Shulgin’s Essential Amphetamines — Part 1
The Curious Pharmacology of Nutmeg Intoxication
When I was still in elementary school and going through a somewhat precocious and concerning (for my parents at least) “occult phase”, I purchased an old book entitled Superstitions of the World (or something like that), filled with an array of superstitions, folk wisdom, and old wives’ tales collected from around the globe, some of them familiar, some less so and some, I have little doubt, invented by the author to fill the 200+ pages commissioned by the publisher. Did you know it’s unlucky to wear a peacock feather in your hat during a waxing gibbous moon? Now you do.
Anyway, set amongst a clutch of somewhat more macabre rituals towards the rear of the book, one caught my attention. It read something like this:
Take two whole nutmegs and grind to a fine powder.
Mix with bread crumbs and a little water to form a thick dough.
Form the dough into nine pills.
Swallow the pills at midnight and, by candlelight, sit before a mirror combing your hair.
The book then assured me that, if I performed this ritual as instructed, I’d catch a glimpse of my future lover in the mirror standing behind me. Just the thought of doing this horrifies me now. However, young and fearless as I was, I made these little doughy pills in my parents’ kitchen on a dreary Sunday afternoon but, perhaps fortunately in reflection, never actually swallowed them (it turns out that two whole nutmegs mixed with bread crumbs makes for some really rather chunky and unappetising “pills”). And, having now met my then future lover, the premonitory apparition would no doubt have been something of a shock.
Although I had absolutely no knowledge of this at the time, it’s long been known that nutmeg — Myristica fragrans — when ingested in large doses, can induce something of a mind-altering effect and was even employed by the Ancient Egyptians as a substitute for hashish. The medical literature includes many examples, usually of people a few years older than I was, consuming large quantities of ground nutmeg, accidentally or otherwise, and being presented to the emergency room with symptoms ranging from nausea and blurred vision to “bizarre behaviour” and, pertinently, multi-sensory hallucinations (which presumably might include a figure in the mirror). It seems that this old nutmeg and mirror ritual was more than mere superstition.
Before going any further, I feel it sensible to point out that this is by no means a recommendation of nutmeg as an easily-procured Kitchen Psychedelic. In non-culinary doses, nutmeg is decidedly toxic, both acutely and possibly chronically. The effects are usually distinctly unpleasant, often frightening, and occasionally dangerous. Liver damage is a real possibility (1)
Having said that, the nutmeg intoxication remains pharmacologically interesting and is, in fact, rather poorly understood. Nutmeg’s essential oil contains a handful of different aromatic molecules, with the closely related terpenes myristicin, elemicin, and safrole having the strongest representation and, as such, thought to be the most likely candidates for its psychoactive properties. Indeed, like the classic psychedelics, myristicin is a (rather weak) agonist at 5HT2 receptors (2), although whether or not this has any role in its cognitive effects has never been determined.
What’s perhaps more interesting is not the constituent aromatic molecules themselves, but what might happen to them once they enter the body. None other than Alexander Shulgin — long before PIHKAL fame and when he was still working for Dow Chemical Company — noticed that the structure of myristicin was curiously similar to that of MMDA (3-Methoxy-4,5-methylenedioxyamphetamine, which would eventually become PIHKAL #132):
"The seed of Myristica fragrans, on ingestion, produces cycles of delirium and giddiness. The components generally believed culpable lie in the non-terpinaceous volatile oil fraction, of which the primary component is myristicin. Very recently, a new, synthetic, psychotomimetic has been described, 3-methoxy-4,5-methylenedioxyamphetamine (MMDA). This base possesses the precise carbon and oxygen skeleton of myristicin, from which it could theoretically be derived, by the addition of a molecule of ammonia.” (3)
In fact, all three of these major aromatic components of nutmeg can be converted to their own PIHKAL entry by the addition of an ammonia (NH3) molecule across the side chain double bond (olefin in old-school Shulgin speak). Elemicin can be converted to TMA (3,4,5-trimethoxy-amphetamine, PIHKAL #157) in a single step and safrole to one of Shulgin’s more well-known (re)creations, MDA (methylenedioxyamphetamine, PIHKAL #100). And all three of these PIHKAL entries are decidedly psychedelic/empathogenic (more in part 2).
