Phenethylamines I have feared and loathed

July 3, 2020

Phenethylamines I have feared and loathed

In the course of a burgeoning interest in psychedelic medicine, one comes across two broad categories of similarly interested characters. You will find that some are neurotically obsessed with rigor and refuse to even discuss what these things do on a subjective level while others will insist you sit down and listen to their story of aligning a colleague’s moon chakra using an herbal intoxicant. While the two sides seem to disagree on pretty much everything, there does seem to be a common distaste for anything that’s not a ‘typical’ psychedelic like psilocybin or ayahuasca. Wait, no, you can’t move that hydroxy group from the 4 to the 5 position! Once the conversation drifts in that direction, they seem to conjure up images of underground drug labs in Ohio run by people named ‘toad pRofit$’ being raided by the DEA. On a cultural level, we’ve decided that if a therapy is run with a shaman using a completely chemically-uninterpretable drug cocktail: totally a-okay. But if it’s run with a synthetic pure compound of known quantity: immediate banishment. It’s silly of course in the sense that in either case there are centrally active compounds with particular affinities and whether yours comes from a three step synthesis or from a plant is really irrelevant to your brain’s serotonin receptors.

That said, I thought it might be fun to talk about the compounds that didn’t quite make it into PIHKAL, or which made it in with a substantial disclaimer. As in, phenethylamines that are both centrally active and unlikely to make it into a clinical trial anytime soon. There are a few genuine reasons for discussing negative valence compounds and they have nothing to do with filling up space. Firstly, getting a better grasp on what doesn’t work and why may give us some clues on how to design better compounds. Given how concentrated the activity seems to be at a few critical ring positions and what a wide variance of effects is hence generated, this may give us some design clues from a therapeutics perspective.

Secondly, phenethylamines in particular are a source of endless fascination because of the interplay of the amphetamine-like TAAR1/D1-agonist effects and the tryptamine-like 5-HT2A-agonist effects. This can be both beneficial, reducing the potential for negative valence during a clinical infusion and also a recipe for disaster if the pharmacodynamics and dosage of the compound are less-than-ideal.

It is also the case that due to these non-specific effects, phenethylamines seem to have a generally less ideal safety profile compared to lysergamides or tryptamines. One notorious nasty side effect is vasoconstriction. Another is serotonin syndrome when the compound has both serotonin transporter activity and is a MAOI. Occasional deaths have been attributed to compounds of this class, though the culprits mostly seem to be general mishandling, inaccurate dosing, mislabeling, or haphazard co-administration. Nevertheless, these and other reasons make me suspect that even ‘safer’ phenethylamines like 2C-B won’t be getting FDA approval anytime soon.

2C-P

2C-P combines the traditional di-methoxylated phenethylamine with a propyl-substitution at the 4 position. The 4 position is the critical R-group for 2C compounds, sort of akin to the 4 and 5 on the indole benzene ring for tryptamines. Substitutions at the 4 tend to change the subjective effects and duration of the drug considerably. With the case of 2C-P it produces a compound with very high potency (6-10 mg dosage range) and quite long periods of activity, up to 20 hours. Yes, 20 hours! Not to mention that peak effects don’t take place for 3-5 hours after oral consumption. The subjective effects themselves tend to vary in terms of valence with some reports of notable physical discomfort. As a potential treatment though, the long activity time and onset time is unlikely to work in its favor.

2C-G

2C-G is another phenethylamine with a somewhat lower potency than 2C-P balanced by an even longer effect time (18-30 hrs!). I was considering not including this on the list primarily because the subjective effects are largely subdued, having no strong visual or tactile components. 2C-G is classified as more of a ‘insight enhancer’ by Shulgin and is probably best suited for a role in psychotherapy. The extremely long effect time seems to cast doubt over that possibility. As with the other phenethylamines, the toxicity and pharmacology of 2C-G is poorly worked out or non-existent altogether.

Bromo-DragonFLY

Somewhere near the top of the list of unfortunate creations to come out of David Nichols’s lab is this monstrosity with two furans fused onto a 2C-B structural variant. Firstly the pharmacology of Bromo-DragonFLY tells us that it is a non-subtype specific 5-HT2 agonist. It’s also a MAO-A inhibitor, which strongly inhibits oxidative deamination of 5-HT, thereby increasing its...