assess alterations in consciousness induced by marijuana, as opposed to changes in performance on various psychomotor tasks - -though they did that as well.  The subjects were college students, all regular marijuana users, who received a 2.8% dose of THC or placebo.  Subjective "intoxication" was measured by the Addiction Research Center Inventory (ARCI), an instrument designed to assess the subjective effects of all sorts of psychoactive drugs.  The ARCI contains a large number of items charting effects on sensation and perception, bodily symptoms and processes, and feelings and attitudes.  Unfortunately, this study, like most using the balanced-placebo design, does not analyze these two conditions separately, but you can still get the idea: subjects who smoked marijuana, even those who were told they were getting placebo, showed strong effects of intoxication; those who received placebo, even those who were told they were getting marijuana, felt little subjective change.  The double-blind deception involved was fairly successful, but 6% of the subjects in the Told THC/Received Placebo condition suspected that they were not smoking real marijuana, and 21% of the subjects in the Told Placebo/Received THC condition suspected that they were smoking the real thing. 

 The Metrik et al. (2012) experiment was intended to study the effects of marijuana intoxication on various aspects of impulsivity, employing a variety of experimental tasks, but yielding mixed and confusing results.



On the Stroop Interference Task, for example, subjects who smoked marijuana sowed a small increase in response latency, while those who were told they were getting the drug showed a larger reduction in response latency.



On a "Stop-Signal" reaction time task, where subjects had to inhibit a dominant response, subjects who smoked marijuana showed a small increase in response latency, while those who received the placebo again showed a slight reduction.




Perhaps the best systematic description of the alterations in consciousness induced by marijuana was provided by Tart in On Being Stoned: the Subjective Effects of Marijuana Intoxication (1971), based on his survey of California college students who were experienced users of the drug.  These changes include:

It's important to point out, though, that these changes are not necessarily experienced by first-time users of the drug.  There is a kind of "culture" to marijuana use, in which novices are taught by mor experienced users what to expect, and what to notice, about their experience (Carlin et al., 1974).

Michael Pollan, in The Botany of Desire (2001), has proposed that there is an important link between the alterations of consciousness experienced under marijuana and the drug's effects on "short-term" memory -- by which they really mean long-term memory.  Remember, in psychology, short-term memory refers to memory that covers about 30 seconds of undistracted time after an event; long-term memory refers to whatever people remember of an event after about 30 seconds of distraction.  Patient H.M. was often characterized as having a "short-term memory disorder", but n fact his short-term memory was reasonably intact.  What H.M. lacked was the capacity to convert short-term memories into long-term memories.  He described his own memory as like awakening from a dream" -- with memory quickly slipping away from him over even a very short retention interval. 

Here is Pollan, inspired by Aldous Huxley's description of his experiences with mescaline in The Doors of Perception writing about marijuana (2001, pp. 159-162, 168-169, 170):




The scientists I spoke to were unanimous in citing short-term memory loss as one of the key neurological effects of the cannabinoids [based mostly on laboratory studies with nonhuman animals].  In their own way, so were the "poets" who tried to describe the experience of cannabis intoxication.  All talk about the difficulty of reconstructing what happened mere seconds ago and what a Herculean challenge it becomes to follow the thread of a conversation (or a passage of prose) when one's short-term memory isn't operating normally.

At any given moment my senses present to my consciousness -- the perceiving "I" -- a blizzard of data no human mind can completely absorb. 

The cannabinoid network [of neurons in the brain] appears to [vigilantly shift] the vast chaff of sense impression from the kernels of perception we need to remember if we're to get through the day and get done what needs to be done.

The THC in marijuana and the brain's endogenous cannabinoids work in much the same way, but THC is far stronger and more persistent than anandamide [an endogenous THC-like chemical, much like endorphin], which, like most neurotransmitters, is designed to break down very soon after its release....

What this suggests is that smoking marijuana may overstimulate the brain's built-in forgetting faculty, exaggerating its normal operations.

