Tree-Hugging Dirt Worship

June 4, 2014

Sasha Shulgin: a Light in the Dark

The great chemist and psychonaut Sasha Shulgin died peacefully of liver cancer on June 2, 2014, at 5 in the afternoon. He was surrounded by caregivers and listening to Buddhist meditation music, and passed with little struggle. I know his work better than the well-meaning obituary writers out there, and I want to tell you what he accomplished in his lifetime. It’s not to a honor the great man, which I could only do an inadequate job of, but to pull away the veil of establishment taboo and show something of the scope of his underappreciated work.

I have to skip right over his prodigal childhood and World War II Navy experience, not to mention his graduate work at Berkeley and his early professional work at Bio-Rad.

Moving right along: in the 1960’s, Sasha worked for Dow Chemical and invented Zectran, the first biodegradable synthetic pesticide (a huge ecological advantage over pesticides like DDT, which linger in the environment and accumulate up the food chain.) He was rewarded with free reign over a generously-appointed corporate lab. Not long before, someone had introduced him to mescaline on a sunny California day, and he’d been totally impressed by the experience (you can see his original write-up in the first of his lab books posted online.) So it was natural enough that mescaline was the substance Shulgin wanted to tinker with in his new lab. He experimented with alterations of the molecule, at first pursuing the all-too common medicinal chemistry approach of sifting for the most potent compounds through animal tests. Dow soon lost interest in Shulgin’s forays into medicinal chemistry (they prefer bulk chemicals and paint to pharmaceuticals, and on top of that, psychedelics became taboo over the course of the 1960’s.)

Shulgin became an independent consultant and set up a ramshackle laboratory on an old farm near San Francisco. He often found paid work testifying for either drug enforcement agencies or defendants accused of drug crimes, while continuing to make new variants of mescaline.

Shulgin believed in investigating new drugs as pure exploration, but hoped to find therapeutically useful drugs and even promote an expansion in human self-awareness as an antidote to human self-destructiveness.

He tested new drugs first on himself. He was aware of Albert Hoffman’s 1943 experience with LSD: Hoffman had started testing LSD at the 250 microgram level, believing that that was the smallest amount of any drug which could possibly have an effect… but Hoffman was knocked on his butt by a drug more potent than any discovered before! Therefor, Shulgin started with miniscule doses, and then took a nearly doubled dose a week or two later, until some hint of activity was found (poisons are just as likely as the next great breakthrough.) This work led to the Shulgin Rating Scale for rating the power of drug experiences, ranging from ” – ” for no perceptible effect up through ” ++++ ” for perceived omnipotence.

If Sasha found something worthwhile, he might take some with his wife Ann (married 1981), and then with a research group made up of close friends. The research group met on Sundays and enjoyed dinner and wine after an experiment. They included psychologists and lawyers and were able to help Sasha publish his work by qualifying as their own Institutional Review Board, for a time. The group soon found that the compounds differed in their qualities as much as in duration and potency. They investigated hundreds of Shulgin-designed derivatives of mescaline and spice rack oils (as from the peyote cactus and parsley,) and information about their synthesis and proper use was eventually collected into the book PiHKAL. Later, Shulgin tinkered with the structures of DMT and psilocin (as from ayahuasca brews and magic mushrooms,) and he wrote up over a hundred novel compounds in the sequel TiHKAL. Some of his more recent synthetic work began from new inspirations found naturally in various psychedelic cacti and poppies.

As the institutional environment became more oppressive, the research group was unable to continue getting published in the peer-reviewed scientific literature. The Shulgins started Transform Press as a vehicle for self-publishing, and published PiHKAL and TiHKAL as fiction during the 1990’s. As a result, Chemical Abstracts, repository of the list of all chemicals known to humankind, has rejected some of Sasha’s compounds as fictional!

