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 course

Classification of Psychoactive Drugs

• Major Psychedelics produce profound effects on perception and imagination.
• Peyote, a natural source of mescaline known to indigenous people of the American Southwest and Central America since pre-Columbian times.
  
• Psilocybin, the active ingredient in "magic mushrooms", popularized by Timothy Leary and Richard Alpert.
  
• Mescaline, popularized by Aldous Huxley in The Doors of Perception. 
  
• Lysergic acid diethylamide (LSD), also popularized by Timothy Leary and Richard Alpert
  
• Minor Psychedelics produce the same sorts of effects, only milder; their major active ingredient is delta-9-tetrahydro-cannanibinol (THC for short)
  
• Marijuana
• Hashish (a more concentrated form of marijuana)
• Narcotic Analgesics (opium derivatives or synthetic opiates)
• Opium, including morphine and codeine, its active ingredients.
• Heroin, a derivative of morphine
• Synthetic Opiates, such as Meperidine (trade name Demerol), Fentanyl, and Methadone (trade name Dolophine).
• Semi-synthetic Opiates, including oxycodone.
  
• Central nervous system Stimulants enhance the effects of neurotransmitters called monoamine neurotransmitters, including norepinephrine and dopamine, to increase alertness, attention, and physical activity; as well as feelings of euphoria.
  
• Amphetamines, including methamphetamine and dextroamphetamine. 
  
• Paradoxically, amphetamines like Adderall, Concerta, and Ritalin are used in the treatment of attention-deficit hyperactivity disorder (ADHD).
• Even more paradoxically, in World War II the German army (Wermacht), not to mention Adolph Hitler himself and other members of the Nazi leadership, were avid consumers of methamphetamine and related drugs during World War II, in order to sustain high levels of physical activity (like doing without sleep).  In the run-up to the war, a German pharmaceutical company synthesized a version of methamphetamine, patented as Pervitin, for factory workers and soldiers.  I say "paradoxically" because Hitler was a health-nut, and official Nazi ideology generally forswore the use of drugs.  The company actually conducted placebo-controlled trials which showed that, while Pervitin increased stamina and output, is also impaired performance on intellectual tasks.  Not a problem, I guess, if you're commanding soldiers: the whole German army was apparently hopped up on Pervitin in the campaign through the Ardennes Forest in 1939-1940.  The whole sordid story is told in Blitzed: Drugs in the Third Reich by Norman Ohler (2017), reviewed in "The Very Drugged Nazis" by Antony Brewer, New York Review of Books, 03/09/2017.  Old habits die hard: After the War, similar drugs were used by East German athletes in international competitions.
  
• Cocaine, based on an alkaloid derived from the leaves of the coca plant, chewed by pre-Columbian Indians of South America for its stimulative properties.
  
• Caffeine, as found in coffee, tea, chocolate, and many soft drinks (think Coca-Cola, whose original ingredients were derived from coca leaves (a source of cocaine) and kola nuts (a source of caffeine).
• Nicotine, as found in tobacco, tobacco substitutes, and tobacco inhalers.
• Central nervous system Depressants, which, generally inhibit brain activity by increasing levels of gammaaminobutyric acid (GABA), a neurotransmitter.
• Alcohol is the most famous and popular CNS depressant.  A mutation in a gene known as ADH4, occurring about 10,000 years ago in the last ancestor shared in common by African apes and humans, permits rapid digestion of ethanol, and reduces its ill effects.  It is possible that early nomadic hunter-gatherers got buzzed on naturally fermenting fruits, and its even been suggested that the desire for beer led to the emergence of a sedentary agricultural lifestyle.  In any event, there is evidence suggestive of a brewery at the Gobekli Tepe archeological site in southwestern Turkey, dating to 11,600 years ago, and certainly at a site in Jiahu, China, dating to 7,000 BCE.  and when our ancestors migrated out of Africa, they took the fermentation technology for making beer and wine with them, or invented it themselves, pretty much
  
• everywhere except Australia.  so that by    (For more see "A 9,000-Year Love Affair" by Andrew Curry, National Geographic, 02/2017.)
  
• Other depressants are the sedative-hypnotic (sleep-inducing) drugs and minor tranquilizers used medically for pain control and also as anxiolytics (anti-anxiety agents).
• Barbiturates, like amytal, Nembutal, and Seconal.
  
• Benzodiazepines like diazepam (Valium) and midazolam (Versed).
  
