Author Topic: Shulgin, Nature, 201, 1120 (1964)  (Read 61914 times)

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Shulgin, Nature, 201, 1120 (1964)
« on: March 04, 2004, 04:07:00 AM »
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).


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Other Shulgin papers from the sixties
« Reply #1 on: March 04, 2004, 05:56:00 PM »
Psychotropic Phenylisopropylamines derived from Apiole and Dillapiole
Alexander T. Shulgin

Nature 215, 1494-95 (1967)

____ ___ __ _

Structure-Activity Relationships of One-Ring Psychotomimetics
Alexander T. Shulgin, Thornton Sargent, Claudio Naranjo

Nature 221, 537-541 (1969)


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.


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Shulgin, Nature, 189, 1011-2 (1961)
« Reply #2 on: March 05, 2004, 05:13:00 AM »
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

   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).


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ethyl homologs of
« Reply #3 on: March 05, 2004, 02:30:00 PM »
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...


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Noteworthy on "tweetio" of MMDA-2
« Reply #4 on: March 05, 2004, 05:30:00 PM »
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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Just another Shulgin's paper
« Reply #5 on: March 13, 2004, 08:29:00 AM »
Possible implication of myristicin as a psychotropic substance
Alexander T. Shulgin
Nature 210, 380-284 (1966).

comment: A lot of info on myristicin and similar compounds as well as some hypotheses on the biotransformation and theoretical modes of its psychotropic action. Off course, most hypotheses were later found erroneous but it is still a good read for non-chemists also.


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Shulgin on N-Alkylated MDA Analogs
« Reply #6 on: March 15, 2004, 08:38:00 AM »
Centrally Active N-Substituted Analogs of 3,4-Methylenedioxyphenylisopropylamine (3,4-Methylenedioxyamphetamine)
Ulrich Braun, Alexander T. Shulgin and Gisela Braun

J. Pharm. Sci. 69(2), 192-195 (1980)


The known central nervous system activity of 3,4-methylenedioxyphenylisopropylamine and its N-methyl homolog prompted the synthesis of a series of analogs with substituents on the nitrogen atom. Most of these analogs (R = alkyl, alkenyl, hydroxy, alkoxy, and alkoxyalkyl) were prepared by the reductive alkylation of 3,4-methylenedioxyphenylacetone with the appropriate amine and sodium cyanoborohydride. Hindered isomers were synthesized indirectly. Measurements of their pharmacological activity in several animal assays and in human subjects indicated that the central activity decreased with the increased bulk of the N-substituent.

This article has been mentioned before in the following posts:

Post 54080

(Sonson: "High-yielding synthesis of MDA from MDP2P", Methods Discourse)

Post 351891

(bbell: "synthesis xtc", Methods Discourse)


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Old Shulgin QSAR article
« Reply #7 on: April 02, 2004, 06:34:00 AM »
Molecular Connectivity Analysis of Hallucinogenic Mescaline Analogs
R. A. Glennon, L. B. Kier, and A. T. Shulgin

Journal of Pharmaceutical Sciences, Vol. 68, No. 7, 906-907 (1979)


The hallucinogenic (psychotomimetic) potency of 10 mescaline analogs was examined by molecular connectivity analysis. Potencies could be described by a two-term relating equation. which explained 94% of the variance in activity. on the basis of structural variation. 2,5-Dimethoxy substitution as well as the nature of the 4-position substituent played an important role in determining hallucinogenic potency. With the relating equation, reasonable potency predictions were made for six compounds not included in the initial investigation.


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Glennon on SAR and new 5-HT2A ligands
« Reply #8 on: April 30, 2004, 06:59:00 PM »
Application of Ligand SAR, Receptor Modeling and Receptor Mutagenesis to the Discovery and Development of a New class of 5-HT2A Ligands
R.B. Westkaemper, R.A. Glennon
Curr. Top. Med. Chem., 2002, 2(6), 575-598
No DOI found

The present review describes our approach to the development of a structurally unique class of 5- HT2A ligands. On the basis of an abbreviated graphics model of a 5-HT2A serotonin receptor, it was hypothesized that introduction of an additional aromatic ring might enhance the affinity of phenylethylamine (an agent that lacks significant affinity for the 5-HT2A receptors). Continued work with such structures, and the continual refinement of graphics receptor models, ultimately led to the identification of AMDA (27, 5-HT2A Ki = 20 nM). AMDA is a 5-HT2A antagonist that, unlike certain other tricyclic 5-HT2A antagonists, binds with very low affinity at dopamine D2 receptors, the serotonin transporter, and the norepinephrine transporter. Comparative structure-affinity studies indicate that AMDA binds in a manner distinct from the tricyclic antagonists Graphics models were employed to identify possible modes of binding. This investigation illustrates the impact of a combination of classical medicinal chemistry, receptor modeling, and molecular biology on novel drug design.

