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Unexplored Dissociatives: The Dioxolanes (Etoxadrol, Dexoxadrol)

Nervewing

Bluelighter
Joined
Jan 5, 2016
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219
I would like to start a thread to generally discuss this fascinating class of compound and maybe hear firsthand from anyone who has had the opportunity to encounter these compounds. I would also like to simply raise awareness of them, for our collective conjecture and analysis with respect to their activity, nature, pharmacology, potency, character, and further expansions within the class. I know these have been mentioned in passing here before but I thought I would start a definitive thread to discuss a series of drugs that I think warrants extensive discussion!
Dioxolane%2B2.png

(Generalized structure of a Dioxolane dissociative. It should be noted that the Ethylamine chain has in most cases presented as a 2-piperidine, though secondary and primary amines may also be possible. The Ar represents a necessary aromatic ring, and the blue lines are other R groups)

For a short intro, the Dioxolanes are a class of drug based on the 2,3-Dioxolane ring. They have been demonstrated to be potent uncompetitive NMDA antagonists. Two compounds have been tested in humans, Etoxadrol and Dexoxadrol, which were tested as potential anesthetics in the 1970's. They were noted for a suite of side effects similar to PCP, including vivid hallucinations, depersonalization, and a triggering of "dream states". This paints a clear picture of an active dissociative hallucinogen, though development of the drugs stopped in the late 70's and they faded into obscurity, never making it to the recreational market.

Dexoxadrol.png


I believe there is a ton of potential in this class of drugs!
I recently posted a thread where I copy an article I wrote about the structure-activity relationships of developing drugs in the family. It is apparent that there is a ton of room for variation and substitution and there may potentially be some really exciting compounds hiding out there!

As with any of my SAR analyses, I accompanied this article with a flowchart to direct the design of these drugs.
Enlarged image of chart (right click>open image in new tab)
pdf download of chart

I also wrote this article which reviews the existing literature on these compounds and has some detailed description of the effects.

I have copied descriptions of the 2 Dioxolanes tested in humans, with firsthand accounts of the effects and presumptive doses from that article here:
Etoxadrol:
Etoxadrol.png

Etoxadrol is a very simple iteration of the basic Dioxolane dissociative structure, with the substitution position being occupied by a simple ethyl group.
This is the one Dioxolanes to carry the distinction of having human trials. It was investigated as a potential novel anesthetic in the early 1970's, in a similar development trajectory as better known dissociatives like ketamine and PCP. Indeed, initial trials in primates showed a very similar physiological profile to ketamine, with about double the potency and a greater duration3.

It was also initially tested on humans around the same time in a set of volunteers. Volunteers were found by word of mouth (Imagine you're at the university of Texas in 1970 and a friend asks if you want to volunteer for a medical study and you find yourself dosed with a brand new dissociative.... if only....)
A .75 mg/kg IV dose produced profound full anesthesia for an 1-1.5 hours. Open eyed hallucinations were not observed in post recovery, though subjects observed a "dream state" while anesthetized4.

"None of these dreams carried connotations of unhappiness to the individual; in fact, the majority were described as pleasant and/or unusual experiences. Consistent ideas of depersonalization, primarily of malinterpretations of self anatomical configurations, were a prominent symptom4"

Sounds familiar?
So this would likely mean Etoxadrol doses at about 30 mg intravenously for desired effects. It is unknown what other ROA's are active, though recreational doses of ketamine IV are around 50 mg, so it can be expected that Etoxadrol would likely also see a 1/2 drop in potency in other ROA's, yielding perhaps a 50-60 mg insufflated dose, if that ROA is safe and active. Oral doses would probably be higher than that.
One volunteer however, found the experience frightening, and a had a prolonged panic reaction.

So etoxadrol is definitely interesting- why have we never seen it?
Another human study elucidated some of the "side effects" of this drug. This study saw patients experience a lasting anesthetic afterglow which some complained about. Patients were difficult to communicate with, offering one word answers5.
Most importantly though, a whopping 20% of patients in this study reported "adverse or threatening dreams", a new and funny way to say "nightmare". These nightmares commonly featured memories from the patient's lives. I find it odd that their full sleep cycles were being tracked after the study, but a later statement elucidates what is really going on-

"Such mental aberrations frequently persisted up to 18 to 24 hours. However, they were voluntarily controlled by most of the patients and could be reinstituted if the patient closed his eyes."

I conjecture that this isn't a sleeping nightmare, but rather an awakened closed-eyed hallucinatory state, the sort that may be familiar to those who have delved deep into dissociatives. I believe that they simply didn't have the terminology to describe it or recognize it as such back then and simply labeled them as "dreams". It is interesting that the imagery invoked in this state however, had such vivid and coherent connection to the patient's memories. It certainly sounds like an interesting experience! (Except for one patient, "who had inadvertently been given 4.65 mg/kg) this effect lasted for 6 days." oops.)
Half of the patients reporting these "nightmares" also reported a psychotic state where they found their thoughts and actions difficult to control. All these symptoms considered, this sounds like a powerful dissociative similar that invokes vivid closed eyed hallucinations at high doses.

Etoxadrol isn't seen because studies were halted after this trial, citing concerns about the "nightmare" effects. It seems like a very similar side effect profile to PCP, which had gained widespread use before those effects had it struck from medical practice. By then it had built enough reputation to develop as a street drug. This likely wasn't seen in Etoxadrol because studies were cut off so early into its development, before it had any chance to develop a wider reputation (and this was probably informed by what had happened with PCP). All signs point to this being an interesting and relatively safe recreational substance.

