Harmaline

Harmaline at a Glance

Harmaline is a β-carboline (harmala) alkaloid found chiefly in the seeds of Syrian rue (Peganum harmala) and in the Amazonian ayahuasca vine (Banisteriopsis caapi). Structurally it is the 3,4-dihydro reduced form of harmine — the same tricyclic skeleton with one extra pair of hydrogens across the C-ring. The two sit one rung apart on an oxidation ladder that runs harmine (fully aromatic) → harmaline (3,4-dihydro) → tetrahydroharmine (fully reduced), and the harmine ⇌ harmaline pair is the defining feature of this molecule.

Its best-characterised action is reversible, competitive inhibition of monoamine oxidase A (MAO-A). Alongside harmine and tetrahydroharmine, this is the enzymatic basis of ayahuasca: MAO-A inhibition shields orally ingested N,N-DMT from first-pass breakdown so it can reach the brain.

Two things make harmaline distinctive rather than just “harmine with extra hydrogens.” First, it is the classic tremorigenic β-carboline — the “harmaline tremor” is a standard laboratory model of essential tremor. Second, it is a weaker MAO-A inhibitor than harmine but a more reliable inducer of nausea and tremor. This page describes what the molecule does; it is educational phytochemistry, not a guide to using Syrian rue, B. caapi or ayahuasca.

Harmaline vs. Harmine (The Oxidation-State Pair)

The single most useful thing to hold onto about harmaline is that it is harmine minus one degree of unsaturation. Harmine is a fully aromatic β-carboline; harmaline is 3,4-dihydroharmine — its pyridine ring is partially reduced. That small change shifts the pharmacology in consistent ways:

• MAO-A potency. Both are reversible, competitive, MAO-A-selective inhibitors, but harmine is markedly stronger. In one enzyme-kinetic series the inhibition constants (Ki) were ~5 nM for harmine versus ~48 nM for harmaline — roughly a tenfold difference — with both barely touching MAO-B ^{1Reference 1Kim H et al. · 1997Inhibition of monoamine oxidase A by beta-carboline derivativesView study →}.
• Abundance in the plant. In Peganum harmala seeds the two accumulate at comparable, very high levels (harmaline ~5.6% and harmine ~4.3% of seed dry weight in one quantification); in the roots harmine dominates and harmaline is minor ^{2Reference 2Herraiz T et al. · 2010beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}.
• Metabolic fate. Both are O-demethylated by the same liver enzymes — harmaline to harmalol, harmine to harmol — with CYP2D6 and CYP1A2 doing most of the work ^{9Reference 9Yu AM et al. · 2003Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmineView study →}.

The practical upshot: in a whole-plant preparation the MAO-A inhibition is a combined effect of harmine (the more potent inhibitor) and harmaline (present in similar quantity), while the tremor and emesis lean more heavily on harmaline.

What It's Used For

Harmaline’s evidence base is dominated by two very different threads: its MAO-A inhibition (well characterised enzymatically, and the reason it matters to ayahuasca) and its tremorigenic action (an unusually well-studied neuroscience model). Most human exposure is as one alkaloid within a whole-plant mixture, so the isolate-vs-plant distinction matters throughout.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. The scores mix a well-characterised enzyme mechanism and a well-studied animal model with thin whole-plant human data — read each row’s basis.

01MAO-A inhibition (the ayahuasca basis)Promising60%Reproducible enzyme kinetics; the mechanism behind oral DMT activity ^{1,2Reference 1Kim H et al. · 1997Inhibition of monoamine oxidase A by beta-carboline derivativesView study →Reference 2Herraiz T et al. · 2010beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}

02Tremorigenic action / essential-tremor modelPromising58%Four decades of animal electrophysiology; a standard preclinical model ^{3,4Reference 3Handforth A · 2012AnimalHarmaline tremor: underlying mechanisms in a potential animal model of essential tremorView study →Reference 4Robertson HA · 1980Harmaline-induced tremor: the benzodiazepine receptor as a site of actionView study →}

03Antiparasitic (antileishmanial)Shaky30%In-vitro activity vs. intracellular amastigotes; whole-extract animal data ^{5,6Reference 5Di Giorgio C et al. · 2004In vitroIn vitro activity of the beta-carboline alkaloids harmane, harmine, and harmaline toward parasites of the species Leishmania infantumView study →Reference 6Rahimi-Moghaddam P et al. · 2011In vitroIn vitro and in vivo activities of Peganum harmala extract against Leishmania majorView study →}

Mechanisms

The load-bearing point is that a single reversible MAO-A block underlies both the wanted effect (protecting oral DMT) and the principal hazard (serotonin excess when combined with other serotonergic agents). The tremor axis is mechanistically separate, acting on the olivo-cerebellar circuit rather than on MAO.

