Harmaline

Use and effects

As a hallucinogen

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

As an MAOI

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

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.

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.

Interactions

Harmaline is a reversible inhibitor of MAO-A (RIMA)". This means that the risk of a hypertensive crisis, a dangerous high blood pressure crisis from eating tyramine-rich foods such as cheese, is likely lower with harmaline than with irreversible MAOIs such as phenelzine. Since harmaline is a RIMA, it could, in theory, induce both serotonin syndrome and hypertensive crises in combination with tyramine, serotonergics, catecholaminergics drugs or prodrugs.

Pharmacology

Pharmacodynamics

Harmaline shows weak but significant affinity for the serotonin 5-HT2A and 5-HT2C receptors in the low micromolar range. However, harmaline and other β-carbolines do not activate the serotonin 5-HT2A receptor even at very high concentrations in vitro. Harmaline shows high affinity for the imidazoline I2 receptor (Ki = 22nM). Unlike ibogaine and noribogaine, harmaline does not bind to the κ-opioid receptor or other opioid receptors.

Harmaline and the psychedelic DOM partially substitute for each other in rodent drug discrimination tests. 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. On the other hand, harmaline and 6-methoxyharman were comparable in terms of DOM substitution. Unlike serotonergic psychedelics, ibogaine and harmala alkaloids like harmaline do not cause pupil dilation or increase blood pressure in humans.

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. This may explain long-lasting motor deficits induced by ibogaine in these rats. However, this phenomenon involves high doses of ibogaine and has not been observed with ibogaine in primates or humans. In any case, the rodent findings are notable in that they further suggest that harmaline and ibogaine share a common mechanism of action.

Pharmacokinetics

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

Chemistry

Harmaline, also known as 7-methoxyharmalan or 3,4-dihydro-7-methoxy-1-methyl-β-carboline, is a β-carboline and a cyclized tryptamine analogue of 6-methoxy-DMT.

Properties

It is fluorescent under ultraviolet light.

Synthesis

The chemical synthesis of harmaline has been described.

Analogues

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

Natural occurrence

Various plants contain harmaline including Peganum harmala (Syrian rue) as well as the hallucinogenic beverage ayahuasca, which is traditionally brewed using Banisteriopsis caapi. Present at 3% by dry weight, the harmala alkaloids may be extracted from the Syrian rue seeds.

History

Harmaline was first isolated from plants in 1841. The chemical structure of harmaline was not correctly identified until 1919. Harmaline was first synthesized in 1927.

Society and culture

Legal status

Australia

Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015). 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.

Canada

Harmaline and Harmalol are considered Schedule III controlled substances by the Controlled Drugs and Substances Act. Every person found to be in possession of a Schedule III drug is guilty of an indictable offence and liable to imprisonment for a term not exceeding three years; or for a first offence, guilty on summary conviction, to a fine not exceeding one thousand dollars or to imprisonment for a term not exceeding six months, or to both. Every person found to be trafficking a Schedule III drug is guilty of an indictable offence and liable to imprisonment for a term not exceeding ten years, or is guilty on summary conviction (first-time offenders) and liable to imprisonment for a term not exceeding eighteen months.

References

References

1. (1975). "Hallucinogenic Agents". Wright-Scientechnica.
2. (1977). "Profiles of Psychedelic Drugs: 4. Harmaline". Journal of Psychedelic Drugs.
3. "Erowid Online Books : "TIHKAL" - #13 HARMALINE".
4. (1994). "Structure-activity relationships of the classic hallucinogens and their analogs". NIDA Research Monograph.
5. (1969). "Psycotherapeutic Possibilities of New Fantasy-Enhancing Drugs". Clinical Toxicology.
6. (2018). "Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile". Frontiers in Pharmacology.
7. (2001). "The Alkaloids: Chemistry and Biology". Elsevier.
8. (1992). "Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques". Birkhäuser Basel.
9. (October 2010). "Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions". Current Drug Metabolism.
10. (March 2024). ["Handbook of Neurotoxicology"](https://books.google.com/books?id=2c2K-epbCDQC&q=harmaline+antidepressant&pg=PA237 }}{{Dead link). Humana Press.
11. "BindingDB BDBM50029799 7-Methoxy-1-methyl-2,9-dihydro-1H-beta-carboline::7-Methoxy-1-methyl-4,9-dihydro-3H-beta-carboline::7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole::CHEMBL2089157::CHEMBL340807::HARMALINE".
12. (October 2001). "beta-carboline binding to imidazoline receptors". Drug and Alcohol Dependence.
13. (February 2021). "β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer's Disease Therapy". Journal of Medicinal Chemistry.
14. (June 1995). "Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity". European Journal of Pharmacology.
15. (April 1998). "Investigation of hallucinogenic and related beta-carbolines". Drug and Alcohol Dependence.
16. (August 2000). "Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors". Drug and Alcohol Dependence.
17. (December 2003). "Binding of beta-carbolines at 5-HT(2) serotonin receptors". Bioorganic & Medicinal Chemistry Letters.
18. (February 1992). "Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies". Brain Research.
19. (January 1983). "DOM-stimulus generalization to LSD and other hallucinogenic indolealkylamines". European Journal of Pharmacology.
20. (1973). "The Healing Journey: New Approaches to Consciousness". Parthenon Books.
21. (2000). "Ibogaine and Noribogaine: Comparing Parent Compound to Metabolite". CNS Drug Reviews.
22. (September 2025). "Old Dog, New Tricks: Ibogaine and Its Analogs as Potential Neurotherapeutics". Journal of Medicinal Chemistry.
23. (2024). "Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine". American Journal of Therapeutics.
24. (May 1998). "Medication development of ibogaine as a pharmacotherapy for drug dependence". Annals of the New York Academy of Sciences.
25. (March 2012). "Fatalities temporally associated with the ingestion of ibogaine". Journal of Forensic Sciences.
26. (October 2020). "Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact". Pharmaceuticals.
27. "Peganum Harmala pamphlet: Syrian Rue". Erowid.
28. (30 September 2015). "Poisons Standard October 2015". Australian Government.
29. (19 September 2019). "Controlled Drugs and Substances Act (S.C 1996, c.19)".