This is no small thing.  Indeed, I would venture that, more than any other singe quality, it is the relentless moment-by-moment forgetting, this draining of the pool of sense-impression almost as quickly as it fills, that gives the experience of consciousness under marijuana its peculiar texture.  It helps account for the sharpening of sensory perceptions, for the aura of profundity in which cannabis bathes the most ordinary insights, and, perhaps most important of all, for the sense that time has slowed or even stopped.  For it is only by forgetting that we ever really drop the thread of time and approach the experience of living in the present moment, so elusive in ordinary hours.  And the wonder of that experience, perhaps more than any other, seems to be at the very heart of the human desire to change consciousness, whether by means of drugs or any other technique....

Memory is the enemy of wonder, which abides nowhere else but in the present.  This is why, unless you are a child, wonder depends on forgetting....

Ordinarily we think of drug experiences as additive -- it's often said that drugs "distort" normal perceptions and augment the data of the senses (adding hallucinations, say), but it may be that the very opposite is true -- that they work by subtracting some of the filters that consciousness normally interposes between us and the world.

This, at least, was Aldous Huxley's conclusion in The Doors of Perception....  In Huxley's view, [mescaline] disables what he called "the reducing valve" of consciousness, his name for the conscious mind's everyday editing faculty.  The reducing valve keeps us from being crushed under the "pressure of reality", but it accomplishes this at a price, for the mechanism prevents us from ever seeing reality as it really is.  The insight of mystics and artists flows from their special ability to switch off the mind's reducing valve.  I'm not sure that any of us ever perceives reality "as it really is" (how would one know?), but Huxley is persuasive in depicting wonder as it happens when we succeed in suspending our customary verbal and conceptual ways of seeing....

So what happens under the influence of drugs or, for that matter, inspiration?  In Huxley's metaphor, the reducing valve is opened wide to admit more of experience.  This seems about right, though I'd qualify it by suggesting (as Huxley's own examples do) that the effect of altered consciousness is to admit a whole lot more information about a much smaller increment of experience....

The usual process by which the grains of perception pass us by slows way down, to the point where the conscious I can behold each grain in its turn, scrupulously examining it from every conceivable angle (sometimes from more angles that it even has), until all there is is the still still point at the hourglass's waist, where time itself appears to pause....

Earlier, in the lecture on "Meditation" I suggested that there might be something artificial about the attempt to achieve nirvana though artificial means like EEG alpha-wave biofeedback.  Pollan has an answer to this, echoing Huxley (2001, pp. 170-171):




Aldous Huxley did his best to argue us out of the view that a chemically conditioned spiritual experience is false -- and he did so long before we knew anything about cannabinoid or opioid receptor networks.  "In one way or another, all our experiences are chemically conditioned, and if we imagine that some of them are purely 'spiritual', purely 'intellectual', purely 'aesthetic', it is merely because we have never troubled to investigate the internal chemical environment at the moment of their occurrence."  He points out that mystics have always worked systematically to modify their brain chemistry, whether through fasting, self-flagellation, sleeplessness, hypnotic movement, or chanting....  What all this suggests is that the workings of consciousness are both more and less materialistic than we usually think: chemical reactions can induce thoughts, but thoughts can also induce chemical reactions.

The sad fact is that most of the research on marijuana and memory has been don on nonhuman animals.  If I were going to do research on marijuana and consciousness, I'd start where Huxley and Pollan started - -with memory, examining the effects of the drug on both "short-term" and "long-term" memory, to determine whether, indeed, marijuana affects STM, and especially the transfer from STM to LTM, and how any such changes relate to the subjective effects of THC intoxication. 

"High Time" -- Editorial Series in the New York Times

In July and August 2014, the New York Times took a strong editorial position favoring the legalization, or at least the decriminalization, of marijuana.  A series of editorials examined the issue from all sides.  the series constitutes the best summary of the current situation -- legal, medical, and social -- that I know. 

Links to the editorials, and the discussion that ensued, are provided in the list below.