• Nonbenzodiazepine sedatives like eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien).
• And, for that matter, we might just as well add common antidepressants, because they're intended to alter mood, and thus alter consciousness.  There are too many of these to list, but here are some common types:
• Tricyclic antidepressants, e.g., imipramine (Tofranil), doxepin (sinequan), block transport of serotonin and norepinephrine, thus effectively increasing the levels of these substances at the synapse.
• Selective serotonin reuptake inhibitors, e.g., fluoxetine (Prozac, Serafem), sertraline (Zoloft): as their name implies, increase levels of serotonin by limiting reuptake by presynaptic neurons.  There are also reuptake inhibitors which act on norepiephrine alone, or on both serotonin and norepinephrine.
• Monoamine oxidase inhibitors, e.g., Marplan, Niamid: as their name implies, inhibit the activity of monoamine oxidase enzymes.
• And we might just as well include the antipsychotic drugs, including the phenothiazines, like chlorpromazine (Thorazine) and thioridazine (Mellaril), which block dopamine receptors, are basically tranquilizers, so I guess you can say they alter consciousness, even though they reduce hallucinations, rather than induce them!.

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

• Drugs and the Brain (1986, 1996) by Solomon H. Snyder, a pioneer of psychopharmacology (along with Steven Matthysse, he's largely responsible for the "dopamine hypothesis" of schizophrenia, is the best resource, especially for readers with a limited background in molecular and cellular neuroscience (which is just about everybody).
• The Dream Drugstore: Chemically altered States of Consciousness (2001) by J. Allan Hobson presents much the same material, couched in the framework of Hobson's AIM model of consciousness, discussed in the lectures on Sleep and Dreams.
• Or you could simply take Dr. David Presti's popular course, "Drugs and the Brain" (MCB 62/Psych 19). 
  

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.

The British may have gotten their opium from India (and sold it to China, leading to the 19th-century Opium Wars), but the Indians may have gotten it from somewhere else.  In "Opium's Human History" Natural History, 03/2019), Lucy Inglis, a historian, notes that the earliest traces of opium poppy have been found in a Neolithic site in the Jordan Valley, dated to 8-10,000 years ago, and the earliest evidence of the use of opium for narcotic and analgesic purposes comes from a Neolithic site in Spain.  Opium poppy has been found in other Neolithic sites as well.  Opium then gradually moved east, into Greece (both Minoan and Mycenaean pottery depicts people with poppy capsules, and Homer mentions poppy in both the Iliad and the Odyssey), Bronze Age Egypt and the rest of the Middle East (the Ebers Papyrus, dated to 1550 BCE, gives instructions for using opium to calm a fussy child). 

Consciousness-Altering Drugs Before the Sixties For more on the history of opium, see Inglis's book, Milk of Paradise: A History of Opium (2018), which provides all the details. Also Psychonauts: Drugs and the Making of the Modern Mind (2023) by MIke Jay, a cultural historian (reviewed by Clare Bucknell in "High Achievers", New Yorker, 04/24-05/01/2023, from which this image is drawn) -- also in Jay's book Emperors of Dreams: Drugs in the Nineteenth Century (2000).   Jay points out that of mind-altering substances such as opium, nitrous oxide, and later ether, hashish, and cocaine were very popular among the English Romantics. And not just poets: none other than William James, looking here very much like a hippie out of Haight-Ashbury in the 1960s.  And also Sigmund Freud, who did some of the earliest medical experiments on cocaine: see his posthumously published Cocaine Papers (1974), edited by Robert Byck and Freud's own daughter, Anna.

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.

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."

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 (known on the steet as "Ecstasy" or "Molly", and commonly used as a date-rape drug) 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  "no currently accepted medical use and a high potential for abuse".  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.

• Overton's Experiment 1 employed a transfer of training procedure: for example, an animal would be trained to turn left when drugged, and to turn right when not drugged (again, of course, everything was properly counterbalanced, and this is true for all the other experiments as well).  Then Overton alternated test sessions between the drugged (D) and non-drugged (ND) states.  He found that the animal's behavior was controlled precisely by the drug: when it was drugged, it turned left; when it was not drugged, it turned right.  There was, apparently, no transfer (or, for that matter, interference) of learning between the D and ND conditions.  As they say in Las Vegas, what happened under barbiturate stayed under barbiturate.
• In addition to the usual 2x2 design, Overton additional control conditions in this experiment.  For example, he trained some animals only in one condition -- to turn left when drugged, or to turn right when not drugged, and then alternated test sessions in both the D and ND states.  These animals performed the conditioned response (CR) when tested in the same state in which the learning originally occurred; when tested in the opposite state, they responded randomly.
  
