Obscure and Unknown: LAE-32

*WARNING* The substances mentioned in this series have little to no record of human use, and thus the effects they have on humans are either poorly understood or entirely unknown. Much of what this information is simply hypotheses based on animal trials or very small human sample sizes. Very little information exists about their acute or long-term toxicity. Under no circumstances should any of these substances be ingested by a human outside of a clinical setting where psychological and physiological effects can be closely monitored and extremely precise doses can be prepared and TITRATED. DO NOT seek any of these out if you do not have access to those resources.

For today's installment, we will be looking at an LSD analogue, one that is very close in structure to the original LSD. Now there's plenty of lysergamide analogues out there, what makes this one unique? Well for one, most information about this one comes from the infamous project MKUltra, the deeply unethical set of human experiments conducted by the CIA with hallucinogens to determine if they had any strategic value. This one showed some unique effects, but was relegated to the dustbin of history when it was determined it couldn't be used in relation to any nefarious purposes. Presenting- Lysergic Acid Ethylamide, or LAE-32 (also called Methergoline).

Looks vaguely familiar

So if you know your terminology, you'll know that the full English name of LSD is Lysergic acid Diethylamide (The abbreviation LSD comes from its German name). The Diethylamide refers to the Nitrogen (the "amide" portion of the name) at the top of the molecule, which in LSD has 2 "horns" attached, the 2 ethyl groups, hence "Diethyl". This one here is just called Lysergic Acid Ethylamide- meaning there is just one ethyl group on that nitrogen, as can be seen at the top of the molecule above. The empty space is replaced by a Hydrogen. 

The first reports on this drug came about during project MKUltra specifically in 1953. A quick rundown on Project MKultra for those who may not know (I did a presentation on this in high school I'm qualified)-
Project MKultra was the top secret program of human experiments conducted by the CIA from 1953-1977, and one of their many exceptionally cruel crimes against humanity. The projects revolved around conquering the human psyche as a front on the battlefield of the cold war during a time of peak "Red Scare" paranoia. Projects revolved around mind control, deprogramming, and interrogation techniques primarily through the use of drugs but also through other techniques including Hypnosis, Sensory deprivation and a wide variety of extreme torture methods like electrical shock and sexual abuse. The potential of these substances as chemical weapons was also explored. 
The dominant impetus for these experiments was the advent of a new substance in psychiatric circles- LSD. LSD and the psychedelic state were at this point was still very poorly understood and many of its effects and consequences were very mysterious. the CIA saw a lot of potential for psychological control.
Experiments were conducted as unethically as possible, among volunteers, but also among prisoners, mental patients, military personnel and government employees, suspected communist sympathizers, and many others without their knowledge or consent. Some experiments consisted simply of torturing people while they were under the influence of psychedelics. Many subjects died or were permanently traumatized or debilitated as a result.
When the CIA realized it could not wrangle LSD to serve its ends, and that those filthy counterculture commies had taken a liking to it, it was made illegal and its prohibition hindered psychedelic research for decades. This serves as one of the darkest chapters in the history of psychoactive research. 

That aside,

LAE-32 is a footnote in the original documents established on the project. It's a fairly simple analogue that was briefly considered for tests alongside LSD. It generated enough interest for a handful of studies, then was mostly forgotten.

The first mention is in declassified project MKUltra documents1. The documents cite a [REDACTED] report in which experiments were carried out on "28 normal persons and some psychotics." Doses of 500-700 μg were administered intravenously. The "normal persons" supposedly entered a schizophrenia-like condition, appearing weak, indifferent, emotionally flat and depersonalized. More interesting however, was that in schizophrenic subjects, it appeared to bring some amount of relief- subjects had become indifferent to their delusions and hallucinations. One researcher noted similarities to prefrontal lobotomies, and diabolically labeled the drug as a "chemical lobotomy". The document then goes on to note "It is possible to think that LAE might have an antagonistic, if not to say an antidotic effect upon L.S.D".

Further testing was done in 1955, which was reported in later documents2. The primary focus of these tests were to explore its potential as an LSD-inhibiting agent. 500 μg of either placebo or LAE was administered, followed by either a placebo or 60 μg of LSD. The presence of LAE had minimal effect on the strength of the LSD, and 500 μg of LAE on its own was noted to give mild LSD-like effects.

The next round of tests were carried out on 12 African American Patients (It's troubling and not at all surprising that they explicitly mention this) and in CIA fashion were of a cruel nature. They were done at the behest of physician Harold Abramson. Patients were kept on a steady LAE experience for the span of a week with repeated and increasing redosing before a dose of LSD was given to observe the effect of building a tolerance. At the end of the week, subjects were being dosed with 1000 μg of LAE.

The author flippantly states "We have the impression that thee were as unpleasant as the effects of LSD-25 given by one of the schedules we have used to develop tolerance in the past". A tolerance had indeed developed, suggesting that they had very similar receptor profile. The study was abandoned after this.

It was also tested on rats, where it was found to inhibit physiological effects of LSD, in a "selective blockade"3. It meanwhile showed very similar, though slightly different effects to LSD in fish4. Another study determined LAE-32 had very similar effects to LSD on handwriting5. Another study using a survey to characterize each drug found LAE-32 to be an all around milder and less distinct experience than LSD, with similar physiological effects but less in the way of sensory or cognitive effects6. This study also noted a shorter duration, with about a 1 hour peak (vs. 3 hours for LSD).

So what does all this dense data mean? It points to LAE-32 as a milder lysergamide that doses much higher than LSD, with effective doses in the range of 500-1000 μg. Effects of the drug on its own seem be similar to character as LSD, but milder and shallower. In rats, it seemed to have an inhibiting effect on the physiological effects of LSD, though this was not observed when both drugs were administered in humans. The duration of the substance was noted at about 1/3 the duration of LSD.

So we're left with an lysergamide with a uniquely short duration. It seems to carry a similar essence to LSD and other lysergamides without the edge. It also doses much higher, up to 1 mg. This could potentially be useful as a potentially foolproof "beginner's psychedelic", for safely introducing new people to the psychedelic experience without risking negative effects as much. The "selective blockade" activity observed in rats makes me wonder if it could perhaps inhibit some of the negative physiological effects induced by LSD. No human studies specifically observing physiological effects from a combination of the two have been done.

Sources and Further Reading:
1-The Black Vault- "MKULTRA 1", DOC_0000017481, 0000017481_0021-0000017481_0022
2-The Black Vault- "MKULTRA 2", DOC_0000151534, 0000151534_0002
3-Strocchi P, Walsh M, Agnati LF (1977) The inhibitory effect of methergoline on LAE-32-induced head-twitches in mice. Neuroscience Letters, 4(3–4): 221-224
4-Evans LT, Geronimus LH, Kornetsky C, Abramson HA (1956) Effect of ergot drugs on Betta splendens. Science 123(1384):26
5-Hirsch MW, Jarvik ME, Abransom HA (1955) Lysergic Acid Diethylamide (LSD-25): XVIII. Effects of LSD-25 and Six Related Drugs upon Handwriting. The Journal of Psychology Interdisciplinary and Applied 41(1):11-22
6-Jarvik ME, Abramson HA, Hirsch MW (1955) Comparative subjective effects of seven drugs including lysergic acid diethylamide (LSD-25). J Abnorm Psychol 51(3):657-62