In 1976 a graduate student (whose name I will try to find) called Sasha Shulgin on the phone to report smashing results with a chemical gleaned from the literature: 3,4-methylenedioxy,N-methylamphetamine, better known as MDMA, ecstasy, or molly. At first Shulgin treated MDMA as a “low-calorie martini,” but as he shared it with the research group he saw it help people make remarkable personal breakthroughs. The drug lacked the colorful or disorienting effects of LSD or other infamous psychedelics, which suggested it would make an ideal drug for psychotherapists to give their patients.

A member of the research group, Leo Zeff, used MDMA in his therapy practice and began sharing the secret with other therapists. He developed new techniques for working with patients under the influence and was known as “The Secret Chief.” People said MDMA was like “six months of therapy in one session,” which is immensely gratifying to both patient and practitioner. Therapists worked with qualified chemists to obtain the chemical, and the practice was perfectly legal.

Someone with less discretion found out and decided that MDMA should be made available to everybody. Larry Hagerty and others in the inner circle of Dallas MDMA dealers were motivated not only by the ample profits, but also by the desire to save humanity much as Sasha himself had described in an especially zealous talk! Thousands and thousands of doses were sold in the Dallas dance club scene. In 1985 the DEA noticed and acted to ban the drug, not only from clubs but from therapists’ offices as well.

MAPS, a non-profit that runs on donations, today funds studies into MDMA to treat the fear of death in the terminally ill, Post-Traumatic Stress Disorder in veterans and rape survivors, and social anxiety in the autistic. MDMA’s capacity to quell human suffering is well-demonstrated, vast and legally forbidden. MAPS faces an uphill battle to fund the extensive testing required by the FDA, which only a few cartelized pharmaceutical companies have ever been able to fund.

Sasha Shulgin produced many interesting compounds besides his role in passing along MDMA. 2C-B is a sense enhancer and aphrodisiac; DiPT disrupts the perception of pitch and harmony; TOMSO is a psychedelic which manifests no effects until combined with alcohol; CPM leads to eyes-closed fantasy, yet the structurally similar MAL leads to visual chaos with the eyes open. ARIADNE has been investigated as an anti-depressant. 5-MeO-DiPT enhances orgasm. All of these compounds may present uses for therapy or creative work, and certainly all of them present clues and new puzzles for brain science. Investigation into them is a legally tortured pursuit, especially in the United States. The vast bulk of Shulgin’s compounds have been only very superficially investigated.

Shulgin’s work is carried on by chemists and therapists around the world, often quietly.

His one-time student David Nichols has worked within the system, and extensively probed the molecular mechanism of MDMA at Purdue’s pharmacology labs. He also is the founding President of the Heffter Institute, which conducts research into psilocin mushrooms as medicine.

Sasha inspired his friends Earth and Fire Erowid to provide the best information about drugs available online. Erowid.org is especially sharp at keeping current with new synthetics that appear on the grey and black markets. The site helps users understand what they are getting into and stay safe, and even to get the most out of their drug experiences just as a therapist would help a patient to do.

Paul Daley came to the Shulgin farm in 2007, to help in the lab after Sasha’s eyes failed due to macular degeneration. Recently the pair was working on techniques for growing peyote, for such time as this becomes legal for the Native American Church. Another project seeks to help cluster headache sufferers with an efficient synthesis for 2-bromo-LSD. 2-bromo-LSD is not a psychedelic or an interesting head drug of any sort, except that it aborts clusters of “suicide headaches” said to be among the most physically excruciating of all human experiences. Shulgin and Daley were working on improving the synthesis of an unapproved drug with little hope for running the approval gauntlet — suggesting that they might have been hoping for others to distribute 2-bromo-LSD in an underground fashion, just as earlier circles of doctors did with MDMA. Their allies in the 2-bromo-LSD project are the Cluster Busters, a patient organization.

In 2013, Daley reported that 87-year-old, blind, dementia-addled Sasha was still joining him in the lab every day. Sasha was no longer on top of the work but he hung around in the lab and cracked corny jokes about whatever was going on. Those are some of the best things about working as a chemist anyway.

