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Phenethylamine

Phenethylamine, or β-phenylethylamine or 2-phenylethylamine, is an alkaloid and monoamine. Phenethylamine also has a constitutional isomer α-phenylethylamine (1-phenylethylamine), which has two stereoisomers: (R)-(+)-1-phenylethylamine and (S)-(-)-1-phenylethylamine. In the human brain, 2-phenethylamine is believed to function as a neuromodulator or neurotransmitter (trace amine). Phenethylamine is a natural compound biosynthesized from the amino acid phenylalanine by enzymatic decarboxylation. It is also found in many foods such as chocolate, especially after microbial fermentation. However trace amounts from food is quickly metabolized by the enzyme MAO-B, preventing significant concentrations from reaching the brain.

Phenylethylamine is a precursor to the neurotransmitter phenylethanolamine.

D-Phenylalanine increases the brain content of phenylethylamine . Phenylethylamine has been shown at least indirectly to satisfy the four main criteria required to demonstrate that a neuroamine sustains mood and that its deficit can be responsible for depression. Antidepressant drug therapy is an indirect (pharmacological) "replacement" of brain phenylethylamine .

Substituted phenethylamines are a broad and diverse class of compounds that include stimulants, hallucinogens, entactogens, anorectics, bronchodilators, and antidepressants.

Chemistry

Phenethylamine is an aromatic amine, which is a colorless liquid at room temperature. It is soluble in water, ethanol, and ether. Similar to other low-molecular-weight amines, it has a fishy odor. Upon exposure to air, it forms a solid carbonate salt with carbon dioxide. Phenethylamine is strongly basic and forms a stable crystalline hydrochloride salt with a melting point of 217 °C. Phenethylamine is also a skin irritant and possible sensitizer.

Neurochemistry

Infusion of phenylethylamine increased extracellular levels of dopamine while at the same time inhibiting DA neuron firings. It also modulates noradrenergic transmission. Phenethylamine, along with tyramine, reversibly depresses the slow GABA_B receptor inhibitory post-synaptic potential in midbrain dopaminergic cells.

Low levels are found in those suffering from attention deficit disorder and often in depression, while levels are elevated in schizophrenia. This is associated with low dopamine in ADHD and depression and high dopamine in schizophrenia.

Chocolate theory of love

In the early 1980s, researcher Michael Liebowitz, author of the popular 1983 book The Chemistry of Love, remarked to reporters that "chocolate is loaded with PEA." This became the focus for an article in The New York Times, which was then taken up by the wire services, then by magazine free-lancers, and evolved into the now-eponymous "chocolate theory of love. However, as noted earlier, phenethylamine is rapidly metabolized by the enzyme MAO-B, preventing significant concentrations from reaching the brain, thus contributing no perceptible psychoactive effect in the absence of a ayahuasca-like mixture.

Substituted phenethylamines

Substituted phenethylamines carry additional chemical modifications at the phenyl ring, the sidechain, or the amino group:

Substituted Amphetamines are homologues of phenethylamines carrying an alpha-methyl (α-CH₃) group at the sidechain carbon atom next to the amino group.
Catecholamines are phenethylamines carrying two hydroxy groups in positions 3 and 4 of the phenyl ring. Examples are the hormones and neurotransmitters dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).
The aromatic amino acids phenylalanine and tyrosine are phenethylamines carrying a carboxyl group (COOH) in alpha position.
2Cs are phenethylamines with methoxy groups attached to the 2 and 5 carbons and no alpha-methyl group.

Pharmacology

Phenylethylamine's half life is 5-10 minutes. Phenylethylamine is metabolized by MAO-A , MAO-B , aldehyde dehydrogenase and dopamine-beta-hydroxylase. Phenylethylamine brain levels can be increased by a 1000 fold when taking an MAO Inhibitor and 3-4 times when taken by itself. Alcohol and THC increase phenylethylamine levels by a 4 fold.

Many substituted phenethylamines are pharmacologically active drugs due to their similarity to the monoamine neurotransmitters:

Stimulants like the plant alkaloids ephedrine and cathinone and the synthetic drug dextroamphetamine and methylphenidate
Hallucinogens like the plant alkaloid mescaline and the synthetic drug 2C-B
Empathogen-entactogens like MDMA (ecstasy) and MDA
Anorectics like phentermine, fenfluramine, and amphetamine
Bronchodilators like salbutamol and ephedrine
Antidepressants like venlafaxine, bupropion and the monoamine oxidase inhibitors phenelzine and tranylcypromine.

Substitution table

Some of the more important phenethylamines are tabulated below. For simplicity, the stereochemistry of the sidechain is not covered in the table. Hundreds of other simple synthetic phenethylamines are known. This is due in large part to the pioneering work of Alexander Shulgin, much of which is described in the book PiHKAL (Phenethylamines i Have Known And Loved).