Pharmacokinetics

Harmaline is orally active but short-lived. After ayahuasca dosing in humans it reaches only low plasma concentrations — on the order of ~9 ng/mL, well below harmine (~222 ng/mL) and tetrahydroharmine (~135 ng/mL) in the same measurements — with a reported elimination half-life around 2 hours ^{7Reference 7Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →}. Its major metabolic route is O-demethylation to harmalol, catalysed principally by CYP2D6 (≈50% of the activity) and CYP1A2 (≈20%) in human liver microsomes ^{9Reference 9Yu AM et al. · 2003Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmineView study →}. Because CYP2D6 is genetically polymorphic, poor metabolisers clear harmaline more slowly and reach higher exposure — harmaline O-demethylase activity was ~9-fold higher in extensive-metaboliser than poor-metaboliser hepatocytes ^{8Reference 8Wu C et al. · 2009Effects of CYP2D6 status on harmaline metabolism, pharmacokinetics and pharmacodynamics, and a pharmacogenetics-based pharmacokinetic modelView study →}. This is doubly notable because harmaline (via MAO-A) sits in a system where CYP2D6-inhibiting or serotonergic co-medications can compound its effects.

Clinical Trials

There are no modern clinical trials of isolated harmaline as a therapeutic. Its human data come from whole-brew ayahuasca pharmacokinetic and observational studies, where it is one alkaloid among several ^{7Reference 7Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →}, and from historical mid-20th-century experimental use. Its most active research role is preclinical — as the tremor-inducing agent in essential-tremor drug screening ^{3Reference 3Handforth A · 2012AnimalHarmaline tremor: underlying mechanisms in a potential animal model of essential tremorView study →}.

Last checked: July 2026.

Isolate vs. Plant Studies

Harmaline’s evidence divides cleanly. The enzyme and animal work uses the isolate — the MAO-A Ki ^{1Reference 1Kim H et al. · 1997Inhibition of monoamine oxidase A by beta-carboline derivativesView study →}, the O-demethylation kinetics ^{9Reference 9Yu AM et al. · 2003Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmineView study →}, and the tremor electrophysiology ^{3Reference 3Handforth A · 2012AnimalHarmaline tremor: underlying mechanisms in a potential animal model of essential tremorView study →} are all pure-compound studies, which is a genuine strength for mechanism. But essentially all human exposure is via whole plants — Peganum harmala seed and Banisteriopsis caapi — where harmaline arrives alongside harmine, tetrahydroharmine, harmalol and (in ayahuasca) DMT ^{2,7Reference 2Herraiz T et al. · 2010beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →Reference 7Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →}. Because harmine is the more potent MAO-A inhibitor and is present in similar amounts, the MAO effect of a real preparation cannot be attributed to harmaline alone. The antileishmanial signal likewise spans both isolate ^{5Reference 5Di Giorgio C et al. · 2004In vitroIn vitro activity of the beta-carboline alkaloids harmane, harmine, and harmaline toward parasites of the species Leishmania infantumView study →} and crude extract ^{6Reference 6Rahimi-Moghaddam P et al. · 2011In vitroIn vitro and in vivo activities of Peganum harmala extract against Leishmania majorView study →}. The honest reading: strong isolate mechanism, no isolate human therapeutic data.

Prevalence in Nature

Harmaline is a Zygophyllaceae/Passifloraceae-associated β-carboline, most concentrated in the seeds of Syrian rue (Peganum harmala), where quantifications have reported it near 5.6% of seed dry weight — an extraordinarily high alkaloid load — with much lower amounts in the roots ^{2Reference 2Herraiz T et al. · 2010beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}. It is also a principal alkaloid of the ayahuasca vine Banisteriopsis caapi, the harmala source in the classic brew, though vine concentrations are far lower and more variable than Syrian rue seed. Smaller or trace amounts are reported in passionflower (Passiflora spp.), among other plants. Across these sources harmaline almost always travels together with harmine (and often tetrahydroharmine), reflecting their shared biosynthesis from tryptophan-derived tryptamine via a Pictet–Spengler-type condensation.

Discovery & Synthesis

Harmaline was first isolated from the seeds of Syrian rue (Peganum harmala) in the 1840s, in the same wave of nineteenth-century work that separated harmine from the same plant; the whole alkaloid family is named after harmal, a common name for Peganum harmala. The structure — a 3,4-dihydro-β-carboline bearing a methoxy group — was pinned down over the following decades as β-carboline chemistry matured.

Synthesis today is straightforward because of the harmine ⇌ harmaline relationship: harmaline can be obtained by partial reduction of harmine, or built directly by a Pictet–Spengler condensation of a suitable tryptamine with an aldehyde/keto-acid followed by the appropriate oxidation-state adjustment. Commercial harmaline for research is generally extracted from Peganum harmala seed (which is exceptionally rich in it) rather than synthesised, because the natural abundance is so high. Its first total synthesis is not precisely documented here.

Patents: not yet researched.