Sasha is survived by his wife Ann, a writer and lay therapist with valuable contributions in PiKHAL and TiKHAL. I find her work on integrating the shadow to be especially interesting and useful. She was also a great support to Sasha, taking care of him when he was ill, and cooking meals for the Sunday experiments.

There is every reason to believe that when these drugs are freed from their taboo status, they will allow us to make strides towards physically understanding the brain-mind correlation, and relieve vast amounts of human suffering. It will take dozens of scientists decades just to chase down all of the suggestions mentioned in PiKHAL and TiKHAL.

Some may eulogize Shulgin as a colorful character, “Dr. X, the inventor of ecstasy” or the like, but understand that Shulgin’s work is just the beginning of an unfolding Big Bang in mind science and medicine. After the superstitious and ignorant Church (of unlimited government authority) stands out of the way, we’ll recognize Shulgin as a giant of science like Galileo or Einstein.

February 24, 2013

The Great Nutmeg Question

Nutmeg is the seed or kernel of Myristica fragrans tree fruits, grated down into a musky-smelling spice. Lately, it seems as if few people are cooking with nutmeg except to sprinkle it on Christmas cookies or other holiday dishes. It was once greatly popular and expensive in Europe, as people liked it for medicine and flavor, but they had no idea where it came from. The fact that people had to buy the spice from Sindbad-like Arab traders who would not reveal the spice’s faraway source lent it a certain mystique.

It turns out that nutmeg is more than it seems, a potent mind-bending drug, which can induce long journeys away from the everyday perception of reality. The fact that a totally innocuous kitchen spice can do this raises certain questions about people’s relationships with the plant, and the relationship of the essential oils in spices to psychoactive drugs.

Firstly, the human-plant relations side of it: as nutmeg is a powerful plant drug, I would assume that there are indigenous people somewhere in the world who are familiar with its use in ritual. I would assume wrong. By the time Europeans and history discovered the Banda Islands, the secret source of nutmeg, the natives were already exporting the whole lot to meet world demand for nutmeg as a flavoring and make money. Nutmeg does have traditional uses as a sedative, sleep aid and analgesic. Writers occasionally note it as a mood elevator or health tonic. As the kernels traveled the world, people occasionally used them in smoking mixtures, snuff or chew, to nobody’s concern. And then, around the turn of the twentieth century, things took a strange turn.

A rumor went around the United States that nutmeg was an abortifacient. Perhaps this is true at a dosage that drives one to death’s door… in any case, young women would sometimes take down spoonfuls of nutmeg hoping to cause an abortion, and then, to their surprise, become highly inebriated with untrustworthy senses and delusions about the nature of the world. Nutmeg’s effects can last for over twenty-four hours after taking it. Some women thought that they were going mad or did mad things and ended up in newspaper stories. In 1902, a Dr. E.E. Hinman reported on treating nutmeg poisonings to the Northwestern Lancet: “In all cases of nutmeg poisoning there was prostration with partial or complete coma. Most of them had vertigo, delirium, chiefly hallucinations of sight, rapid, feeble pulse, and free urination. In five instances the nutmegs were taken to produce abortion, and in every case without accomplishing the desired result.”

Hysterical woman falling out of chair.

Prostrated by nutmeg.

Soon, prisoners caught on to the story about nutmeg causing delirium and hallucinations, and they were smuggling it out of the kitchen to experience the terror and insanity for themselves, such is the human drive to experience altered states. Actually, the experience may not run so terribly for everybody (prisoner Malcolm X measured doses out in a matchbox, and described the effects as being like four or five joints). Still, the seed is surprisingly strong stuff. Fortunately, most people don’t like it as a drug — the heavy effects of higher doses come with heavy side effects — so it is little abused, and the US government hasn’t snatched it out of our spice racks yet. Periodically, the news media notices that teenagers or ultra-poor people are getting high on nutmeg, and there is almost a big deal made of it. Occasionally, someone takes enough to do themselves in.

