The Psychotomimetic Properties of 3,4,5-Trimethoxyamphetamine

Shulgin, Alexander T.; Bunnell, Sterling; Sargent, T.

doi:10.1038/1891011a0

Cited by 37 publications

(9 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The compounds studied contain one or more of the following types of structural modifications: (1) addition ofmethoxy groups at various positions on the benzene ring, (2) introduction of the methylenedioxy group at ring positions 3-4, or (3) variations in the length and branching of the side chain. Shulgin et al (1961) had proposed the "mescaline unit" (ED mescatine/ED analog) as a measure of relative potency of mescaline analogs. In this calculation, the effective dose represents the arithmetic mean of the ED1 and ED100 values for the free base.…”

Section: Discussionmentioning

confidence: 99%

Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals

Hardman

Haavik

Seevers

1973

Toxicology and Applied Pharmacology

119

View full text Add to dashboard Cite

dioxy-N,e-dimethyl-fl-phenylethylamine) has been studied in the mouse, rat and guinea pig following ip administration and in the mongrel dog and rhesus monkey following iv administration. The LD50 value for each agent has been determined in each species. For 7 of the 8 drugs tested the LD50 value is significantly lower in the rat than in the mouse or guinea pig. A comparison of the observable signs of drug action in the dog and monkey shows the dog to be the preferred species for evaluating the effects of these agents. The relevant literature regarding the actions of the drugs has been reviewed. Modifications in the mescaline structure which are represented by the 7 analogs and which alter pharmacologic activity include: decreased potency following removal of the 5-methoxy group or N-demethylation, and increased potency following alpha substitution on the side chain or introduction of the 3,4-methylenedioxy group. Mescaline was one of the first drugs recognized as having hallucinogenic properties. Although the effects of mescaline in man have been described by many investigators (Stockings, 1940; Hock, 1951), the mechanisms by which mescaline alters central nervous system function are not yet clear. It has been suggested that the psychotomimetic action may arise owing to competition for adrenergic receptors (Ratcliffe, 1971; Speck, 1957), or cholinergic receptors (Clemente and Lynch, 1968), and that psychotomimetic action may result from metabolism in vivo to form an active material (Block et aL, 1952). 1 The investigations reported here were performed at the University of Michigan and supported by Army Chemical Center Contract DA-18-108-CML-5663 during the period 1953-54. The reports were declassified in October 1969.

show abstract

Section: Discussionmentioning

confidence: 99%

Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals

Hardman

Haavik

Seevers

1973

Toxicology and Applied Pharmacology

119

View full text Add to dashboard Cite

show abstract

“…A frequently cited example is that of N,N-Diisopropyltryptamine (DiPT), a substituted tryptamine and 5-HT 1A/2A agonist remarkable for producing auditory distortions, in contrast to the predominantly visual effects of classic psychedelics (Shulgin and Carter, 1979 ; Shulgin and Shulgin, 1997 ; Kometer and Vollenweider, 2016 ). Adding to this particular example, over 200 psychoactive substituted phenethylamines and tryptamines presenting an ample range of reported subjective effects are described in the work of A. Shulgin (Shulgin et al, 1961 , 1969 ; Shulgin and Shulgin, 1995 , 1997 ). While most of these compounds are either confirmed or suspected serotonergic psychedelics, others (such as 3,4-methylenedioxyamphetamine [MDA] and 3,4-methylenedioxymethamphetamine [MDMA]) act primarily as monoamine transporter substrates that facilitate the presynaptic release of 5-HT, dopamine (DA) and norepinephrine and have received the alternative denomination of “entactogens” (Nichols, 1986 ).…”

Section: Introductionmentioning

confidence: 99%

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

Zamberlán

Sanz

Vivot

et al. 2018

Front. Integr. Neurosci.

View full text Add to dashboard Cite

Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user (“set”) and the surroundings (“setting”). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of “set” and “setting,” to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands (“functional selectivity”). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to “in silico” estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid’s Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds.

show abstract

“…In the earliest such report, adding an alpha‐methyl group to the structure of mescaline provided the phenylisopropylamine (PIA) analogue, 3,4,5‐trimethoxyamphetamine (TMA) (Hey 1947). This analogue had roughly twice the potency of mescaline (Shulgin et al . 1961).…”

mentioning

confidence: 99%

Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT_2A receptor agonists

Parrish

Braden

Gundy

et al. 2005

Journal of Neurochemistry

View full text Add to dashboard Cite

Experiments compared a series of phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT 2A receptors. The (±) phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol compared to their phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT 2A receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)-and (S)-phenylisopropylamines with their phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies.In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT 2A receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the receptor must be considered.

show abstract

The Psychotomimetic Properties of 3,4,5-Trimethoxyamphetamine

Cited by 37 publications

References 2 publications

Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals

Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT_2A receptor agonists

Contact Info

Product

Resources

About

The Psychotomimetic Properties of 3,4,5-Trimethoxyamphetamine

Cited by 37 publications

References 2 publications

Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals

Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT2A receptor agonists

Contact Info

Product

Resources

About

Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT_2A receptor agonists