4-Substituted-2,5-dimethoxyamphetamines (DO''x'') is a
chemical class
Chemical classification systems attempt to classify elements or compounds according to certain chemical functional or structural properties. Whereas the structural properties are largely intrinsic, functional properties and the derived classi ...
of
substituted amphetamine
Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
derivatives featuring
methoxy
In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula .
On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position a ...
groups at the 2- and 5- positions of the
phenyl ring, and a
substituent
In organic chemistry, a substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule.
The suffix ''-yl'' is used when naming organic compounds that contain a single bond r ...
such as
alkyl
In organic chemistry, an alkyl group is an alkane missing one hydrogen.
The term ''alkyl'' is intentionally unspecific to include many possible substitutions.
An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...
or
halogen
The halogens () are a group in the periodic table consisting of six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the radioactive elements astatine (At) and tennessine (Ts), though some authors would ...
at the 4- position of the phenyl ring.
They are 4-substituted derivatives of
2,5-dimethoxyamphetamine (2,5-DMA, DOH) and are
structurally related to the
naturally occurring
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...
phenethylamine psychedelic
mescaline
Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...
.
The most well-known DOx drugs are
DOM,
DOI,
DOB,
DOET, and
DOC.
DOI is widely used in
scientific research
The scientific method is an empirical method for acquiring knowledge that has been referred to while doing science since at least the 17th century. Historically, it was developed through the centuries from the ancient and medieval world. The ...
.
DOM has been used as a
recreational drug
Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...
, while DOET was an
experimental
An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into cause-and-effect by demonstrating what outcome occurs whe ...
pharmaceutical drug
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...
.
Most compounds of this class are
potent and
long-lasting psychedelic drug
A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
s, and act as
selective 5-HT2A,
5-HT2B, and
5-HT2C receptor
Receptor may refer to:
* Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s.
A few bulkier derivatives such as
DOAM have similarly high
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Pa ...
for 5-HT
2 receptors but have reduced
activational efficacy and do not produce psychedelic effects.
DOI has been found to have extraordinarily potent
anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
effects.
These properties are not shared by all other related drugs and appear to be mediated by
functionally selective serotonin 5-HT
2A receptor activation.
The anti-inflammatory effects of DOI and related drugs may have medical applications.
Use
Side effects
DOx drugs like
DOM have been associated with certain
side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s that have not occurred to the same extent with other psychedelics like
LSD.
Examples of such side effects include physical symptoms like
sweating,
tremor
A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
s, and large increases in
heart rate
Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
.
Interactions
Pharmacology
Pharmacodynamics
Actions
The DOx drugs act as
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s of the
serotonin
Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
5-HT2 receptors, including of the serotonin
5-HT2A,
5-HT2B, and
5-HT2C receptors.
Their
psychedelic effects are thought to be mediated specifically by activation of the serotonin 5-HT
2A receptor.
In contrast to other amphetamines, DOx drugs like
DOC,
DOET, and
DOM are inactive as
monoamine releasing agents and
reuptake inhibitors.
Some of the DOx drugs, including
DOB, DOET,
DOI, and DOM, are agonists of the rat,
rhesus monkey
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies split between two groups, the Chinese-derived and the Indian-derived. Generally brown or g ...
, and/or human
trace amine-associated receptor 1 (TAAR1) with varying potencies.
Effects
In contrast to
amphetamine
Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
s like
(–)-cathinone, but similarly to
mescaline
Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...
, DOM has shown no
stimulant
Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...
-like or
reinforcing effects in
rhesus monkey
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies split between two groups, the Chinese-derived and the Indian-derived. Generally brown or g ...
s.
Conversely however, DOC has shown reinforcing effects, including
conditioned place preference (CPP) and
self-administration
Self-administration is, in its Medicine, medical sense, the process of a subject administering a Pharmacology, pharmacological substance to themself. A clinical example of this is the subcutaneous "self-injection" of insulin by a Diabetes, diabetic ...
, in rodents similarly to
methamphetamine
Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...
.
This is analogous to other findings in which various
2C and
NBOMe
The 25-NB (25''x''-NB''x'') series, or NBOMe series, also known as the ''N''-benzylphenethylamines, is a family of serotonergic psychedelics. They are substituted phenethylamines and were derived from the 2C (psychedelics), 2C family. The most c ...
drug
A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
s have been found to produce brain
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
Dopaminergic pathways, Dopaminergic brain pathways facil ...
elevations and reinforcing effects in rodents.
Pharmacokinetics
The DOx drugs are
orally active and many have doses in the range of 1 to 10mg and
durations in the range of 8 to 30hours.
Some DOx drugs, such as DOM and DOB, appear to have durations that increase non-linearly with dosage, for instance 8hours at lower doses and as long as 30hours or even up to 3 or 4days at higher doses.
This suggests that the
pathways mediating the
metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
of these drugs can saturate.
The DOx drugs are metabolized primarily by ''O''-
demethylation
Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...
.
However, DOM is primarily metabolized by
hydroxylation at its
methyl group
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...
.
History
DOM was the first psychedelic of the DOx series to be discovered.
It was first
synthesized by
Alexander Shulgin at
Dow Chemical Company in 1963, who had had his first
psychedelic experience
A psychedelic experience (known colloquially as a trip) is a temporary altered state of consciousness induced by the consumption of a psychedelic substance (most commonly Lysergic acid diethylamide, LSD, mescaline, psilocybin mushrooms, or N,N- ...
