There are medicinal chemists who work to synthesize drugs they hope will produce therapeutic effects in their users.
Feb 1 2011, 12:00am
The chemical structures of the eight most commonly encountered arylcyclohexylamines.
There are medicinal chemists who work on an unseen side of the pharmaceutical industry. Like their legally sanctioned counterparts, they work to synthesize drugs they hope will produce therapeutic effects in their users. But they do not work with billion-dollar budgets or advertising agencies; doctors are not bribed to distribute their products with ergonomic pens or fine terrycloth beach towels. Their advertising comes solely from word of mouth and semicautionary articles like the one you are about to read.
The creation of these chemicals is an extraordinary feat of interdisciplinarity; often the pharmacologist, the chemist, the posologist, the toxicologist, and the experimental animal are all the same human being. This is the way drugs have been developed since the beginning of medical history—it is only in recent years that the practice of self-experimentation has become stigmatized, and accordingly these experimenters, like M., must remain shrouded in mystery.
M. is one of the most respected chemists in his underground field. Singlehandedly, he has popularized and discovered numerous novel drugs for gray-market distribution. His most recent investigation of ketamine and its chemical variations produced a new dissociative anesthetic named methoxetamine, which has recently made its way into the nostrils and anuses of lay experimenters worldwide. Methoxetamine is an exemplary product of rational drug discovery; each of its atoms is the result of arduous study and consideration, all created independently on a minuscule budget. But the success of drugs like methoxetamine does not entail great profits for their inventors. Indeed, it is they who wring their hands most over the unknown fate of the chemicals they conceive. Herein we shall explore the great bioethical quandary faced by the underground medicinal chemist.
Vice: How did your interest in the chemistry of dissociatives begin?
M.: Well, when I was a young boy, only 13, I was badly hurt in an IRA bombing in London. My left hand had to be amputated after the explosion, and I knew I’d lived through a psychological stress that most people cannot even conceive. I would definitely say this triggered my interest in altered states. When you lose a limb, especially when the limb is exposed to serious trauma before the loss, there is a significant chance you’ll be left with an agonizing phantom limb.
Right, treatment for phantom limb has been one of the great riddles of neuroscience. Have you tried Ramachandran’s mirror-box therapy?
Oh yes, I’ve read Phantoms in the Brain and tried an awful lot of things. It’s a complete bastard to treat. God knows how many drugs I’ve been prescribed. Antidepressants, anti-epileptics, muscle relaxants—none of them really worked. For the worst excesses of phantom-limb pain, traditional painkillers like opiates don’t even touch it. You might as well not even bother with them. I was prescribed high doses of pethidine [also known as Demerol] but returned the bottle to my doctor because it wasn’t doing me any good whatsoever. When I came back, my doctor was agog. He said, “Nobody returns pethidine!” The pain involved can be so bad as to effectively detach your mind from consensus reality. Without suitable analgesia I end up looking like a psychiatric inmate, just rocking backward and forward, unable to do anything, sometimes for more than a day. All that considered, anything that does work is an absolute godsend.
And what works?
I discovered a long time ago that ketamine and cannabinoids helped my phantom hand. I’m quite convinced these classes work by distorting body image so severely that you phase out triggers for the pain. I have experienced profound proprioceptive distortions after intramuscular PCP injection, as if my whole body were a proportional model of the sensory homunculus. But in a sense, what I feel is not hallucination or a distortion, I actually find dissociatives corrective, that is, they make the phantom disappear. This is not just an idiosyncratic response on my part; there are at least three articles published on the effectiveness of ketamine in treating phantom-limb pain. It’s dished out by British pain-management clinics for just that purpose in the form of a nauseatingly artificial lemon-flavored linctus. Needless to say, the whole lot of it gets squirted up the arse to bypass my taste buds, but even this has its drawbacks… like sticky, sugary bum cheeks!