• Experiment 2 employed a relearning design.  The animals were originally trained in the D state, and then were retrained on the same response in the ND state.   But the animals showed essentially no savings in relearning -- the dissociation between D and ND states appeared to be complete.
• Experiment 3 examined the concurrent acquisition of D and ND responses.  The experimental group received 2 training trials per day -- one D, the other ND; a control group received only 1 trial per day, either D or ND.  Overton found that the learning curves for the two groups were highly similar.  This means that the drug did not interfere with the acquisition of the CR.  Rather, it is the change in drug state that interferes with retrieval.
• Experiment 4 looked at dose-response effects on SDL.  All the animals were given 2 training trials per day, one D and the other ND.  But there were 5 subgroups, given different doses of barbiturate: 25, 20, 15, 10, or 5 mg/kg.  All the groups except the 5 mg/kg group eventually learned to respond differentially.  Apparently, the lightest drug dose was not sufficient to produce a drug dissociation.  Training went faster at the higher dosage levels. 
  
• In other experiments, Overton compared pentobarbital with other discriminative stimuli.  To compare with the D state, for example, subjects would be trained in the presence of a simple external discriminative stimulus (S_D; e.g., a tone or a light), or compound external S_D (e.g., a tone and a light); or under conditions of food or water deprivation (inducing internal states of hunger and thirst); or after receiving an injection of gallomine, a drug that mimics the peripheral effects of pentobarbital on locomotion, but has no effects on the central nervous system.  Overton found that pentobarbital was a more powerful than any other condition tested, suggesting that SDL was probably not mediated by sensory cues or minor peripheral cues.

• Anesthetic agents (including barbiturates, ethyl alcohol, chloral hydrate, ether, and nitrous oxide) yield the strongest effects.
• Librium, a benzodiazepine, also yields strong effects.
• And so does nicotine, the active (and addictive) ingredient in tobacco smoke (sat least in animals; in humans, maybe not so much)..
• More moderate SDL effects have been obtained with marijuana, various narcotics, and hallucinogens such as LSD.
• Weak effects have been obtained with physostygmine, chlorpromazine, and imipramine.
• Interestingly, no SDL effects have been observed with caffeine (which is, after all, a CNS stimulant), aspirin, or lithium carbonate.
  

• The effects on learning are proportional to the dose of the drug.
• The time-course of SDL parallels the obvious effects of the drug on CNS functioning (as indicated, for example, by ataxia).
• Animals can discriminate between different doses, high or low, of a single drug.
• And most interestingly, drugs are largely interchangeable within a pharmacological class.  That is, SDL induced by one type of barbiturate, such as pentobarbital, can be breached by another barbiturate, such as phenobarbital.  In fact, pharmaceutical researchers often use SDL, or at least DDL, to classify new and experimental drugs.

• The first is largely terminological: animal researchers like Overton tend to refer to SDL, while human researchers like Eich tend to refer to SDM.
• State-dependency in humans tends to be asymmetrical.  That is, there is more transfer from ND to D than from D to ND.  Or, put another way, state-dependency is greatest when encoding occurs in D.
• In general, psychoactive drugs impair both encoding and retrieval.
• SDM effects in humans are also relatively weak, probably due to ethical constraints on the dosages that can be administered to human subjects.

• In free recall, the retrieval cues are relatively uninformative, in that they only provide information about the spatiotemporal context in which the event occurred.
• What were the words on the list you studied?  
• In cued recall, the cues are more informative, because they provide information about the general nature of the target -- for example, its category membership.
• What were the animal names on the list you studied?  
• In recognition, the cues are the most informative of all, because they are copies of the targets to be remembered.
• Did the list include lion or tiger?

• Environmental context: Studies by Smith, Glenberg, & Bjork, among others, also documented place-dependent memory (PDM), in which memory is best if retrieval takes place in the same physical environment as that in which encoding occurred. Eich has suggested that both drug SDM and environment PDM are mediated by the emotional states created by, or associated with, the contextual manipulations.
• Emotional state: Experiments by Eric Eich and his colleagues, among others (summarized by Eich, 1995), have shown that memory is best when the subject's emotional state (happy or sad) at the time of retrieval matches that which was present at the time of encoding. Note that the only emotional states studied so far in the laboratory have been happiness and sadness.  Other emotional states, such as the basic emotions of fear, anger, and disgust, have not received any attention at all (hint, hint).