So, that is the anthropology of nutmeg in brief. There is still the question of how nutmeg does its thing. Since we don’t really understand how the human brain correlates with consciousness all that well, we can’t really truly describe the mechanism of action of any psychoactive drug whatsoever. We can, however, take a stab at relating the chemical constituents of the seed to better-understood drugs and their pharmacology.

One of the first strong efforts at dissecting the action of nutmeg took place in the mid-1960’s, to be published in 1967. Alexander “Sasha” Shulgin, a prolific American inventor of synthetic psychedelics, and two Chilean colleagues, Thornton Sargent and Claudia Naranjo, submitted an article to Psychopharmacology Bulletin: “The Chemistry and Psychopharmacology of Nutmeg and Several Related Phenylisopropylamines.” The team assumed that nutmeg’s power lay in the volatile or “essential” oil fraction of the spice, not in its fatty butter or pulpy cellulose structure. So, they pressed the kernels to express the butter, and steam distilled the essential oil from the crushed remainders. They fractionally distilled the oil, meaning that it was distilled and redistilled until each individual compound was almost completely separated from every other compound. By analyzing each fraction, the team could determine exactly which compounds were in nutmeg oil and how much of each.

Many of the chemicals in nutmeg oil are common throughout nature or well-understood, and thus were seen as poor candidates for explaining its psychoactivity (for example, pinene and sabinene are present in high concentrations across many plant species. However, the most interesting thing known about their pharmacology was that they are irritants.) Other chemicals are present in such tiny amounts that they are probably not the main contributors to nutmeg’s action (unless they are extremely potent).

Eventually, the researchers focused their attention on three “phenylisopropylamine” compounds: safrole, myristicin, and elemicin. These components of Oil of Nutmeg bear a striking resemblance to a series of synthetic psychedelics Sasha Shulgin was working on, modifications of the mescaline molecule. — — The researchers hypothesized that the human liver adds nitrogen to the three phenylisopropylamines as they pass through, so converting them into their psychedelic amphetamine counterparts — safrole to MDA, myristicin to MMDA, and elemicin to TMA. The liver is known to “transaminate” many kinds of compounds, lending the hypothesis some plausibility.

Nutmeg oil components and their hypothetical products

Phenylisopropylamine Psychedelic Amphetamine

SAFROLE

SAFROLE

MDA

MDA

ELEMICIN

ELEMICIN

TMA

TMA

MYRISTICIN

MYRISTICIN

MMDA

MMDA

If the researchers’ hypothesis is true, the effects of nutmeg should roughly correspond to the effects of MDA, MMDA, and TMA in the same proportions as nutmeg oil contains safrole, myristicin, and elemicin. All three psychedelic amphetamines have been explored somewhat as single compounds. MDA catalyzes an opening of empathy and creates sparkling visual changes. MMDA is a psychedelic generally reported as being relaxing, while exhibiting the wrinkle that impressive visual effects are only achieved with the eyes closed. TMA is definitely psychedelic and nausea-causing, but I cannot find enough reports on it to comment as to the particular character of its activity. In general, psychedelics activate certain serotonin receptors which cause “sensory gating channels” in the brain and mind to open up, increasing awareness and the sense of novelty, as well as sometimes creating special effects such as synesthesia. Psychedelics do not necessarily act as stimulants, even though many are chemically described as “amphetamines.”

Sasha Shulgin devised a way to challenge the transamination theory. He prepared a cocktail of psychedelic amphetamines to imitate the effects of 5 grams of average nutmeg, assuming that the phenylisopropylamines would be metabolized with 100% efficiency. It consisted of 100 mg of white powder, divided into 1 part (by mass?) MDA, 2 parts TMA, and 5 parts MMDA. He reports that the cocktail “produced quite a sparkle and considerable eye-dilation. But then, I have never taken 5 grams of nutmeg, so I cannot make any comparisons.” Nice experimental design, Dr. Shulgin! Couldn’t you have taken 2 or 3 days out of your busy life to get high on nutmeg (as an experimental control)? Writing in the Entheogen Review, Ibo Nagano describes 5 grams of nutmeg as a threshold dose “marked by euphoria, relaxation, mood elevation, hilarity and enhancement of the senses,” which I suppose could mean the same as “quite a sparkle.” Please note that nutmegs vary considerably in their potency and exact composition, and you cannot presume to get certain effects at certain dosages unless you know already know your source pretty well — and in that case, put down the shaker bottle, you addict!

