Harmine

Harmine, also known as banisterine or telepathine, as well as 7-methoxyharman or 7-methoxy-1-methyl-β-carboline, is a β-carboline and a harmala alkaloid which has hallucinogenic effects and monoamine oxidase inhibitor (MAOI) activity. It occurs in a number of different plants, most notably Peganum harmala and Banisteriopsis caapi. Harmine reversibly inhibits monoamine oxidase A (MAO-A), an enzyme which breaks down monoamines, making it a reversible inhibitor of monoamine oxidase A (RIMA). Harmine does not inhibit MAO-B.

Harmine is found in various plants—including tobacco, Passiflora species, lemon balm, and several Banisteriopsis species—as well as in some butterflies of the Nymphalidae family. It was first isolated and named by German chemist Julius Fritzsche in 1847 from Peganum harmala seeds, later identified in Banisteriopsis caapi under various names, with its structure determined in 1927.

The biosynthesis of harmine likely begins with L-tryptophan, which is decarboxylated to tryptamine—an intermediate also used in serotonin synthesis—before undergoing a series of reactions to form harmine, with feeding experiments supporting tryptamine’s role as an intermediate rather than a primary precursor. It is essential for enabling the oral activity of DMT in ayahuasca and is also used as a fluorescent pH indicator and in PET imaging to study MAO-A-related brain disorders.

Pharmaceutical-grade harmine hydrochloride is safe and well-tolerated at oral doses below 2.7 mg/kg in healthy adults, with higher doses causing mild to moderate gastrointestinal and neurological side effects and limited psychoactive effects. Recent patents focus on creating harmine derivatives with reduced toxicity.

Use and effects

Hallucinogen

Harmine is a hallucinogen at reported doses of 25 to 75mg subcutaneously, 150 to 200mg intravenously, and 300mg or more orally. Along with harmaline and tetrahydroharmine, harmine is one of the psychoactive constituents of Banisteriopsis caapi. Syrian rue or synthetic harmine is sometimes used to substitute B. caapi in the oral use of DMT.

Harmine was used or investigated as an antiparkinsonian medication since the late 1920s until the early 1950s. It was replaced by other medications.

Adverse effects

A 2024 Phase 1 clinical trial investigating pharmaceutical-grade harmine hydrochloride in healthy adults found that the maximum tolerated dose (MTD) is approximately 2.7 mg/kg body weight.

Below this threshold, harmine is generally well-tolerated with minimal adverse effects. Above 2.7 mg/kg, common adverse effects include nausea and vomiting, which typically occur 60–90 minutes after ingestion. Other reported effects include drowsiness, dizziness, and impaired concentration. These effects are generally mild to moderate in severity and resolve within several hours.

No serious adverse cardiovascular effects were observed at any dose tested (up to 500 mg), though rare instances of transient hypotension occurred during episodes of vomiting. Unlike some traditional preparations containing harmine (such as Ayahuasca), pure harmine did not cause diarrhea in study participants.

The study found that adverse effects were more common in participants with lower body weight when given fixed doses, leading the researchers to conclude that 2.7mg/kg represents a more useful threshold than fixed dosing.

Pharmacology

Pharmacodynamics

{| class="wikitable floatright" style="font-size:small;"

|+

|-

! Target !! Affinity (K_i, nM)

|-

| 5-HT_1A || >10,000

|-

| 5-HT_1B ||

|-

| 5-HT_1D || >10,000 (calf/pig)

|-

| 5-HT_1E ||

|-

| 5-HT_1F ||

|-

| 5-HT_2A || 230–397 (rat)

|-

| 5-HT_2B ||

|-

| 5-HT_2C || 5,340 (rat)

|-

| 5-HT₃ ||

|-

| 5-HT₄ ||

|-

| 5-HT_5A ||

|-

| 5-HT₆ ||

|-

| 5-HT₇ ||

|-

| α_1A–α_1D ||

|-

| α₂ || >10,000 (rat)

|-

| α_2A–α_2C ||

|-

| β₁–β₃ ||

|-

| D₁ ||

|-

| D₂ || >10,000

|-

| D₃–D₅ ||

|-

| H₁–H₄ ||

|-

| M₁–M₅ ||

|-

| I₁ || 629 ()

|-

| I₂ || 10

|-

| σ₁, σ₂ ||

|-

| MOR || >100,000 (bovine)

|-

| DOR || >100,000 (bovine)

|-

| DOR || >100,000 (bovine)

|-

| ||

|-

| Benzodiazepine site| || >10,000 (rat)

|-

| Phencyclidine site| ||

|-

| || 11,000–41,000 () (mouse)

|-

| || 22,000 () (mouse)

|-

| || 12,000 ()

|-

| || 1.0–16.9 (K_i)<br />1.0–380 ()

|-

| || 120,800 (K_i)<br /> ()

|-

| || 12–700 ()

|- class="sortbottom"

| colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs:

|}

The pharmacology of harmine has been studied. It showed affinity (K_i) for the serotonin 5-HT_2A receptor (K_i = 230–397nM) and for the serotonin 5-HT_2C receptor (K_i = 5,340nM), but not for the serotonin 5-HT_1A receptor, the dopamine D₂ receptor, or the benzodiazepine site of the GABA_A receptor (all K_i = >10,000nM). However, in contrast to serotonergic psychedelics, harmine has been found to be inactive as an agonist of the serotonin 5-HT_2A receptor. Harmine has been found to increase dopamine release in the nucleus accumbens in a serotonin 5-HT_2A receptor-dependent manner as evidenced by reversal by ketanserin, but this may instead be via indirect serotonin 5-HT_2A receptor activation.