• In fragmentary amnesia, the patient fails to recall specific experiences that occurred during period of intoxication, but experiences no discontinuity in consciousness.  The critical memory may eventually return, in whole or in part -- either spontaneously, after a passage of time; when reminded of the event; or during a later period of intoxication, after the manner of drug state-dependent memory.  Even after recovery, however, the memory may remain somewhat vague or hazy -- a pattern reminiscent of traumatic retrograde amnesia.
• In en bloc amnesia, the patient experiences a total amnesia for an extended period of time, the hours of a drinking bout.  In addition, the patient will recognize the loss of time, and feel a gap in memory.  Apparently, these memories cannot be recovered.  The first experience of en bloc amnesia often arouses anxiety, and even a decision to renounce alcohol (which is usually unsuccessful, because the person is, after all, typically already an alcoholic).  Note that the pattern of en bloc amnesia is similar to that observed in anterograde amnesia, as in Patient H.M.  Some researchers have suggested that alcoholic blackout, especially in this extreme case, might serve as a laboratory model for organic amnesia.

• The first possibility is encoding failure, or what Washburne referred to as "amnesia by inattention".  In this view, the intoxicated person fails to attend to important events in his environment, including his own behavior.
• The second obvious possibility is retrieval failure, or "amnesia by dissociation", by which Washburne essentially meant something like state-dependency (although this precise term had not yet been introduced).

• Phenothiazines such as chlorpromazine, sometimes referred to as "antipsychotic" or "neuroleptic" drugs, but better thought of as major tranquilizers;
• Barbiturates, another class of major tranquilizers, such as sodium barbiturate, sodium amytal, and sodium pentothal, so-called "hypnotic" drugs often used to induce a sleep-like state (these are highly addictive, and increase a patient's risk for accidental overdose or suicide);
• Benzodiazepines such as diazepam, midazolam, and Valium.  These "minor tranquilizers", also known as "anxiolytic" or "anti-anxiety" drugs, are less addictive, and generally less risky in other respects as well. 
  

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.  

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.

• For the test of cued recall, the patients were read cues from both the critical and the neutral lists, and asked to produce the corresponding term.  Performance was no better with the critical than the neutral cues, indicating that the patients had no explicit memory for the list.
• The impairment of explicit memory was confirmed by a recognition test.
• However, a free-association test produced a significant priming effect, about 23% over baseline.

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),

• Placebo refers to "Any treatment... used for its ameliorative effect on a symptom or disease but... [which] is not specifically effective for the condition being treated."
• Placebo Effect refers to "The nonspecific psychological or psychophysiological effect produced by a placebo."

• The median effect size (D) for the drug groups was 1.55 standard deviations (SDs), while D for the placebo was 1.16 SDs, suggesting that only about 25% of the response to the medications was a true drug effect, with the remaining 75% due to placebo effects. 
  
• They also found that the correlation between the effect of the drug and the effect of the placebo was an astounding .90, indicating that 81% (.90²) of the variance in drug response was accounted for by variance in placebo response.
• The three types of antidepressant medication used in these studies did not differ significantly in effect size: tricyclic and tetracyclic, D = 1.52; SSRIs, D = 1.68; Other, D = 1.43. 
  
• The ratio of placebo to drug performance was virtually the same for all three drugs, .74-.76.  This result is similar to Evans's finding, discussed in the earlier lectures, that the placebo/drug ratio is a constant, approximately .5, across a wide variety of analgesic drugs.

• K&S also analyzed 19 studies of psychotherapy for depression which included a wait-list or no-treatment control group. 
  
• The mean D for psychotherapy was 1.60, about the same as for drug treatment (this is a common finding), compared to D = 0.37 for the controls. 
  
• The correlation between psychotherapy and control effect sizes was -.27.
• Comparing the placebo condition in the drug studies to the control condition in the psychotherapy studies, K&S then estimated the size of the placebo effect, compared to spontaneous remission (or what is sometimes called the natural history effect) as D = .79. 
  

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. 