This is a must read for every bee interested in the molecular action of hallucinogens. This article provides an insight in the structural differences between agonists and antagonists at the 5-HT2A rececptor.
Lego really enjoyed this article!


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nice find Lego!
« Reply #9 on: May 02, 2004, 01:26:00 PM »
Great review. I'm a bit sceptical about AMDA. This promising affinity dosen't meen that there is magic to be found in AMDA type of componds. For instance, 4-(n)hexyl-2,5-dimethoxy-AMPH has 16,4 times more 5-HT2A affinity than DOB, but considering the character of DOAM, the 4-(n)hexyl would most likely be pretty uninteresting. Let's hope AMDA will show interesting activity...


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Human Psychopharmacology of MMDA
« Reply #10 on: May 06, 2004, 02:22:00 PM »
Animal Pharmacology and Human Psychopharmacology of 3-Methoxy-4,5-Methylenedioxyphenylisopropylamine (MMDA)
A.T. Shulgin, T. Sargent and C. Naranjo

Pharmacology 10, 12-18 (1973)


A rationale is presented for the investigation of the synthesis and pharmacology of 3-methoxy-4,5-methylenedioxyphenylisopropylamine (MMDA) as a potential psychodysleptic compound; these experiments are reported. The chemical synthesis and physical properties of this compound are described. The pharmacologic effects of MMDA in several animal species are presented, as are its clinical effects in man. The animal pharmacology was generally unremarkable, except for a hypotensive effect in the dog, and the therapeutic index (LD50 rat/MED50 human) was 85. The subjective effects of MMDA in man include an enhancement of feeling and of eyes-closed visual imagery, but no hallucinogenesis or other disturbance of the sensorium. Reality testing and environmental contact are not affected except for a tendency to withdraw into a state of drowsiness, or into a world of fantasy and visual imagery. The induced state of increased availability of emotion was easily manipulated in the psychotherapeutic setting used, and appeared to lead to an enhanced insight into subconscious content.


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The ambigous term "piperonylacetone"
« Reply #11 on: May 06, 2004, 04:09:00 PM »
Potential Misrepresentation of 3,4-Methylenedioxyamphetamine (MDA). A Toxicological Warning.
Alexander T. Shulgin & Peyton Jacob III

Journal of Analytical Toxicology, Vol 6, 71-75 (1982)


The illicit synthesis of the popular drug 3,4-methylenedioxyamphetamine (MDA) has frequently called upon the precursor piperonylacetone, which is reductively aminated with ammonium hydroxide. The term "piperonylacetone" has been used for two distinct chemical entities in the chemical literature, viz. 3,4-methylenedioxyphenylacetone or 3,4-methylenedioxybenzylacetone. It is only the first of these two chemicals which will give rise to MDA. The second chemical has been made commercially available as piperonylacetone and, employing the usual recipes, produces 1-(3,4-methylenedioxyphenyl)-3-aminobutane. This amine could be mistaken for MDA if only simple presumptive tests are employed. This latter base is largely unexplored pharmacologically and toxicologically and, as it may reasonably appear in illicit drug traffic misrepresented as MDA, it may well represent a clinical problem of unforseeable consequences.


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nice article
« Reply #12 on: May 10, 2004, 03:07:00 AM »

after having experienced different dosages with different people,
a foaf acknowledges all points in this article except point #6:
no subject has ever expressed anxiety at all. on the contrary, they
all found themself in a wonderful bodyspace. the probable explanation
is that the subjects in the article were in a psychotherapy setting.
the visions are everyday things, but there is no apparent meaning -
no problems force themselves into the foreground, although one certainly
could if one wanted. this makes the drug very special in that there is
no push. it's like letting one's subconsciousness be on the loose.

other observations:
* on high dosages (400+, in two doses) there are definite OEVs. the
kind of where there's no relation between what is seen and what is there
and which take quite some focussing effort to see what's really there.
* even on high dosages there is practically no body load
* excess alcohol intake has a bad effect on the visions. what used to be
visions turn into dreams not unlike nodding off from opiates.

all in all: a pretty unique drug. but probably nothing for the
"fuck my mind harder"-crowd.