Harmine has also shown affinity for the imidazoline I₂ receptor (K_i = 10nM).

In contrast to harmaline and 6-methoxyharmalan, which fully substituted for the psychedelic drug DOM in rodent drug discrimination tests, but similarly to harmane, harmine failed to significantly substitute for DOM and produced behavioral disruption at higher doses. Similarly, harmine did not produce the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. However, in a subsequent study, harmine did produce the head-twitch response.

Pharmacokinetics

The pharmacokinetics of harmine have been studied and described.

Chemistry

Harmine, also known as 7-methoxy-1-methyl-β-carboline, is a substituted β-carboline and cyclized tryptamine derivative. Analogues of harmine include harmaline and tetrahydroharmine, among others. A positional isomer of harmine is 6-methoxyharman and analogues of that isomer include 6-methoxyharmalan and 6-methoxytetrahydroharmine (6-MeO-THH).

Synthesis

The chemical synthesis of harmine has been described.

The harmine-containing plants include tobacco, Peganum harmala, two species of passiflora, and numerous others. Lemon balm (Melissa officinalis) contains harmine.

In addition to B. caapi, at least three members of the Malpighiaceae contain harmine, including two more Banisteriopsis species and the plant Callaeum antifebrile. Callaway, Brito and Neves (2005) found harmine levels of 0.31–8.43% in B. caapi samples.

The family Zygophyllaceae, which P. harmala belongs to, contains at least two other harmine-bearing plants: Peganum nigellastrum and Zygophyllum fabago.

Biosynthesis

The coincident occurrence of β-carboline alkaloids and serotonin in Peganum harmala indicates the presence of two very similar, interrelated biosynthetic pathways, which makes it difficult to definitively identify whether free tryptamine or L-tryptophan is the precursor in the biosynthesis of harmine. However, it is postulated that L-tryptophan is the most likely precursor, with tryptamine existing as an intermediate in the pathway.

The following figure shows the proposed biosynthetic scheme for harmine. The Shikimate acid pathway yields the aromatic amino acid, L-tryptophan. Decarboxylation of L-tryptophan by aromatic L-amino acid decarboxylase (AADC) produces tryptamine (I), which contains a nucleophilic center at the C-2 carbon of the indole ring due to the adjacent nitrogen atom that enables the participation in a Mannich-type reaction. Rearrangements enable the formation of a Schiff base from tryptamine, which then reacts with pyruvate in II to form a β-carboline carboxylic acid. The β-carboline carboxylic acid subsequently undergoes decarboxylation to produce 1-methyl β-carboline III. Hydroxylation followed by methylation in IV yields harmaline. The order of O-methylation and hydroxylation have been shown to be inconsequential to the formation of the harmaline intermediate.

In 1905, the Colombian naturalist and chemist, Rafael Zerda-Bayón suggested the name telepathine to the then unknown hallucinogenic ingredient in ayahuasca brew. In 1923, the Colombian chemist, Guillermo Fischer-Cárdenas was the first to isolate harmine from Banisteriopsis caapi, which is an important herbal component of ayahuasca brew. He called the isolated harmine "telepathine". In 1925, Barriga Villalba, professor of chemistry at the University of Bogotá, isolated harmine from B. caapi, but named it "yajéine", which in some texts is written as "yageine". but this supposedly novel compound was soon also shown to be harmine.

Society and culture

Names

Harmine is the most common name of the compound. It is also known by other names including banisterine, banisterin, telepathine, telopathin, leucoharmine, yagin, and yageine, among others. A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.

Research

Pancreatic islet cell proliferation

Harmine is currently the only known drug that induces proliferation (rapid mitosis and subsequent mass growth) of pancreatic alpha (α) and beta (β) cells in adult humans. These islet sub-cells are normally resistant to growth stimulation in the adult stage of a human's life, as the cell mass plateaus at around age 10 and remains virtually unchanged.

See also

• Substituted β-carboline
• Harmala alkaloid
• Dimethyltryptamine/harmine
• Dimethyltryptamine/β-carbolines

References

External links

• Harmine - Isomer Design
• Harmine - PsychonautWiki
• Harmala Alkaloids - Erowid
• Harmine - TiHKAL - Erowid
• Harmine - TiHKAL - Isomer Design