• Joffe et al. (1996) examined 48 studies, only two of which had been included in K&S's analysis, and found that placebo/drug ratio was 71% -- a figure comparable to that obtained by K&S.  .
• Wallach & Maidhof (1999) found that 65% of patients improved in the drug condition, while 46% of patients improved on placebo, again yielding a placebo/drug ratio of 71%

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 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 drug.  This 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:

• Sensory perception ("patterns, forms, figures,meaningful designs")
  
• Mental imagery ("more vivid than usual")
  
• Time perception ("time passes more slowly")
  
• Body image ("feels light or floating")
  
• Sense of identity ("lose all sense of self")
  
• Memory ("unusually rapid forgetting")
  
• Thinking ("ideas are more original than usual")
  
• Judgments of meaning or significance ("commonplace sayings... seem to have new meanings, more significance")
  
• Emotion ("almost invariably feel good")
  
• Self-control ("inhibitions are lowered")
  
• Interpersonal relations ("deep insights into other people)

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.  And, in fact, some fundamentalist Christians have pointed out that the Bible (both the Hebrew Bible and the New Testament) prohibits "sorcery" of all kinds, including the use of drugs in an attempt to communicate with, or divine knowledge from, God.

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. 

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.

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 (an attmpted 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.  Lesson #2: it's a mistake to think there is a linear relationship between body weight and dose.  Lesson #1: don't do stupid, pointless experiments.

Intelligence agencies also took an interest in LSD and other psychedelic drugs.  In the 1950s, there was great concern about Soviet and Chinese "brainwashing" of American soldiers and others held captive during the Korean War.  The Pentagon and the the CIA experimented with psychedelics, both to develop techniques to resist brainwashing, and to employ in their own mind-control efforts, in a project first known as Project Bluebird and later as MK-ULTRA.  MK-ULTRA was first exposed in the 1970s by an investigation headed by Frank Church, a US senator, and by The Search for the Manchurian Candidate (1978) a book by John Marks, an investigative journalist who is the brother of Patricia Marks Greenfield, a psychologist at UCLA.  If Leary is the "hero" of LSD research, its antihero is Sidney Gottlieb, a chemist working for the CIA who at one point possessed the entire supply of the drug produced by Sandoz.  Gottlieb's story is told in Poisoner in Chief (2019) by the journalist Stephen Kinzer (for a review, see "When the CIA Was Into Mind Control" by Sharon Weinberger, author of Imagineers of War: he Untold Story of DARPA, the Pentagon Agency that Changed the World, an excellent history of the Defense Advanced Research Projects Agency, New York Times, 10/20/2019) MKULTRA never went anywhere, and was discontinued in the 70s -- but not before psychedelics were administered to a large number of unwitting "subjects" -- including Frank Olson, whose LSD-abetted death (he jumped out of a window during a bad trip) is documented in Wormwood (2017), a docudrama mini-series broadcast by Netflix.  Lesson #2: don't do stupid, pointless experiments.  Documentation of the whole sordid story, including material released by the CIA under the Freedom of Information Act, are available online.

Marks's book took its title from The Manchurian Candidate (1959), a thriller by Richard Condon about an American soldier captured during the Korean War who was brainwashed and sent back to the United States as a sleeper agent.  The book was made into a fabulous 1962 movie by John Frankenheimer, and starring Frank Sinatra, Laurence Harvey, Janet Leigh, and Angela Lansbury.  The film was remade by Jonathan Demme in 2004; it's good, but try to see the original first.  In Condon's book, and the movies, the brainwashing was accomplished through conditioning, not drugs. 

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.

• LSD: The Consciousness-Expanding Drug, ed. by David Solomon (1964), for a selection of early papers.
• Storming Heaven: LSD and the American Dream by Jay Stevens (1987), for a popular history.
• Timothy Leary: An Autobiography by R. Greenfield (2006); Link to my review of this book.

• A questionnaire assessing subjective effects of the drug, completed 30 minutes, again 2, 5, and 8 hours, and finally 1 day, after administration.
• A series of projective tests (remember, these people were mostly psychoanalysts), including Human Figure Drawing and the Rorschach inkblots.
• Behavioral observations, rated by scales derived from psychoanalytic theory for things like regression.
• Experimental tests of memory (digit span, serial sevens), comprehension, word-naming, rhyming, arithmetic calculation, and -- everyone's favorite -- Stroop interference.

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.

Don't try this at home!  MDMA purchased on the street is likely to be far more potent than the doses used in this study, and may be adulterated with various toxic substances.  If you suffer from PTSD, get your family physician to refer you to a qualified mental-health practitioner for treatment.