Introduction: Our Position

1. States' Rights

2. Criminal Justice

3. History

4. Health

5. Track Records

6. Regulation

Of greatest relevance to this course is Philip Boffey's summary of the medical and scientific evidence about marijuana (#4 in the list above), which I summarize here:

  • The bottom line: Marijuana can have serious negative effects on health, especially when current strains are ingested as food.
    • But these are relatively mild compared to other banned drugs, such as prescription painkillers.
    • And marijuana is less harmful than alcohol or tobacco, which are both legal and addictive.
    • "Casual use by adults poses little or no risk for healthy people."
  • Marijuana is not typically addictive in the technical sense of producing tolerance and withdrawal.
    • Marijuana has "less than a third of the addictive potential of cigarettes".
      • A 1999 Institute of Medicine report found that 32% of tobacco users become "dependent", compared to 9% of marijuana users.
    • Though there is some evidence of tolerance and withdrawal effects among heavy users.
    • But it affects the "pleasure centers" in the brain and can create psychological dependence.
  • There is little evidence that marijuana use serves as a "gateway" to the use of other, more dangerous drugs.
  • Heavy use of marijuana, beginning in the teenage years, may result in cognitive loss.
    • But the direction of causality has not yet been settled.

In 2016, the Oakland Museum of California mounted Altered State: Marijuana in California, a major exhibition devoted to marijuana culture in California.


See also

  • "Marijuana: The High and the Low" by Jerome Groopman, New York Review of Books, 02/20/2014.
  • The Health Effects of Cannabis and Cannabioids: The Current State of Evidence and Recommendations for Research (2017), by: the Committee on the Health Effects of Marijuana of the National Research Council, the operating arm of the National Academies of Science, Engineering, and Medicine.




Major Psychedelics

Mescaline, psilocybin, LSD, and other "major psychedelics" have profound psychological effects, testifying to the potency of the drugs involved.  Even with these substances, however, the effects on mental function are moderated by extraneous variables, such as the setting in which the drug is taken (medical, research, or recreational), the subjects "set" or expectations (as in placebo effects), and the personality of the subject (for a comprehensive review, see LSD, Marijuana, Yoga, and Hypnosis by T.X. Barber, 1970).


Mescaline was identified as the major ingredient in peyote by Heffter in 1896, though some claim that other substances in the peyote plant also contribute to the experience. Methoxyamphetamine is a much more powerful synthetic version of mescaline.

LSD was synthesized by Albert Hoffman in 1943, as an offshoot of his work for Sandoz, a Swiss pharmaceutical firm, on medical uses of the ergot fungus.  Technically, it is LSD-25, referring to the 25th semisynthetic compound that Hoffman produced.  In trials on laboratory animals, it appeared to be inert, but when Hoffman took some himselfHoffman described his experiences as follows (quoted in Snyder, 1996):

Last Friday, April 16, 1943, I was forced to interrupt my work in the laboratory in the middle of the afternoon and proceed home, being affected by a remarkable restlessness combined with a slight dizziness.  at home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination.  In a dreamlike state with eyes closed I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.  After some two hours this condition faded away.

On April 19, after taking merely 0.25 mg of LSD-25, which we now know to be a massive dose, Hoffman reported a more intense experience:

Everything in my field of vision wavered and was distorted as if seen in a curved mirror....  Pieces of furniture assumed grotesque, threatening forms....  The lady next door, whom I scarcely recognized,... was no longer Mrs. R. but rather a malevolent, insidious witch with a colored mask....  Even worse than the demonic transformations of the outer world were the alterations thta I perceived in myself, in my inner being.  Every exertion of my will, every attempt to put an end to the disintegration of the outer world and the dissolution of my ego, seemed to be wasted effort.  A demon had invaded me, had taken possession of my body, mind and soul.  I jumped up and screamed, trying to free myself from him, but then sank down again and lay helpless on the sofa....  I was siezed by the dreadful fear of going insane.  I was taken to another world, another place, another time.  My body seemed to be without sensation, lifeless, strange.  Was I dying?  Was this the transition?  At times I believed my self to be outside my body, and then perceived clearly, as an outside observer, the complete tragedy of my situation....  Would [my wife and three children] ever understand that I had not experimented thoughtlessly, irresponsibly, but rather with the utmost caution, and that such a result was in no way forseeable?

Sandoz thought that LSD might have uses in psychotherapy, and provied samples for free to researchers -- including, eventually, Timothy Leary and his colleagues at the Harvard Psilocybin Project.  And the rest is history.

