Harmaline

As a hallucinogen

The harmala alkaloids are psychoactive in humans.^[5] According to Alexander Shulgin, harmaline is the only harmala alkaloid that has a reputation of being hallucinogenic.^[2][6] However, other harmala alkaloids and β-carbolines, like harmine, tetrahydroharmine (THH), 6-methoxyharmalan, and 6-methoxytetrahydroharman, have also been reported to be hallucinogenic.^[7] Harmaline produces vivid dream-like visual effects and physical discomfort at doses of 150 to 400 mg orally or 70 to 100 mg intravenously, often leading users to seek solitude in a quiet, dark environment.^[2][1] The hallucinogenic effects of harmaline and other β-carbolines are said to be qualitatively distinct from and unlike those of serotonergic psychedelics like LSD but similar to those of ibogaine.^{[8][9][10][11]} Taken orally, the onset of harmaline is 1 to 2 hours, peak effects occur after around 2 hours, and its duration is 5 to 8 hours.^[1][2] Conversely, its onset by intravenous injection is within seconds and its duration is much shorter by this route than with oral administration.^[2]

As an MAOI

Harmaline is a monoamine oxidase inhibitor (MAOI), or more specifically a reversible inhibitor of monoamine oxidase A (RIMA).^[12][1] The effective doses for this activity are 70 to 150 mg orally.^[1]

Harmaline-containing plants and tryptamine-containing plants are used in ayahuasca brews. The inhibitory effects on monoamine oxidase A (MAO-A) allows dimethyltryptamine (DMT), the psychoactively prominent chemical in the mixture, to bypass the extensive first-pass metabolism it undergoes upon ingestion, allowing a psychologically active quantity of the chemical to exist in the brain for a perceivable period of time.^[13]

Besides DMT, harmaline has also been used to inhibit the metabolism of and thereby potentiate 5-MeO-DMT, which like DMT is otherwise orally inactive and has a very short duration.^[1]

Pharmacodynamics

Harmaline shows weak but significant affinity for the serotonin 5-HT_2A and 5-HT_2C receptors in the low micromolar range.^[7][18] However, harmaline and other β-carbolines do not activate the serotonin 5-HT_2A receptor even at very high concentrations in vitro.^[16] Harmaline shows high affinity for the imidazoline I₂ receptor (K_i = 22 nM).^[17] Unlike ibogaine and noribogaine, harmaline does not bind to the κ-opioid receptor or other opioid receptors.^[22]

Harmaline and the psychedelic DOM partially substitute for each other in rodent drug discrimination tests.^[23][7] Harmaline was much more effective in substituting for DOM than harman and harmine, which did not achieve significant generalization and produced behavioral disruption at higher doses.^[23] On the other hand, harmaline and 6-methoxyharman were comparable in terms of DOM substitution.^[23] Unlike serotonergic psychedelics, ibogaine and harmala alkaloids like harmaline do not cause pupil dilation or increase blood pressure in humans.^[2][8]

Harmaline and ibogaine have both been found to produce neurotoxicity against Purkinje cells in the cerebellum in rats that is mediated by upstream olivocerebellar pathway activation.^{[24][25][26][27]} This may explain long-lasting motor deficits induced by ibogaine in these rats.^[28] However, this phenomenon involves high doses of ibogaine and has not been observed with ibogaine in primates or humans.^[28][29][30] In any case, the rodent findings are notable in that they further suggest that harmaline and ibogaine share a common mechanism of action.^[24]

Pharmacokinetics

The elimination half-life of harmaline has been reported to be about 2 hours.^[3]

Properties

It is fluorescent under ultraviolet light.

Synthesis

The chemical synthesis of harmaline has been described.^[1]

Analogues

Analogues of harmaline include harmine, tetrahydroharmine, harmalol, 5-methoxyharmalan, 6-methoxyharmalan, and ibogamine, among others.^[1]

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