Shulgin’s imitation nutmeg amphetamine cocktail superficially supported the transamination hypothesis. However, on another occasion, human volunteers consumed myristicin in the amount present in almost 40 g nutmeg — a dosage seen in typical emergency room visits — yet the volunteers experienced only subtle effects. As myristicin is by far the most abundant aromatic in Oil of Nutmeg, and it makes such a lame psychedelic, we can rule out the idea of it being converted efficiently by the liver. If 100% of the material was converted, each volunteer would have synthesized about 400 mg of MMDA in their own body, and likely been knocked on their butt. Additionally, while the transamination reactions were made to work in laboratory liver cultures, several investigators have not been able to demonstrate such a reaction in living animals.

There is still a possibility for partial transamination of the phenylisoproylamines in the human body. Perhaps small amounts of nutmeg oil are transformed into psychedelic amphetamines, which act synergistically to create a stronger effect than any one would produce alone. On the other hand, the phenylisoproylamines might be active at some of the same receptors as psychedelics, but at a weaker level. In the end, the 1967 research suggested a lot of things and proved almost nothing.

No one seemed interested in the problem again until 2000, when Bernard C Sangalli and William Chiang submitted a paper to Clinical Toxicology. A young woman swallowed roughly 20 g of nutmeg on a friend’s advice without really knowing what it was. When she woke up the next morning still feeling drunk and high after dreaming of being covered in centipedes, she asked her mother to take her to the hospital — thus, becoming the case study that spurred Sangalli and Chiang to investigate nutmeg. (She recovered after a few days’ rest.)

The duo list many components of nutmeg oil with notes about any known actions of those compounds. Some are stimulants, others depressants, others anesthetics, and so on. Where information is lacking, the authors suggest a strategy of comparing nutmeg to other plant materials containing some of the same or similar chemicals. For example, methysticin and kavain are two compounds from kava kava, which contain within them structures strongly resembling myristicin. The kava compounds are known local anesthetics, which work by inhibiting voltage-operated sodium channels (making nerves less conductive). Thus, the anesthetic medicinal/side effect of nutmeg may be tentatively pinned on myristicin and its interaction with the voltage-gated sodium channels. To hypothesize about each nutmeg effect and compound in this way, and then to test each hypothesis, sounds like a fun project to amuse a few research teams for the next several decades. Nutmeg is not amenable to a simplistic, reductionist approach — there are clearly multiple compounds working together to create the nutmeg syndrome, and quite possibly none of these compounds will create impressive effects working alone. I must say that this is less satisfying than Shulgin’s transamination hypothesis, but it does seem to be the truth: this is one tough nut to crack. At least it is providing us with good questions to ask.

One final note. Sangalli and Chiang lament that nutmeg’s “use is perpetuated in easy access resources such as the Internet.” Nutmeg use was perpetuated throughout the twentieth century, mostly in the absence of the Internet. I believe that having a lack of information perpetuates nutmeg use. People with adequate information would probably turn nutmeg down, or at least keep the dose limited to levels that others report enjoying. People who end up in the E.R. were usually working from ignorance or faulty information, so the researchers’ attitude of “let’s keep this information locked up in libraries where no one will look at it” is completely counterproductive. I kind of have to celebrate the honest people who share their awkward nutmeg experiences via Youtube and Erowid and the like. This young woman didn’t regret her experience but I hardly think she’s going to inspire a thousand imitators (I believe that she is a smaller person who took about 20 g, based on her previous “Nutmeg High” video):

Blog at WordPress.com.