Psilocybin is the active ingredient in so-called "magic mushrooms", identified by Hoffman in 1958 (psilocyn is another).  Hoffman's self-experimentation convinced him that the experience induced by psilocybin was essentially the same as that induced by LSD -- if not as potent.  Both ingredients have a chemical structure very similar to the neurotransmitter serotonin.

Another herbal hallucinogen from the shamanic tradition of Mexico is Salvia (salvia divinorum), a member of the mint family (also known as "diviner's sage", "Sally-D", and "magic mint").  According to an article in the New York Times ("Popularity of a Hallucinogen May Thwart Its Medical Uses" by Kevin Sack & Brent McDonald, 09/09/2008), Salvia has emerged as a popular drug only in the last decade or so, and there is so little literature on it that even the US Drug Enforcement Agency has been unable to decide whether to list it, like marijuana and LSD, as a controlled substance.  However, this lack of scientific evidence has not prevented several states, and several countries in Europe and Asia, from banning or otherwise regulating the substance.  Salvia is usually smoked, though it can also be chewed or consumed in a tincture.  According to the article, "Users often report a sudden dissociation from self, as if traveling through time.  The experience tends to be solitary, introspective and sometimes fearful....  Regular users say it can be a restorative, even spiritual tonic, and recall their visualizations with precision".  The effects of even a small dose of salvia can be very powerful, sometimes resembling the out-of-body experience, and often quite unpleasant or disturbing.  Perhaps for this reason, online sales often come with the caution to use it only with a "sober sitter" in attendance.  The active ingredient in Salvia, Salvinorin A, stimulates only the kappa opioid receptor in the brain, in contrast to LSD, which may stimulate as many as 50 different receptors.  For this reason, it may constitute a new class of psychedelic substance.  As with LSD and marijuana, there is some interest in its potential medical uses, as in psychotherapy or pain relief, but little research is available to date, and most use appears to be recreational.  As of 2009, the federal Drug Enforcement Administration did not regulate Salvia, listing it only as a "drug of interest", but a number of states list it as a "Schedule 1" drug, along with LSD and Ecstasy.

As with all the other substances discussed here, Don't try this at home alone !

Research on LSD and psilocybin in the United States began in 1949, soon after LSD was synthesized -- first as a means of simulating psychosis, and then as a vehicle for psychotherapy, especially as a treatment for alcoholism.  Although a large literature developed, most of it was of poor quality, anecdotal or lacking in essential controls.  In the hands of the "Cambridge Quartet" of psychedelic researchers -- Timothy Leary, Richard Alpert (later known as Baba Ram Das), Huston Smith (subsequently a professor of religious studies at UC Berkeley), and Andrew Weil (the alternative-medicine guru) -- the use of both drugs quickly gravitated toward spiritual, and then frankly recreational uses.  At this point, the drugs themselves were banned, and research ground to a halt. 

Some early "research" on LSD was tragically pointless.  A case in point is that of Tusko, an elephant at the Oklahoma City Zoo, who received about 3,000 times the normal human dose of LSD (a correction for differences in body weight), to see if it would trigger an episode of musth, an episode of aggressive behavior which occurs naturally from time to time in male elephants (West et al., Science, 1962).  It didn't.  Instead, Tusko suffered a sort of epileptic seizure while his mate, Judy, tried to help him.  The whole sad story is told in Elephants on Acid and Other Bizarre Experiments (2007) by Alex Boese.

LSD and the other major psychedelics entered popular culture in the 1960s, and were prominent features of the counterculture that emerged in that decade.  Much of the art that papered college dormitory rooms, like the poster on the left for concerts produced by Bill Graham in San Francisco, and the graphics of Peter Max, was dubbed "psychedelic" art.  After participating in one of Ken Keesey's "acid tests" (popularized by Tom Wolfe in the Electric Kool-Aid Acid Test. Owsley Stanley, the audio engineer for the Grateful Dead (image on right), developed a cottage industry in his laboratory in Point Richmond, manufacturing millions of doses of LSD and other psychedelics for recreational consumption.



