The Hive > Novel Discourse
azole:
As requested by Ganesha
(Post 492720 (not existing)):
Nature, 201, 1120-1 (1964).
3-Methoxy-4 5-methylenedioxy Amphetamine,
a New Psychotomimetic Agent
The establishment of trimethoxyamphetamine (Ib, TMA)
as being of greater psychotropic potency than either ?-ethyl mescaline (Ic) (ref. 1) or mescaline itself (Ia) (ref. 2) has led to the examination of analogues which retain the three carbon chain but vary in other areas of the molecule. The presence of elemicin (3,4,5-trimethoxy allylbenzene) in the aromatic ether fraction of oil of nutmeg3, and the proposal of a possible in vivo mechanism of its conversion to TMA (ref. 4) have afforded an explanation of the psychotropic action5 of nutmeg. The substance myristicin (II) is the major component of this fraction, and if it were to undergo the transformation parallel to that proposed for elemicin, a second amphetamine, 3-methoxy-4 5-methylenedioxy amphetamine (MMDA, IVa), would result.
This latter amphetamine has been synthesized from myristicin in vitro, by a three-step process. trans-Isomyristicin, obtained from myristicin by heating in alcoholic potassium hydroxide, is converted by means of tetranitromethane to ?-nitro isomyristicin. Reduction of this nitropropene with LiAlH4 led smoothly to MMDA, which was isolated as the hydrochloride. Examination of MMDA in mice and dogs displayed a behavioural and toxicological pattern similar to that of TMA, both quantitatively and qualitatively. Preliminary human evaluation revealed initial intoxication at about 1.0 mg/kg (as free base). More extensive assay has confirmed a thoroughly effective hypnogogic dementia at less than 2.0 mg/kg. The psychotomimetic syndrome was complete at this level: increased dosages (to 3.2 mg/kg) merely prolonged the duration of the episode. Thus the potency of MMDA is somewhat greater than TMA and nearly three times greater than mescaline.
Substitution of either an ethylenedioxy or a trimethylenedioxy group for the methylenedioxy moiety (compounds IVb and IVc) resulted in a marked decrease in psychotropic effectiveness. These amphetamines were prepared from the aldehydes IIIb and IIIc by condensation with nitroethane followed by reaction with LiAlH4. A prohibitively small yield of the ethylidine analogue IIId precluded further synthetic efforts.
As with TMA, the effects of MMDA are hallucinogenic and permit complete recall. They will be reported shortly, in full, with appropriate synthetic detail.
Alexander T. Shulgin
Dow Chemical Co.,
Western Division,
Walnut Creek, California.
1Shulgin A. T., Experientia, 19, 127 (1963).
2Peretz, D. I., Smythies, J. R., and Gibson, W. C., J. Mental Sci., 101, 317 (1955). Shulgin, A. T., Bunnell, S., and Sargent, T., Nature, 189, 1011 (1961).
3Shulgin, A. T., Nature, 197, 379 (1963).
4Shulgin, A. T., Mind, 1, 299 (1963).
5Weiss, G., Psychiat. Quart., 34, 346 (1960). Truitt, jun., E. B., Calloway, E., Braude, M. C., and Krantz, jun., J. C., J. Neuropsychiat., 2, 205 (1961).
Rhodium:
Psychotropic Phenylisopropylamines derived from Apiole and Dillapiole
Alexander T. Shulgin
Nature 215, 1494-95 (1967) (https://www.thevespiary.org/rhodium/Rhodium/chemistry/dmmda.shulgin.html)
____ ___ __ _
Structure-Activity Relationships of One-Ring Psychotomimetics
Alexander T. Shulgin, Thornton Sargent, Claudio Naranjo
Nature 221, 537-541 (1969) (https://www.thevespiary.org/rhodium/Rhodium/djvu/shulgins.djvu)
Abstract
Human dose-response relationships for psychotomimetic phenethylamines:
An isopropylamine side chain and triple methoxy substitution provide optimum activity.
Available data suggest possible structures for the hypothetical psychotogen of schizophrenia.
azole:
As requested by Ganesha:
Nature, 189, 1011-1012 (1961) (also cited in
Post 307150 (moo: "Ok, let's quote Alexander Shulgin et al.", Novel Discourse)).
The Psychotomimetic Properties of
3,4,5-Trimethoxyamphetamine
dl-3,4,5-Trimethoxyamphetamine (dl-TMA), first prepared as a homologue of mescaline in 1947 1, has remained to a large measure unexplored. A single paper has described its effects in human subjects2, demonstrating that the drug allows stroboscope-induced hallucinations at the levels employed, namely, 0.8-2.0 mgm./kgm., orally. In the present work, dl-3,4,5-trimethoxyamphetamine was synthesized by the general method of Ramirez and Burger3 and was chemically identical to that previously described1. Pharmacological similarity was demonstrated by the administration of between 1.6 and 2.0 mgm./kgm. as the hydrochloride, to three adult male subjects. The responses were found to be parallel in intensity and duration to those described earlier2, although the vivid hallucinations reported were not observed.