Selected Phenethylamines
Short Name	R^α	R^β	R²	R³	R⁴	R⁵	R^N	Full Name
Tyramine					OH			4-hydroxy-phenethylamine
Dopamine				OH	OH			3,4-dihydroxy-phenethylamine
Epinephrine (Adrenaline)		OH		OH	OH		CH₃	β,3,4-trihydroxy-N-methylphenethylamine
Norepinephrine (Noradrenaline)		OH		OH	OH			β,3,4-trihydroxyphenethylamine
Phenylephrine		OH		OH			CH₃	β,3-dihydroxy-N-methylphenethylamine
6-Hydroxydopamine			OH		OH	OH		2,4,5-trihydroxyphenethylamine
Salbutamol		OH			OH	CH₂OH	C(CH₃)₃	β,4-dihydroxy-3-hydroxymethyl-N-tert-butyl-phenethylamine
Beta-methyl-phenethylamine		CH₃						β-methylphenethylamine
Amphetamine	CH₃							α-methylphenethylamine
Methamphetamine	CH₃						CH₃	N-methylamphetamine
Methylphenidate								N,α-butylene-β-methoxycarbonylphenethylamine
Ephedrine, pseudoephedrine	CH₃	OH					CH₃	N-methyl-β-hydroxyamphetamine
Acetylamphetamine	CH₃			COCH₃				α-methyl-3-acetylphenethylamine
Cathine	CH₃	OH						β-hydroxy-amphetamine
Cathinone	CH₃	=O						β-ketoamphetamine
Methcathinone	CH₃	=O					CH₃	N-methyl-β-ketoamphetamine
Bupropion	CH₃	=O		Cl			C(CH₃)₃	3-chloro-N-tert-butyl-β-ketoamphetamine
Fenfluramine	CH₃			CF₃			CH₂CH₃	3-trifluoromethyl-N-ethyl-amphetamine
Phentermine	2CH₃							α,α-dimethylphenethylamine
Mescaline				OCH₃	OCH₃	OCH₃		3,4,5-trimethoxyphenethylamine
MDA	CH₃			-O-CH₂-O-				3,4-methylenedioxyamphetamine
MDMA	CH₃			-O-CH₂-O-			CH₃	3,4-methylenedioxy-N-methylamphetamine
MDMC	CH₃	=O		-O-CH₂-O-			CH₃	3,4-methylenedioxy-N-methyl-β-ketoamphetamine
DOM	CH₃		OCH₃		CH₃	OCH₃		2,5-dimethoxy-4-methylamphetamine
DOB	CH₃		OCH₃		Br	OCH₃		2,5-dimethoxy-4-bromoamphetamine
DON	CH₃		OCH₃		NO₂	OCH₃		2,5-dimethoxy-4-nitroamphetamine
2C-B			OCH₃		Br	OCH₃		2,5-dimethoxy-4-bromophenethylamine
2C-C			OCH₃		Cl	OCH₃		2,5-dimethoxy-4-chlorophenethylamine
DOI	CH₃		OCH₃		I	OCH₃		2,5-dimethoxy-4-iodoamphetamine
2C-I			OCH₃		I	OCH₃		2,5-dimethoxy-4-iodophenethylamine
2C-D			OCH₃		CH₃	OCH₃		2,5-dimethoxy-4-methylphenethylamine
2C-E			OCH₃		CH₂-CH₃	OCH₃		2,5-dimethoxy-4-ethylphenethylamine
2C-F			OCH₃		F	OCH₃		2,5-dimethoxy-4-fluorophenethylamine
2C-N			OCH₃		NO₂	OCH₃		2,5-dimethoxy-4-nitrophenethylamine
2C-T-2			OCH₃		S-CH₂CH₃	OCH₃		2,5-dimethoxy-4-ethylthio-phenethylamine
2C-T-4			OCH₃		S-CH(CH₃)₂	OCH₃		2,5-dimethoxy-4-isopropylthio-phenethylamine
2C-T-7			OCH₃		S-CH₂CH₂CH₃	OCH₃		2,5-dimethoxy-4-propylthio-phenethylamine
2C-T-8			OCH₃		S-CH₂-C₃H₅	OCH₃		2,5-dimethoxy-4-cyclopropylmethylthio-phenethylamine
2C-T-9			OCH₃		S-C(CH₃)₃	OCH₃		2,5-dimethoxy-4-tert-butylthio-phenethylamine
2C-T-21			OCH₃		S-CH₂-CH₂-F	OCH₃		2,5-dimethoxy-4-(2-fluoroethylthio)-phenethylamine
Short Name	R^α	R^β	R²	R³	R⁴	R⁵	R^N	Full Name

Relation to amphetamine

Despite the negative stigma tagged to amphetamine (alpha-methylphenethylamine) ("speed", "amp", "uppers") and methylamphetamine (N-methyl-alpha-methylphenethylamine) ("speed", "meth", "ice", "crystal") and its recreational compounds, the phenylethylamine comprises not only these so called toxic or dangerous amphetamine or methamphetamine, it makes up many drugs with important uses including medical ones like bronchodilators; used for dilating or "opening" the bronchi and bronchioles, which is benefit to and can save the life of an asthmatic (with salbutamol or albuterol or epinephrin for someone with life-threatening allergic reactions), important neurotransmitters like dopamine, epinephrine (Adrenaline), (which humans depend on for normal functioning and survival), and some medically used stimulants like amphetamine (Adderall, Dexedrine), methylamphetamine (Desoxyn), methylphenidate (Ritalin, Concerta and others); which benefit people with ADHD and ADD (attention and behavioral disorders affecting many children and some adults), narcolepsy (person with insomnia that can fall asleep at anytime during the day), chronic fatigue syndrome(CFS), syndrome that inflicts unexplainable pain, fatigue, interruption of normal sleep, cognitive impairments (confusion, forgetfulness, and a cloudy mental or head feeling), ataxia, nausea and gastrointestinal problems like IBS and other negative symptoms, and can be used for traumatic brain injury (TBS). The majority of phenylethylamines used by many have some or all of the actions of the stigmatized amphetamine and methamphetamine (though sometimes they lack the recreational abuse) and also share great structural similarity to methamphetamine and amphetamine.