Fascinating. I had never considered the possibility that ketamine’s therapeutic effect on phantom limb is psychogenic—like a proprioceptive antihallucination. Recently there was an experiment done with ketamine and the rubber-hand illusion. Subjects given a ketamine infusion could feel the rhythmic strokes of a motorized paintbrush on a rubber hand in their visual field, as if the rubber hand were their real hand. So ketamine can both remove and embody an illusory appendage. Your background is in mainstream pharmacology, studying phenmetrazine2 analogs, correct?
Yes, after receiving a bachelor’s degree in biochemistry I was working on my masters in neuropharmacology. I synthesized an array of phenmetrazine analogs and quantified their potency as anorectics. But in order to do these experiments, you’ve got to kill rats. They train you to use noble words like sacrifice, but truthfully they just get a lab technician to smash the rat’s head open, or cut it in half with a pair of scissors. My conscience couldn’t hack it. So I became a teacher.
You did what?
I taught neurobiology as part of my postgraduate degree. But then I transitioned from academia into the sort of independent research I’m doing now.
You were the first person to report on the effects of synthetic cannabinoids like JWH-018, long before Spice Gold, and the first to comment on desoxypipradrol, 1-ethynylcyclohexanol, 5-APB, and methoxetamine. You have your finger in many pies… so to speak.
After receiving my degree I was just talking to people with similar interests, and I got to know a lot of people who had their expertise on the organic-chemistry side of things. Often these people were looking for somebody from a pharmacology background to suggest promising drugs, and it all went from there. As far as my own synthetic chemistry goes, I hung up my Leibig condenser a long time ago due to police visits and galloping paranoia, and, most important, I promised my ex-partner I would leave that life behind before we got hitched. She is a clinical toxicologist so she knows all too well what kind of damages these reckless behaviors can incur.
1 I know you may look at an octosyllabic word and immediately be turned off by this entire exchange, but please don’t let the vocabulary boundary stop you. These concepts, at least on the level I’m discussing them, are pretty simple. Arylcyclohexylamines are a chemical class that features an aryl group attached to a cyclohexane ring. They comprise a pharmacologically diverse class of stimulants, opioids, and, most commonly, dissociatives like PCP and ketamine. They generally have a chemical backbone that looks like this:
2 Phenmetrazine is a bicyclic amphetamine analog that has become legendary since its clinical discontinuation. It’s the campfire lore of the psychostimulant aficionado and was the favored stimulant of John Lennon.
Methoxetamine: not just your average recreationally dissociative phantom-limb drug.
There is definitely a demand for pharmacologists who can suggest novel structures. Some research chemical vendors keep a group of PhDs on hand to act as advisers in the selection and synthesis of new drugs.
Well, I have been researching compounds and suggesting ones that would possibly be interesting to have synthesized for one company. I was participating in an investigation of the structure-activity relationships of a whole range of arylcyclohexylamines, along the same lines as Alexander Shulgin’s research group, and it was all going swimmingly. I was putting all my thinking into the aryl and amino substitutions of PCP and ketamine-like dissociatives, some of which are very, very promising.
Which ones specifically?
3-MeO-PCP and 3-MeO-PCE are simply incredible drugs. They have a true capacity for healing, as the 3-methoxy group infers µ-opioid receptor affinity3 and removes the manic pressure of thought that can make PCP quite a disturbing and unpleasant drug. With the 3-methoxys there is such incredible laughter and boundless sexual energy. 3-MeO-PCP produces an inner stillness as if all the leaky naggings of the subconscious are completely muted. At 15 mg I felt 3-MeO-PCP was possibly the most amazing drug I had ever consumed, and 3-MeO-PCE seemed to have the full capacity to be the next LSD. It’s a barrel of laughs, with none of the shambolic lurching of ketamine. I felt as if I was Peter Sellers as Inspector Clouseau in a world of desperately struggling Charlie Chaplins. I laughed until I had tears rolling down to my thighs! The arylcyclohexylamines have a tremendous therapeutic potential, but they have a great abuse potential as well.
Yes, it would seem methoxetamine has already been welcomed with open arms.