More recently, clinical research on both LSD and psilocybin has restarted, especially targeting anxiety and depression -- including the relief of anxiety and depression in terminally ill patients.  And more experimental research has resumed on the effects of these substances on consciousness, and what they can tell us about the neural correlates of consciousness.  This revived interest has also led to the development of a new generation of psychedelic drugs, such as nicergoline.  There are lots of other ostensibly psychedelic drugs, including some synthetic ones, but these lectures focus on the "classics" of mescaline, psilocybin, and LSD.  In contrast with marijuana, where research has focused on its effects on human performance (short-term memory, perceptual-motor coordination, and the like), from the beginning research on the major psychedelics focused on its "consciousness-altering" effects.   Presumably, this is because of the religious-spiritual peyote,), literary (mescaline), and countercultural (LSD) context in which these drugs were taken.

In these lectures, I treat mescaline, psilocybin, and LSD as one single class of drugs which have very similar effects on consciousness.

For a historical account of the "Cambridge Quartet" of psychedelic researchers (if that's what they were) at Harvard, see The Harvard Psychedelic Club: How Timothy Leary, Ram Dass, Huston Smith, and Andrew Weil Killed the Fifties and Ushered in a New Age for America by Don Lattin. 

See also:


Jackson's Excellent (Alleged) Adventure on Acid

There is a story, probably apocryphal (I got it from Marty Seligman, who was one of my teachers in graduate school, who admitted it was apocryphal, but too good to resist), that Jackson Pollock, the American abstract expressionist painter (this is painting, Convergence, from 1952, in the Albright-Knox Art Gallery in Buffalo, New York), once participated in an experiment in which he took LSD and then was asked to respond to the cards of the Rorschach Inkblot Test (this is Card V).  According to the story, the exchange went as follows:


Examiner: "OK, now look at this card, and tell me what you see."

Pollack: "Oh, wow!"

Examiner: Tell me what you see!

Pollack: "Oh, wow!"

Examiner: "Jackson, Jackson, tell me what you see!"

Pollack: "It's a bat!"

Much of the initial interest in mescaline, psilocybin, and LSD was stimulated by these drugs' apparent ability to induce profound mystical religious, and spiritual experiences.  In an attempt to capture this aspect of the psychedelic experiment, Walter Pahnke, a psychiatrist who was also a student at Harvard Divinity School, conducted what became known as The Good Friday Experiment as part of his doctoral dissertation (supervised by Timothy Leary, who was at that time on the psychology faculty at Harvard and director, with Richard Alpert, of the Harvard Psilocybin Project).  Pahnke recruited a number of Protestant divinity students student from Andover-Newton Theological Seminary, none of whom had any previous experience with the drug, and gave them a dose of psilocybin during Good Friday services at Boston University's Marsh Chapel (got all these institutions straight?).  Pahnke pulled out all the stops: the experiment was conducted in the basement of Marsh Chapel, illuminated only by candlelight, with organ music piped in from the sanctuary upstairs, along with a sermon delivered by Howard Thurman, who had been a mentor to Martin Luther King, Jr. (King had received a doctorate from BU under Thurman's guidance).  In an attempt at a double-blind placebo protocol, half of the subjects received 30 milligrams psilocybin, and they were matched with subjects who received a dose of nicotinic acid (vitamin B6), a central nervous system stimulant, as an active placebo (the antipsychotic drug Thorazine was also available for emergencies, to bring anyone down who experienced a "bad trip").  However, the protocol broke down after about 1 hour, when it became eminently clear who had taken which substance!  An interesting feature of the Good Friday Experiment was that, at Leary's insistence, the research assistants, who were designated guides, took psilocybin at the same time -- with predictable results.  The experiment became legendary for the chaos that ensued

But Pahnke tried.  Based on his extensive reading of the literature on Christian and non-Christian mystical experiences (he was a divinity student, after all), he developed a Mystical Experiences Questionnaire, with a number of subscales intended to measure changes in the "sense of unity", transcendence of time and space, sense of sacredness, and the like.  Examples of the scales of the MEQ are provided in the table below (numbers refer to the ordering of items in the full questionnaire; some questions were filler items that were not scored).  Based on their responses to the MEQ, Pahnke judged that 40% of the psilocybin group, but none of the placebo group, had a "complete" mystical experience.  Adopting a less-stringent criterion, of high scores on at least 7 of the 9 categories assessed in the MEQ, 80% of the psilocybin subjects, but again none of the placebo subjects, had a mystical experience during the experiment.