Notice that each of these hypothesised metabolic products is an amphetamine, which differs from a phenethylamine only by an additional methyl (CH3) group attached to the same carbon as the amine (NH2) group. Compare the structures of mescaline (3,4,5-trimethoxy-phenethylamine) and TMA (3,4,5-trimethoxy-amphetamine):
Shulgin identified a further seven potentially psychoactive amphetamines derivable from the components of various essential oils which form his suitably named Essential Amphetamines — I’ll discuss their chemistry, pharmacology, and effects further in part 2.
Shulgin surmised that the simple chemical transformation to the amphetamines might be easily achieved by metabolic enzymes in the liver after consuming the nutmeg or its essential oil. In other words, it’s not the myristicin, nor the elemicin or safrole, that gets you “high” after choking down 20g of ground nutmeg powder, but the MMDA, TMA, and MDA formed in your liver and then delivered to your brain that does the trick.
It’s a beautiful idea. But is it true?
There are a number of possible metabolic routes from myristicin to MMDA, but Shulgin suggested addition of oxygen to the double bond (by a mono-oxygenase enzyme) to form an epoxide, which is then converted to the ketone, which is finally converted to the amine by a transaminase enzyme.
All of these transformations are well-known in biochemistry, but this doesn’t mean myristicin is actually metabolised this way. To test the hypothesis, a solution containing myristicin was passed through livers isolated from rats (a technique known as ex vivo perfusion) and the perfusate collected on the other side. As predicted and hoped, analysis of the perfusate clearly revealed the presence of MMDA.
The same result was obtained by homogenising the liver and incubating the cells with myristicin for 5 hours. Oxygenating the cells during incubation with myristicin dramatically increased the amount of MMDA detected, indicating that, as Shulgin proposed, conversion to MMDA proceeds via the addition of oxygen (forming the epoxide). (4)
Although this study is highly suggestive, it certainly doesn’t prove that MMDA (or TMA/MDA) is responsible for the mildly psychedelic effects of nutmeg. Other studies failed to detect MMDA in the urine of rats fed myristicin and there have been no studies in humans (5). If MMDA (and the other substituted amphetamines) are generated inside the liver after nutmeg consumption, they are likely to be minor metabolites. Other pathways for the metabolism and excretion of nutmeg’s aromatic molecules are better characterised and almost certainly dominate.
All in all, if you’re interested in experiencing the effects of these Shulgin creations, it’s certainly advisable to source the molecules themselves rather than relying on the fidelity of a putative enzymatic transformation in vivo. If you want to synthesise MMDA, starting from myristicin is one of the easiest ways to do it. Likewise, safrole is one of the most common precursors to both MDA and MDMA and is controlled as a List I chemical in the US and a Table I drug precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. Try ordering large quantities of it and you should expect a knock on the door.
Reminds of a similar experience with Yohimbine, although I was a bit older (actually a medical student at the time).
This was in the late Jurassic Era, literally pre-Internet, and I somehow obtained ground up bark, which I cooked up like expresso. Sadly, the stuff looked so nasty I didn't dare drink it, which is probably just as well.
Before I'd ever heard of MDMA, my psychonaut buddy convinced me to swallow several teaspoons of ground nutmeg and honey and adventure with him on a trip to West Point. This was in the early 80's and we ended up swimming across the Hudson River that afternoon to a blueberry and black fly island and back through a seagoing ship channel. So definitely delusional. This mixture was less nauseating than the ground morning glory seeds I'd tried with another friend in the 70's, although that evening my stomach was cramping and I had a vicious headache, but I think that was from the dried coconut we ate for fuel.