The methoxetamine molecule was something I had floating around in my head for about three years. I just knew it would really be something fantastic; it contains every necessary functional group to produce the perfect dissociative. I felt it would be like a stress-free version of ketamine. Eventually I found someone who was interested and made a small batch, and when I tested it… I was blown away. It doubtless has great potential as an antidepressant. A vendor took interest and synthesized a batch for public distribution, and it took off. Now there are all kinds of fake variations for sale, tiletamine4 analogs and whatnot. The popularity was not a surprise, but I was surprised by the willingness of Chinese laboratories to synthesize it. A few years ago Chinese labs would not produce arylcyclohexylamines under any circumstances. In China, those suspected of trafficking large quantities of ketamine are executed.
In Singapore, ketamine dealers face 15 strokes of a brine-soaked rattan cane to the bare buttocks… probably in addition to execution. Risky business. When you were working with these things you had a psychotic episode of some sort—what exactly happened?
I felt it was my responsibility to test these chemicals for toxicity in a large variety of doses. It is simply not ethical to give untested drugs to other people—it’s the equivalent of throwing an unknown substance into phase IV clinical trials. I was acutely aware these arylcyclohexylamines had the potential to become extremely popular drugs. For a period I was also using methoxetamine daily to treat my phantom-limb pain, and that had clouded my judgment. Lastly, I was in a difficult place because my beloved cat, Nesbitt, a pet I had all of my adult life, had just died. He was 22 years old and I knew it was coming but it really affected me badly. I was indulging in a lot of self-destructive behaviors without actually realizing it, so I tested a 50-mg intramuscular dose of 3-MeO-PCP, and, well, I ended up in what I have been told was a catatonic state.
The death of a beloved pet is always very difficult.
My partner came home and found me, or at least my mind, somewhere past Alpha Centauri. The first thing I remember is riding in an ambulance, being asked all sorts of questions by paramedics about what it was and how much I’d taken. In their opinion I was a fruit loop. As I later found out, they also thought I’d tried to commit suicide after finding some printed pages full of vitriolic rants in a drawer next to my computer. It took bloody ages for them to believe that the rants were written years ago as a form of therapy where you put down your feelings in writing in order to exorcise said feelings. It was three weeks before I convinced them I was not a suicidal maniac, but rather that I was a pharmacologist investigating the structure-activity relationship of 3-methoxylated arylcyclohexylamines… That was one they’d never heard before.
So why did they section you for three full weeks?
At first I was a bit, well, not quite totally with it because of the side effects of the drugs. Also I think they looked at the medical reports and saw PCP and thought, “Oh my God!” But during medication time they started to notice I was not behaving like the rest of the patients and eventually came to the conclusion that maybe there wasn’t that much wrong with me. I did feel a bit like Randle McMurphy. Let me tell you that if you ever think you’re going insane, try a fortnight in a secure psychiatric ward! I encountered real crazies there, which in comparison with, I’m just a tad eccentric.
And what happened when you were released?
That was the final straw for my partner, and she said she would not sit idly by and watch me self-destruct. When I came home she was gone, Nesbitt was still dead, and all of the arylcyclohexylamines I had been researching had been confiscated and destroyed.
That’s really terrible. Alexander Shulgin always felt that the dissociatives had no use as psychotherapeutic drugs, and John Lilly found that even when you think the effects of ketamine have worn off there is a lingering undercurrent of dissociation that prevents you from reaching baseline.
And despite the fact that I knew all of that, I still ignored what should have been indicators that I was slipping. The arylcyclohexylamines light up too many of the reward systems in the brain, with the dopamine-reuptake inhibition, the NMDA antagonism, and the µ-opioid affinity. They lend themselves to abuse and escape to fantasy. I used to find myself raving about chemicals I had only tried once or twice, saying they were Huxley’s soma or moksha, or Polidamma’s Nepenthe. I’ve come to realize that dissociatives have a really dark side to them that classic serotonergic psychedelics don’t.
Right. One methoxetamine user reported a dissociative-identity-disorder-esque psychotic episode. He impulsively fondled a stranger’s breasts, as if controlled by an external force. A nearly identical breast-fondling automatism was reported by John Lilly under the influence of ketamine. Perhaps the suppression of a breast-honking impulse is mediated by the NMDA receptor.
