Obscure and Unknown: Dioxolane dissociatives

*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 entry of obscure and unknown we will be looking at an entire family of well established hallucinatory dissociatives, once tested for their potential for anesthesia. These drugs are well documented for their hallucinatory effects, though they were all aborted early in their development and only appeared in receptor assays after limited human trials were abandoned. Their fate was sealed for their propensity to give patients "nightmares", a term that was misused when in actuality, subjects experienced vivid closed-eyed hallucinatory episodes. Drawn out anesthesia and rare psychotic effects also spelled death for these compounds, as this was probably reminiscent of the trials and tribulations of testing PCP as an anesthetic. These are the Dioxolanes, namely Etoxadrol, Dexoxadrol, WMS-2539, and WMS-2508. 

The generalized structure of a Dioxolane dissociative

The Dioxolane name refers to the basis of these structures, the Dioxolane molecule, a 5-member ring with 3 Carbons and 2 Oxygens on the 1 and 3 positions (In the diagram above its the ring in the center that looks like it has a little ovo face goin on. Kinda looks like the face of a little bug or somethin). It is worth noting that Dioxolane refers to a much broader chemical family derived from this simple molecule and the vast vast majority of Dioxolanes are not psychoactive. The four known to be dissociatives have a common structure, with a piperidine on the 2 position of the Dioxolane ring and a phenyl ring attached to the 5 position. They vary in having another group attached to the 5 position, and two have a substitution on the piperidine ring. It is unknown if the Dioxolane group retains its dissociative effects with other substitutions at either the 2 or 5 position, or if the entire Piperidine-Dioxolane-Phenyl structure must be retained to conserve those effects.
As of now the pharmacophore (active constituent) of NMDA antagonists is not fully understood, though several structural activity relation studies have attempted to determine where Dioxolanes fit into this picture1,2.

So just what are these substances like? Let's delve into their variations, starting with the most well studied Dioxolane in humans, Etoxadrol.

Etoxadrol

Etoxadrol

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."

So 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

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.

WMS-2539

WMS-2539 was a result of several studies to develop analogues of dexoxadrol. This one is distinguished by having a fluorine on the 4 position of the piperidine ring. This substance has never been tested in humans or animals, but receptor assays have demonstrated that it is at least very potent, with it's potency lying about halfway between MK-801 and Dexoxadrol10. So if you consider a dose of MK-801 ~ 500 ug, then a dose of WMS-2539 may be in the range of 10-15 mg. Though I am not the best at math.

WMS-2508

WMS-2508 is another analogue that was determined to be a powerful NMDA antagonist, with an OH group substituted onto the 4 position Piperidine. This had a Ki value of 44 nm, which was within an active range relative to the compound it was being compared to, MK-801. I cannot speculate on a possible dosage for this one, but the authors found it highly promising and supposedly quite potent11.

Sources and Further Reading:
1-Sax M, Wünsch B (2006) Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity. Curr Top Med Chem. 6(7):723‐732
2-Thurkauf A, Mattson MV, Richardson S, Mirsadeghi S, Ornstein PL, Harrison Jr. EA, Rice KC, Jacobson AE, Monn JA (1992) Analogues of the dioxolanes dexoxadrol and etoxadrol as potential phencyclidine-like agents. Synthesis and structure-activity relationships. J Med Chem 35(8):1323‐1329.
3-Hidalgo J, Dileo RM, Rikimaru MT, Guzman RJ, Thompson CR (1971) Etoxadrol (CL-1848C) a new dissociative anesthetic: studies in primates and other species. Anesth Analg. 50(2):231‐239.
4-Wilson RD, Traber DL, Barratt E, Creson DL, Schmitt RC, Allen CR (1970) Evaluation of CL-1848C: a new dissociative anesthetic in normal human volunteers. Anesth Analg. 49(2):236‐241.
5-Frederickson EL, Longnecker DE, Allen GW. (1976) Clinical investigation of a new intravenous anesthetic--etoxadrol hydrochloride (CL-1848; U-37862A). Anesth Analg. 55(3):335‐339
6-Jacobson AE, Harrison EA, Mattson MV, Rafferty MF, Rice KC, Woods JH, Winger G, Solomon RE, Lessor RA, Silverton JV (1987) Enantiomeric and diastereomeric dioxadrols: behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties. Journal of Pharmacology and Experimental Therapeutics 243(1):110-117
7-Lasagna L, Pearson JW (1965) Analgesic and Psychotomimetic properties of Dexoxadrol. Proc Soc Exp Biol Med. 118:352‐354.
8-Brady KT, Woolverton WL, Balster RL (1981) Discriminative Stimulus and Reinforcing Properties of EtoxadroLand Dexoxadrol in Monkeys. Journal of Pharmacology and Experimental Therapeutics 220(1):56-62
9-Pechnick RN, Wong CA, George R, Thurkauf A, Jacobson AE, Rice KC (1989) Comparison of the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Neuropharmacology 28(8):829‐835
10-Banerjee A, Schepmann D, Köhler J, Würthwein E-U, Wünsch B, (2010) Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists. Bioorganic & Medicinal Chemistry 18(22):7855-7867
11-Banerjee A, Fröhlich R, Schepmanna D, Wünsch B (2010) Synthesis and NMDA receptor affinity of dexoxadrol analogues with modifications in position 4 of the piperidine ring. Med. Chem. Commun. 1:87-102