, with
mescaline
Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...
(3,4,5-trimethoxyphenethylamine), in 1960.
Shulgin personally tried DOM on January 4, 1964 and discovered its psychedelic effects.
2,4,5-Trimethoxyamphetamine (TMA-2; "DOMeO") had been synthesized by Bruckner in 1933, but its psychedelic effects were not described until Shulgin tried the compound and reported its effects in the
scientific literature
Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...
in 1964.
Prior to this,
3,4,5-trimethoxyamphetamine (TMA; α-methylmescaline) had been synthesized by Hey in 1947, being found by him to produce
euphoria
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...
, and was described by Peretz and colleagues in 1955 as clearly producing psychedelic effects.
Following his discovery of DOM, Shulgin developed
DOET and found that at low doses it was a remarkable "
psychic energizer" without producing psychedelic effects at these doses.
Dow Chemical Company decided to move forward with
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s of DOET as a potential
pharmaceutical drug
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...
for such purposes.
Shulgin and Dow Chemical Company filed a
patent
A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...
for DOET in 1966, although it was not published until 1970.
Dow Chemical Company tasked
Solomon H. Snyder at
Johns Hopkins University
The Johns Hopkins University (often abbreviated as Johns Hopkins, Hopkins, or JHU) is a private university, private research university in Baltimore, Maryland, United States. Founded in 1876 based on the European research institution model, J ...
with clinically studying DOET.
In April 1967, following the banning of
LSD in
California
California () is a U.S. state, state in the Western United States that lies on the West Coast of the United States, Pacific Coast. It borders Oregon to the north, Nevada and Arizona to the east, and shares Mexico–United States border, an ...
in 1966, DOM emerged as a
street drug and legal LSD alternative with the name "STP" (allegedly short for "Serenity, Tranquility, and Peace") in the
Haight-Ashbury district in
San Francisco
San Francisco, officially the City and County of San Francisco, is a commercial, Financial District, San Francisco, financial, and Culture of San Francisco, cultural center of Northern California. With a population of 827,526 residents as of ...
.
This occurred due to DOM being publicly distributed for free in the form of high-dose
tablets by LSD distributor
Owsley Stanley, who had personally learned of DOM from Shulgin.
It is unclear why Shulgin provided information about DOM to Stanley, since doing so had the potential to risk Shulgin's professional career and the DOET clinical studies.
One possibility is that Dow Chemical Company was not further looking into DOM and Shulgin thought that it was a promising drug that would otherwise be forgotten.
In any case, street use of DOM was short-lived because the tablets caused a public health crisis due to them often producing very long
durations (up to 3–4days), intense experiences, worrying physical
side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s, and
hospitalizations.
DOM was first reported on in the media and scientific literature in 1967 as a result of the crisis.
DOM became illegal in the
United States
The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
in 1968.
Dow Chemical Company terminated its clinical research program on DOET due to the DOM public health crisis.
DOET was subsequently first described in the literature by Snyder and colleagues in 1968.
Snyder continued to be interested in DOET as a potential medicine, but it was never further developed.
Snyder also described
2,5-dimethoxyamphetamine (2,5-DMA), which had been synthesized and tested by Shulgin, in the literature in 1968.
DOM and DOET were further described in the scientific literature by Shulgin in 1969.
In addition, Shulgin discussed DOM, DOET, TMA-2, and 2,5-DMA in a book chapter on hallucinogens published in 1970.
The earlier DOx drugs like DOM and DOET were subsequently followed by
DOB, which was developed by Shulgin and colleagues like
Claudio Naranjo, in 1971,
and by
DOI,
DOC, and a few other
analogues, which were developed by another research group, in 1973.
After this, numerous other DOx drugs were synthesized and characterized, both by Shulgin and other scientists.
Following its discovery, DOI has become widely used in
scientific research
The scientific method is an empirical method for acquiring knowledge that has been referred to while doing science since at least the 17th century. Historically, it was developed through the centuries from the ancient and medieval world. The ...
in the study of the serotonin 5-HT
2 receptors.
List of DOx drugs
The DO''x'' family includes the following members:
Related compounds
A number of additional compounds are known with alternative substitutions:
See also
*
2,5-Dimethoxyamphetamine
*
Substituted mescaline analogue
*
2Cs,
4Cs,
25-NB,
FLY
*
Substituted amphetamine
Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...
s
*
Substituted benzofurans
*
Substituted cathinones
*
Substituted methoxyphenethylamine
*
Substituted methylenedioxyphenethylamines
*
Substituted phenethylamine
Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...
s
*
Substituted tryptamine
Substituted tryptamines, or simply tryptamines, also known as serotonin analogues (i.e., 5-hydroxytryptamine analogues), are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all trypt ...
s
* ''
PiHKAL
''PiHKAL: A Chemical Love Story'' is a book by Alexander Shulgin and Ann Shulgin published in 1991. The subject of the work is Psychoactive drug, psychoactive phenethylamine Derivative (chemistry), chemical derivatives, notably those that act ...
''
* ''
The Shulgin Index''
References
External links
PiHKAL ("Phenethylamines I Have Known And Loved")by
Alexander "Sasha" Shulgin (1991)
DOx - PsychonautWiki DOX - Tripsitter
{{DEFAULTSORT:Dox
Alexander Shulgin
Chemical classes of psychoactive drugs
DOx (psychedelics)