It has been found, however, that with an increased dosage of the drug, the psychotropic response changed in a most dramatic manner. Dosages of 2.8-3.5 mgm./kgm. were given to five adult male subjects, all of whom had had previous experience with either mescaline or lysergic acid diethylamide.
The physical changes observed were similar for all subjects employed. In each case, after about half an hour, there ensued a period of autonomic distress, characterized by sweating, tremor, and chills as well as nausea and dizziness. This phase lasted no more than an hour. The slight but definite systolic blood pressure increase of about 10 mm. mercury returned to normal at the end of this phase. The concurrent diastolic increase was barely perceptible (c. 2 mm. mercury). During the remainder of each experiment (approximately another 6-8 hr., which includes the period of extreme mental derangement described below) very few overt physical signs of drug effect were evident. Pupillary dilatation and slight motor inco-ordination were noted. Pulse increase was negligible.
The psychic changes observed, however, were extreme and showed considerable individual variability. The initial effects, at about 2 hr. from the ingestion of the drug, were mescaline-like, involving intensification of visual experience, including amplification and distortion of colour, texture, form, and spatial relationships. These effects were distinctly less than those expected from a pharmacologically equivalent dose (2×) of mescaline. Auditory and tactile sensations were also intensified, and both paræsthesia and synæsthesia were noted on occasion. None of the subjects displayed the enhanced capacity for empathy characteristic of mescaline.
The emotional responses elicited during the period of maximum dl-3,4,5-trimethoxyamphetamine intoxication (3-5 hr. from the start of the experiment) were striking in their intensity. Anger, hostility, and megalomaniac euphoria dominated the subject's thoughts and conversation. Actual acts of hostility were not observed, but it was felt that, in at least two subjects, provocation would have precipitated homicidal violence. All subjects reported imagery, either patterned or scenic, with eyes closed. Recollection of past experiences did not seem to be enhanced, and intellectual performance appeared to be somewhat impaired. Once the plateau of intoxication had passed, return to normal was rapid. The subjects experienced no clouding of consciousness, and subsequent recall of events was excellent.
Due to unexpectedly anti-social character of the response to larger doses of the drug (a response unobserved in more than 40 mescaline subjects), a warning concerning adequate supervision during experimentation with this new drug seems desirable.
Investigations employing the optical isomers, as well as structural homologues, of dl-3,4,5-trimethoxyamphetamine are in progress.
Alexander T. Shulgin
Sterling Bunnell
Thornton Sargent III
Research Department,
The Dow Chemical Company,
P.O. Box 351,
Pittsburg, California.
1 Hey, P., Quart. J. Pharm. Pharmacol., 20, 129 (1947).
2 Peretz, D. I., Smythies, J. R., and Gibson, W. C., J. Mental Sci., 101, 317 (1955).
3 Ramirez, F. A., and Burger, A., J. Amer. Chem. Soc., 72, 2782 (1950).
Ganesha:
Ethyl homologs of 2,4,5-trimethoxyphenylisopropylamine
Alexander T. Shulgin;
J. Med. Chem.; 1968; 11(1); 186-187
Of the six possible 1-(trimethoxyphenyl)-2-aminopropanes (trimethoxyamphetamines) TMA-2 was most potent and it serves in this present report as the reason for the synthesis of the seven possible ethyl homologs.
Thanks to azole for pointing out the correct journal...
Ganesha:
Ethyl homolog of MMDA-2
2-ethoxy-4,5-methylenedioxyamphetamine has also been prepared and evaluated in man. This information is taken directly from Pihkal, page 795:
The allyl ether of sesamol (3,4-methylenedioxy-allyloxybenzene) was rearranged to the 2-allyl phenol which was, in turn, converted to the ethyl ether. Reaction with tetranitromethane gave the nitrostyrene intermediate which had a mp of 120-121 °C. The final hydrochloride salt of EMDA-2 had a mp of 188-188.5 °C. At 135 milligrams, there have been reported eyes-closed visual phenomena, with intense colors. The overall duration is similar to MMDA-2 (some 10 hours) and there are reported sleep disturbances. At 185 milligrams, the feelings were intensified, there were "marvelous eyes-closed visuals (the colors were incredible), good concentration, but distinct body-tingles and rushes." The time span was about 12 hours from start to finish, but it proved to be impossible to sleep afterwards. This homologue is thus about a third the potency of MMDA-2.
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