Dexoxadrol:
Dexoxadrol.png

Dexoxadrol is the other well known Dioxalane dissociative. Dexoxadrol is the (+) enantiomer of the generalized molecule Dioxadrol, with the (-) enantiomer being called Levoxadrol. Levoxadrol has been demonstrated as being inactive however6.
Dexoxadrol is probably the most studied and best understood of the Dioxalanes, being thorouhgly studied in vitro and in animal trials, but still having little history of human testing. Thankfully the one human trial is remarkably detailed.

The earliest reports on Dexoxadrol describe it as a psychomimetic anesthetic, both a stimulant and depressant. These reports predate the term "dissociative anesthesia" and the connection between NMDA antagonism and dissociative effects. A 1965 study was the first and only human trials performed on the drug, with subjects being given a 20 mg oral dose. 5/74 subjects reported interesting side effects described as such:

"one complained of feeling “dopey, weak, and helpless”; one complained of light-headedness and numbness and was observed to weep; one complained of light-headedness, itching, of having “no feeling,” being “drunk,” and of “not being here.” Of the other 2 patients, one stated that she felt drunk, and said that she was “not entirely present.” She also said that her “hands had no real feeling” and seemed a bit numb. Four hours after the dose, all that remained was a slight light-headedness. The final patient was very upset, wept, and tried to get out of bed. She found it difficult or seemed unwilling to explain what was the matter. She said that her upper limbs seemed numb and as if they did not quite belong to her. There was no similar feeling in the lower limbs. She tried to bite her left arm several times as if to convince herself that it really belonged to her.7"

This all sounds like the constellation of typical effects from dissociative anesthetics, which frankly can be quite distressing in those not expecting them. The authors classified this drug as a psychotomimetic anesthetic for these reasons. This study also mentioned that when tested in animals, it increase their sensitivity to noxious stimuli.

All other studies were done in vitro or in animals. Dexoxadrol was found to elicit the same reaction as PCP in drug discrimination tests with monkeys6. Another study in monkeys studied the rate at which monkeys would self-administer the drug (in addition to Etoxadrol) to determine addictive potential- the reinforcement pattern between PCP, Etoxadrol and Cocaine was very similar, indicating that Etoxadrol triggered pleasurable effects in the monkeys and they sought more. They also repeated dosing of Dexoxadrol, though this was more erratic8. A study in rats noticed that Dexoxadrol increased body temperature9.

So here we see Dexoxadrol as perhaps less euphoric than Etoxadrol, though very similar to both (and PCP). Indeed the subjective effects described by patients for Dexoxadrol seem a tad more distressing, though this was also people with no frame of reference for such experiences in 1965. It seems that 20 mg was a low oral dose as it only triggered hallucinatory effects in a small proportion of subjects. An oral dose that users may find "recreational" would probably be in the range of 30-50 mg orally.
An (extremely) dubious vendor who lists Dexoxadrol on their site meanwhile (not linked), describes it as such:

"The side effects caused due to the medication of Dexoxadrol are quite unusual and dangerous. It causes hallucinations and nightmares in the users. It has been reported that Dexoxadrol creates unpleasant conditions before the users. The dreams that came after the usage of this medicine range from pleasant to frightening. In dreams, it seems as they are in some other world that has no relation to the reality. But in most users, the results are outstanding rather than insane."

That sums it up well it seems, and it would be very interesting to try.


Does the community at large think it would be worthwhile to explore these compounds further? Some testers mentioned dysphoria, and lacking the dopaminergic activity seen in arylcyclohexylamines, these may indeed be without inherent euphoria. The vividness of the effects stands out as fascinating to me however, and perhaps different pharmacodynamics or downstream effects can be brought about through variations in the design of these compounds. I would at least be extremely interested in trying them,
 
Thanks for posting this topic! I absolutely think these sound worthwhile to explore, I am always interested in new chemical families that result in psychedelic and/or dissociative drugs. The subjective effects notes for etoxadrol sound really interesting, a deeply dissociative peak for a ketamine-esque duration, followed by the genesis of a long-lasting closed-eye visual state that can be entered and exited at will? Fascinating stuff.
 
Would totally cobain for this. Even if Im quite into disso euphoria, I would for science and sharing the new pharmacocinetics with all you, dissoheads
 
Thanks for posting this topic! I absolutely think these sound worthwhile to explore, I am always interested in new chemical families that result in psychedelic and/or dissociative drugs. The subjective effects notes for etoxadrol sound really interesting, a deeply dissociative peak for a ketamine-esque duration, followed by the genesis of a long-lasting closed-eye visual state that can be entered and exited at will? Fascinating stuff.
Yesssss I honestly don't think they would have universal appeal.... and perhaps may not function as the hard recreational drugs that other dissos can be sometimes. It would probably be a niche thing for certain psychonauts seeking something interesting. But with the litany of odd psychedelics and dissos that have come out, there definitely is a market for such things! Maybe smaller than something that could be seen as a K or PCP substitute, but there definitely would be at least some people interested in trying these! (like me pick me I volunteer myself as guinea pig)
 
In spanish guinea pig=cobain. We call it cobaya. To do the "cobaya" is to bioassay some untested chemical in oneself... So I thought it would make sense in english too
 
Thanks for posting this! I, too, am always fascinated by the idea of exploring new classes of chemicals. Both drugs appeared in an article about PCP synthesis that was originally on rhodium.ws and was subsequently archived on Erowid. Somewhere I still have printouts of a couple of journal articles detailing the synthesis of these compounds. Might be very interesting to try, but probably not as recreational as arylcyclohexylamines, as others have already said.

I have always been a firm believer in the therapeutic potential of dissociatives when used properly and responsibly. Perhaps there is some hidden value in these two and derivatives thereof.

Again, thanks for another excellent thread. I always enjoy your threads and experience reports.
 
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