Ariadne, also known chemically as 4C-D or 4C-DOM, by its developmental code name BL-3912, and by its former tentative brand name Dimoxamine, is a little-known

psychoactive drug A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

of the

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

, phenylisobutylamine, and 4C families. It is a homologue of the psychedelics

2C-D 2C-D, also known as 2C-M or as 2,5-dimethoxy-4-methylphenethylamine, is a psychedelic drug of the 2C family that is sometimes used as an entheogen. It was first synthesized in 1970 by a team from the Texas Research Institute of Mental Sciences, a ...

and DOM. The drug is a

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

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 ...

, including of the serotonin 5-HT_2A receptor. However, it is non-

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

ic in animals and humans, although it still has some

psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

effects. It may be non-hallucinogenic due to lower-

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

partial agonism of the serotonin 5-HT_2A receptor. Ariadne was developed by

Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American biochemist, broad researcher of synthetic psychoactive compounds, and author of works regarding these, who independently explored the organic chemistry and ph ...

. It was studied at Bristol Laboratories as an

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

and for various other uses but was never marketed. There has been renewed interest in Ariadne in the 2020s owing to increased interest in psychedelics for treatment of

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

Effects

In his 1991 book ''

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 ...

'',

reported testing Ariadne on himself up to a dose of 32mg, finding that it produced "the alert of a psychedelic, with none of the rest of the package". Very little published data exists about the human pharmacology of Ariadne apart from Shulgin's limited testing; unpublished human trials reportedly observed some

effects, but no

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s. In his 2011 book '' The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds'', Shulgin described (''R'')-Ariadne as increasing mental alertness and producing feelings of

well-being Well-being is what is Intrinsic value (ethics), ultimately good for a person. Also called "welfare" and "quality of life", it is a measure of how well life is going for someone. It is a central goal of many individual and societal endeavors. ...

at doses of 25 to 50mg. It was claimed to improve symptoms of

manic depression Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that each last from days to weeks, and in some cases months. If the elevated m ...

in psychotic individuals at doses of 50 to 100mg and to improve symptoms of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

at a dosage of 100mg/day. Doses of up to 300mg resulted in an

altered state of consciousness An altered state of consciousness (ASC), also called an altered state of mind, altered mental status (AMS) or mind alteration, is any condition which is significantly different from a normal waking state. It describes induced changes in one's me ...

but still no psychedelic effects. For comparison, DOM shows psychoactive sub-hallucinogenic effects at doses of 1 to 3mg and psychedelic effects at doses of more than 3mg.

Interactions

Pharmacology

Pharmacodynamics

Ariadne is a potent and selective

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-HT_2A, 5-HT_2B, and 5-HT_2C receptors. However, it is less

efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

in activating the serotonin 5-HT_2A receptor, including the G_q, G₁₁, and β-arrestin2 signaling pathways, compared to the related drug DOM, and this weaker partial agonism may be responsible for its lack of psychedelic effects. In addition to the serotonin 5-HT₂ receptors, Ariadne is a lower-

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 ...

agonist of the serotonin 5-HT₁ receptors. Ariadne shows essentially no activity at the

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s. Ariadne shows a markedly attenuated

head-twitch response The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

, a behavioral proxy of psychedelic effects, in animals, although it does still significantly induce a weak head-twitch response. The drug substitutes for DOM in rodent drug discrimination tests, albeit with dramatically lower potency than DOx drugs like DOM itself, DOET, and

DOB DOB or Dob often refers to date of birth. DOB or Dob may also refer to: Biochemistry * 2,5-dimethoxy-4-bromoamphetamine, Bromo-DMA, a psychedelic drug ** Meta-DOB, related substance ** Methyl-DOB, related substance * HLA-DOB, human gene Organiz ...

. It has also been shown to produce stimulus generalization in rats trained to respond to

LSD Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a semisynthetic, hallucinogenic compound derived from ergot, known for its powerful psychological effects and serotonergic activity. I ...

and

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

. Ariadne's capacity to fully substitute for MDMA is not shared with DOM and is unusual among psychedelics, but is shared with α-ethyltryptamine (αET). In monkeys, Ariadne was found to possibly increase motivation, as it caused monkeys that had stopped running mazes to begin running them again. Ariadne has also been found to be effective in an

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

, where it reversed motor deficits similarly to

levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...

. Serotonin 5-HT_2A receptor agonists have been found to increase

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

levels in the

nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for ' nucleus adjacent to the septum') is a region in the basal forebrain rostral to the preoptic area of the hypo ...

and other mesolimbic areas and non-hallucinogenic serotonin 5-HT_2A receptor agonists like Ariadne may do so without producing psychedelic effects. This action may underlie the preliminary observations of effectiveness of Ariadne in the treatment of

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

in animals and humans. It is thought that the reduced efficacy of Ariadne in activating the serotonin 5-HT_2A receptor is responsible for its non-hallucinogenic nature in humans.

Chemistry

Ariadne, also known as 4-methyl-2,5-dimethoxy-α-ethylphenethylamine, is a

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 ...

and

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 ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. It is the analogue of 2,5-dimethoxy-4-methylamphetamine (DOM) in which the α-

methyl 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 as ...

group A group is a number of persons or things that are located, gathered, or classed together. Groups of people * Cultural group, a group whose members share the same cultural identity * Ethnic group, a group whose members share the same ethnic iden ...

has been replaced with an α- ethyl group and is the analogue of 2,5-dimethoxy-4-methylphenethylamine (2C-D) with an ethyl group substituted at the α carbon. Ariadne's alternative name ''4C-DOM'' or ''4C-D'' stands for "four-carbon DOM", whereas the name of 2C-D stands for "two-carbon DOM". Another name of Ariadne is ''α-Et-2C-D'', which stands for α-ethyl-2C-D.

Racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

Ariadne is additionally known by the former developmental code name ''BL-3912'', while the (''R'')-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

of Ariadne is known by the former developmental code name ''BL-3912A''. Other related compounds include 4C-B (the α-ethyl homologue of 2C-B and

) and 4C-T-2 (the α-ethyl homologue of 2C-T-2 and Aleph-2).

History

Ariadne was first synthesized by

. Shulgin reported that the drug was tested by Bristol Laboratories as an

, in an anecdote where he was explaining how human testing is invaluable (compared to animal testing) on drugs that change the state of the mind. He said, "Before they launched into a full multi-clinic study to determine whether it's going to be worth the animal studies or not, every person on the board of directors took it." In '' The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds'' (2011), he described it also being evaluated for increasing mental alertness in geriatric individuals, treating

, and treating

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

and

. The tentative commercial name of Ariadne was ''Dimoxamine''. (''R'')-Ariadne was said to have completed phase 2

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, but the actual clinical data were never disclosed and further development was halted due to strategic economic reasons.

References

External links

4C-D (ARIADNE) - Isomer Design

Ariadne Experience Reports - Erowid

The Small & Handy 4C-D Ariadne Thread - Bluelight

ARIADNE - PiHKAL - Erowid

ARIADNE - PiHKAL - Isomer Design
{{Chemical classes of psychoactive drugs 5-HT2B agonists 5-HT2C agonists 4C (psychedelics) Abandoned drugs Alexander Shulgin Experimental non-hallucinogens Non-hallucinogenic 5-HT2A receptor agonists Phenylisobutylamines Pro-motivational agents