Pahnke also conducted a followup session with these subjects 6 months after the Good Friday Experiment., and found that these mystical effects persisted even after the drugs wore off.  It appeared that a single "trip" with psilocybin had profound, and long-lasting effects on the subjects' personalities.  A followup by Doblin (1991), conducted about 25 years after that Good Friday, confirmed that the effects were, essentially, permanent.



A somewhat more secular approach was taken by Harriet Linton-Barr, Robert Langs, and their colleagues at the Postgraduate Center for Mental Health, a psychoanalytically oriented research group affiliated with New York University (Linton and Langs, 191962a, 1962b, 1964; Linton et al., 1964; Langs, 1967, 1971; Langs & Barr, 1968; all of this research is summarized in Linton Barr, Langs, et al., 1972)Their subjects, who were naive to LSD (which almost everyone was in 1959), and judged to be in good mental health, received 100 micrograms of LSD; controls received a placebo of lemon juice in water. That's not a very good placebo, of course, not even as good as the nicotinic acid used in Pahnke's Good Friday Experiment.  But really, when it comes to LSD and psilocybin, it's pretty clear that subjects can tell pretty quickly then they've gotten the placebo, so it's probably just as well not to be a stickler about it.  Anyway, the subjects completed a number of tests both before and after ingesting the drug, including:

Repeated measures on the total questionnaire score showed that LSD had its peak effect about 2-5 hours after administration, and had worn off by the time of final testing the next day.  The Stroop test showed a substantial interference effect while on the drug, but this was no different from that observed in the placebo group.  However, we now know Stroop interference is a good index -- some call it the "gold standard" of automaticity.  Linton and Langs didn't know about automaticity, however, it in the future it would be interesting to compare the effects of LSD on both automatic and controlled processes. 


And given Pollan's remarks about short-term memory and the mystical experience under marijuana, a good test of memory functions would be in order as well.  Linton Bar, Langs, et al. found no effect of LSD on Digit Span performance, but did find profound effects on the more cognitively demanding Serial Sevens task.



As part of the effort to revive the therapeutic uses of psychedelic drugs (see below), Griffiths et al. (2006), with the Psilocybin Research Initiative at Johns Hopkins University Medical School, conducted a replication of Pahnke's Good Friday Experiment with additional controlsThey recruited by advertising for adults with a history of "religious" or "spiritual" participation, who had no prior experience with psilocybin or other hallucinogens.  The experiment was conducted in a medical laboratory, not a chapel (and not on Good Friday, either!); the subjects wore masks to block extraneous stimuli, and listened to classical music.  Following a double-blind protocol, some subjects received 30 milligrams of psilocybin; controls received a dose of methylphenidate, better known as Ritalin, a more CNS stimulant than nicotinic acid (and thus, arguably, a better active placebo).  Assessing mystical experiments with a variant on Pahnke's MEQ, known as the Pahnke-Richards Mystical Experiences Questionnaire, they found elevated scores on all scales, compared to the placebo group.  In a follow-up study, additionally employing a new Persisting Effects Questionnaire, study, the scores of the psilocybin group continued to be elevated -- in fact, hardly unchanged! -- 14 months later, with no untoward effects.  Griffiths et al. concluded, as stated in the title of their paper, that a single dose of "[p]silocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance".  In their view, effects like these justify clinical trials on the use of psilocybin to relieve anxiety and depression in cancer patients

Link to the Pahnke-Richards Mystical Experiences Questionnaire

Link to the Persisting Effects Questionnaire

Link to the States of Consciousness Questionnaire

 

A Psychedelic Revival?