There’s a scientific study for you! We still have much to learn about the human brain.
3 The µ-opioid receptor is generally thought to initiate the euphoric, reinforcing effects of heroin and co. Recent work by J. V. Wallach on the pharmacology of 3-MeO-PCP has shown that it actually has insignificant affinity for the µ-opioid receptor, which suggests that methoxetamine is quite possibly an insignificant opioid as well. This is not to say methoxetamine is not addictive or pleasurable, simply that it probably produces said effects through a different pharmacological mechanism.
4 Tiletamine is the primary component in Telazol, a veterinary tranquilizer that is used to anesthetize polar bears, elk, and sea lions. Its effects are often described as “cold and clinical,” although that has not stopped a number of veterinarians from using it in great excess.
Pyschonaut John Lilly constructed this ketamine dose-to-response curve and wrote of his experiences (speaking in the third person): “Later John was to find that there was a small residual effect that lasted several hours. The falling curve did not go completely to zero. The overvaluation trap would be found much later to be caused by this small residual effect unnoticed in the first set of experiments.”
Copyright 1988, 1997 by John Lilly. From The Scientist: A Metaphysical Autobiography, John Lilly, MD, by permission of Ronin Publishing, Berkeley, CA. www.roninpub.com.
How would you advise people who experiment with methoxetamine to proceed?
If people had responsibility, that would be enough, but some people just don’t know the meaning of the word responsible and you see train wrecks happen all the time. There have already been methoxetamine hospitalizations from a few people who overdosed, and there was a suicidal girl who went to her mate’s flat, picked up a bag of unknown powder, and decided to kill herself with it, not knowing that it was methoxetamine. She wasn’t harmed, but it ended up in the papers. And you know, I’ve just recently seen in Sweden someone who intravenously injected methoxetamine and MDAI and died.
Wait, what was this?
Somebody in Sweden injected 100 mg of methoxetamine and 400 mg of MDAI.
And this person died?
Yeah, there were cardiac problems, and the person died. Just knowing that if it weren’t for my involvement, methoxetamine would have never reached the market. It leaves more than an awful taste in your mouth. You cannot help but feel like, “If I hadn’t opened my mouth in the first place, this never would have happened.” But people have contacted me to say thank you because methoxetamine helped them. I know some people have found relief from depression that nothing has ever touched before. Methoxetamine’s anti-depressant effect is immediate, and it lasts a bloody long time. It could banish an emotional blight on people’s lives, and it has a dose low enough that it should not harm the urinary bladder like ketamine. There is a big positive side to it, but when something negative like an overdose happens, you can’t help but feel like crap about the whole thing.
I asked the chemist David Nichols how he felt about the deaths and amputations related to 4-MTA and Bromo-Dragonfly and he said he was “deeply disturbed.”
You’ve got to be disturbed unless you have some psychotic trait in your personality. I just know I caused this: I am responsible for a human death. In a way, it’s the burden to bear for anyone who brings a drug to the market. I mean, think about thalidomide. It still gets used to treat leprosy, or Hansen’s disease I think it’s called now. I bet if the chemist Wilhelm Kunz is alive, he still has nightmares about all of the birth defects that occurred in the 60s no matter how much good it does for people with leprosy. Those are the things that feed nightmares.
You never know. The chemist Louis Fieser felt no guilt for the invention of napalm.
Yeah, but then again one percent of the population have psychotic personality disorders and they feel no empathy or guilt and they can do things like that. Just like I said with the postgrad research, killing the animals was too much for me to deal with.
You shouldn’t blame yourself; all technological innovations have the capacity to hurt people.
Well, it’s my good Catholic guilt. You can take the boy out of Catholicism but you can’t take the Catholicism out of the boy, and I just look for things to feel guilty about at times. You can take the boy out of 3-methoxylated-arylcyclohexylamines but you can’t take the 3-methoxylated-arylcyclohexylamines out of the boy, they say… Ay, let’s hope that’s not the case.