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More early Shulgin articles
« Reply #13 on: May 28, 2004, 09:00:00 AM »
Psychotomimetic Agents Related to Mescaline
Alexander T. Shulgin

Experientia 19, 127-128 (1963)

____ ___ __ _

Psychotomimetic Amphetamines: Methoxy 3,4-Dialkoxyamphetamines
Alexander T. Shulgin

Experientia 20, 366-667 (1964)


(kudos to lugh for retrieving copies of these)


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MDA Analogs as Analgesics (in German)
« Reply #14 on: June 21, 2004, 02:15:00 AM »
Study of the Central Nervous Activity and Analgesia of the N-Substituted Analogs of the Amphetamine Derivative 3,4-Methylenedioxyphenylisopropylamine
Braun, U., Shulgin, A. T., and Braun. G.

Arzneimittel Forschung/Drug Research, Vol. 30(1), No. 5, 825-830 (1980)


N-Substituted analogs of 3,4-methylenedioxyphenylisopropylamine (MDA) were tested for analgesic potency and influence on motor activity in mice following oral administration. These compounds also were tested for their psychotomimetic potency in man. Unsubstituted MDA and its monoalkyl homologs with a low number of C-atoms (N-methyl-, N-ethyl-MDA) showed both enhancement of motor-activity in mice and psychotomimetic effects in man. MDA and N-methyl-MDA also showed an analgesic effect which was enhanced by the inclusion of a weakly basic group (N-allyl, N-hydroxyethyl). These latter two compounds, however, did not influence motor-activity, which makes them more recommendable as possible analgesic compounds. Structural parallels between these compounds, morphine, endorphins and enkephalins, may explain their similar spectrum of pharmacological effects.

(Kudos to 'legal' for fetching the article!)


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Stereospecific Requirements for Hallucinogenesis
« Reply #15 on: September 10, 2004, 09:49:00 AM »


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Monomethylthio analogs of TMA-2
« Reply #16 on: September 30, 2004, 06:47:00 AM »
Monomethylthio analogs of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane
Peyton Jacob, , III George Anderson, , III Charles K. Meshul, Alexander T. Shulgin, Neal Castagnoli

J. Med. Chem. 20, 1235-1239 (1977)


Regiospecific syntheses of the three monomethylthio analogues of 1-(2,4,5-trimethoxypheny1)-2-aminopropane are described. The three isomeric amines were evaluated for potential psychotomimetic potency using the rabbit hyperthermia assay. Enantiomeric compositions and time-concentration curves in rat brains were determined following intraperitoneal administration of each compound. The biological data are contrasted with the corresponding results obtained with the potent human psychotogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM).


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Three Shulgin Articles
« Reply #17 on: November 11, 2004, 06:06:00 AM »
Centrally Active Phenethylamines
Alexander T. Shulgin & Michael F. Carter

Psychopharm. Commun. 1(1), 93-98 (1975)


The two-carbon homologs of two potent psychotomimetic agents are described. Unlike the parent isopropylamine compounds (4-methyl-2,5-dimethoxyamphetamine, DOM, STP; and 4-bromo-2,5-dimethoxyamphetamine, PBR, 4-BR) these phenethylamines lead to an intoxication state which is, normal subjects, of short duration and of greatly increased sensory enhancement, but which does not superimpose hallucinogenesis. These two phenethylamines, 4-methyl-2,5-dimethoxyphenethylamine (II) and 4-bromo- 2,5-dimethoxyphenethylamine (III), are active in man at oral levels of 0.1 to 0.2 mg/Kg, approximately one-tenth the potency of their three-carbon counterparts.
____ ___ __ _

A Protocol for the Evaluation of New Psychoactive Drugs in Man
Alexander T. Shulgin, L. Ann Shulgin and Peyton JacobIII

Meth. and Find. Exptl. Clin. Pharmacol. 8(5), 313-320 (1986)


A protocol is presented that has proven effective in the determination, in man, of the psychotomimetic potency and qualitative nature of action of a new drug. It involves a minimum of animal screening, but relies heavily upon the use of experienced human subjects. This procedure has been successful in the discovery of over 200 novel CNS-active agents.
____ ___ __ _

Characterization of Three New Psychotomimetics
Alexander T. Shulgin & David E. Nichols

The Psychopharmacology of Hallucinogens, pp. 74-83 (1978)

Ed: Stillman, R. C. Willette, R. E., New York; Pergamon[/u]