Aside from its recreational uses, LSD came to the attention of researchers because of its potential use in psychotherapy, especially for alcoholism and drug abuse. These clinical uses spurred experimental research on their psychological and physiological effects. However, experimental research and clinical practice was soon contaminated by recreational use (think timothy Leary). As a result, the US Food and Drug Administration (FDA) classified all hallucinogenic drugs as "Schedule I" drugs, with no medical use, and essentially shutting down basic research as well. However, psychotherapeutic interest in psychedelics has recently been revived, and it is now possible to read reports in professional journals of preliminary clinical studies of the effectiveness of LSD, psilocybin, and even ketamine "(Special K", a powerful anesthetic) and MDMA (Ecstasy, better known at "the date-rape drug") in the treatment of post-traumatic stress disorder (PTSD), anxiety and depression (including anxiety and depression secondary to cancer), and alcohol and drug abuse (see 'Hallucinogens as Medicine" by Roland Griffiths and Charles Grob, Scientific American, 12/2010; "The Trip Treatment" by Michael Pollan, New Yorker, 02/09/2015; "High Science" by Hampton Sides, National Geographic, 06/2015). Like marijuana, the major psychedelics have also been used in the treatment of anxiety and depression associated with medical illnesses, such as cancer.  Most of this research has focused on marijuana (which is gradually being legalized, at least at the state level) and psilocybin (which is a natural as opposed to synthetic compound, with a long history of use by indigenous people in the Americas, and doesn't have the "outlaw" and "countercultural" connotations of LSD).

If the initially positive results hold up, the clinical success may lay the foundation for more experimental research on the psychological effects of psychedelic drugs. At present, however, potential investigators are bound by the same legal constraints as affected potential investigators generations ago. In the current instance, for example, the fact that psychedelic drugs are illegal has forced investigators to get funding from a private foundations, chiefly the the Multidisciplinary Association for Psychedelic Studies (MAPS; founded by Rick Doblin, who led the replication of the "Good Friday Experiment), and the Heffter Research Institute. MAPS and the Hefter Institution also sponsor an annual "Psychedelic Science" conference: the 2012 and 2013 meetings were held, of course, in Oakland, home of Oaksterdam University. The hope is that the success of these small, privately funded clinical trials will spur interest on the part of government agencies, such as the Defense Department (for treatment of PTSD in veterans), NIMH (anxiety disorders, depression), NIDA and NIAAA (for substance abuse), and NIH (for cancer and other life-threatening illnesses).  Meanwhile, in California and other states, taxes on medical and recreational marijuana are being used to subsidize new research on medical applications of both major and minor psychedelics.

Unfortunately, in many of these small, privately funded clinical studies, there are none of the usual controls to determine the actual source of any effects. The patients typically receive the drug in the context of ongoing psychotherapy, so we do not know whether the effects are due to the drug the psychotherapy, or some combination; there is no random assignment, so we don't know about selection effects. . The trials are not run double-blind (or even single-blind), and there is no control for patient (or investigator) expectations that might give rise to placebo effects. And, as with medical marijuana today, there is always the danger that recreational use will be confused with clinical and research use, threatening the entire research enterprise, and fostering ignorance of the effects of these substances and their theoretical implications.

Unfortunately, research on marijuana has been stymied by the fact that, even though sales of the substance are legal in states like Colorado (and, to a lesser extent,  California and Oregon), as of 2015, scientific and medical researchers must procure their marijuana from a single government-approved supplier (affiliated with the University of Mississippi, no less!).  The problem is that this "official" crop of marijuana contains much less tetrahydrocannabinol (THC) and cannabidiol (CBD), the primary ingredients in marijuana, than what is currently being sold for medical use and personal consumption (THC gives users their euphoric "high", but some research indicates that CBD has therapeutic effects in the treatment of post-traumatic stress disorder).  Therefore, the findings of officially sanctioned marijuana research may not generalize outside the laboratory, where "high-grade" marijuana is actually in use. 

The situation with respect to other psychedelic substances is even worse, as there are no licensed suppliers for drugs such as LSD and psilocybin.

For an account of this revival, see Neuropsychedelia: The Revival of Hallucinogen Research Since the Decade of the Brain (2012), by Nicholas Langlitz, an anthropologist.

 

This page last modified 05/10/2017.