Toxicity & Safety

Harmaline carries a moderate flag. The dominant hazard is its MAO-A inhibition, which imports the whole interaction profile of the MAOI drug class; layered on top are its reliable emesis and its tremorigenic/neurotoxic effects at higher doses.

Safety at a Glance

⚠️ Moderate toxicity

• MAOI interaction risk. As a reversible MAO-A inhibitor, combining harmaline with serotonergic drugs (SSRIs/SNRIs, some other antidepressants, certain opioids like tramadol/meperidine) or with other MAOIs can precipitate serotonin toxicity; tyramine-rich foods can raise blood pressure.
• Reliably emetic. Nausea and vomiting are common with harmala-alkaloid–containing preparations — part of the well-known “purge” of ayahuasca.
• Tremor, ataxia and neurotoxicity at high dose. Harmaline is the prototype tremor-inducing β-carboline; large amounts cause tremor, incoordination and CNS toxicity.
• Interacting metabolism. Cleared mainly by CYP2D6/CYP1A2; CYP2D6 poor-metaboliser status or CYP2D6-inhibiting co-medications raise exposure.

Full Safety & Interactions Detail

MAOI-class interactions. Because harmaline reversibly inhibits MAO-A, it raises synaptic serotonin, noradrenaline and dopamine and shares the classic MAOI cautions. The best-documented real-world hazard is the ayahuasca + serotonergic-drug combination: Callaway and Grob described a serotonin-syndrome-type reaction attributed to ayahuasca taken with an SSRI, and this combination is broadly advised against ^{10Reference 10Callaway JC · 1998Ayahuasca preparations and serotonin reuptake inhibitors: a potential combination for severe adverse interactionsView study →}. Tyramine-containing foods carry the theoretical hypertensive-crisis concern of the MAOI class, though reversible inhibitors like harmaline are generally considered lower-risk on that axis than irreversible MAOIs.

Emesis and acute effects. Harmala-alkaloid preparations are reliably nauseating and emetic, and at higher doses harmaline itself produces tremor, ataxia and sedation/CNS disturbance — consistent with the tremor pharmacology above ^{3,11Reference 3Handforth A · 2012AnimalHarmaline tremor: underlying mechanisms in a potential animal model of essential tremorView study →Reference 11Moloudizargari M et al. · 2013Pharmacological and therapeutic effects of Peganum harmala and its main alkaloidsView study →}.

Metabolic and pharmacogenetic notes. Harmaline is O-demethylated to harmalol chiefly by CYP2D6 and CYP1A2 ^{9Reference 9Yu AM et al. · 2003Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmineView study →}; CYP2D6 poor metabolisers (or people on CYP2D6 inhibitors) reach higher harmaline exposure ^{8Reference 8Wu C et al. · 2009Effects of CYP2D6 status on harmaline metabolism, pharmacokinetics and pharmacodynamics, and a pharmacogenetics-based pharmacokinetic modelView study →}, which could amplify both wanted and adverse effects.

Legality (educational note). The harmala alkaloids themselves are not, in general, scheduled controlled substances in most jurisdictions, but the DMT they are combined with in ayahuasca is a controlled (Schedule I–type) substance in many countries; specific legal exemptions exist for some religious ayahuasca use. Legal status varies by country and changes over time — this is context, not advice.

What this covers. The isolated molecule and whole-plant cautions — not a complete toxicology dossier, and it is not use guidance. Pregnancy/lactation decisions belong to the herb or product page where intake is decided, not to this molecule page.

Dosage

There is no recommended dose for harmaline — it is not an approved medicine, and the material below is descriptive, not a recommendation. In research and in traditional practice, harmaline reaches people almost entirely as one alkaloid within a whole plant (Syrian rue seed, Banisteriopsis caapi), where the total harmala-alkaloid content, the co-present DMT, and individual CYP2D6 metabolism all shape the effect. Reported human plasma levels after ayahuasca are low (~9 ng/mL) and short-lived (half-life ~2 h) ^{7Reference 7Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →}. Because of the MAOI interaction profile and the emetic/tremorigenic effects, harmala-alkaloid exposure is meaningfully hazardous when combined with other drugs. These are research and pharmacokinetic figures, not a personal recommendation.

References

1. Kim H, Sablin SO, Ramsay RR (1997). Inhibition of monoamine oxidase A by beta-carboline derivatives. Archives of Biochemistry and Biophysics. https://pubmed.ncbi.nlm.nih.gov/8990278/
2. Herraiz T, González D, Ancín-Azpilicueta C, Arán VJ, Guillén H (2010). beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food and Chemical Toxicology. https://pubmed.ncbi.nlm.nih.gov/20036304/
3. Handforth A (2012). Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor. Tremor and Other Hyperkinetic Movements. https://pubmed.ncbi.nlm.nih.gov/23440018/
4. Robertson HA (1980). Harmaline-induced tremor: the benzodiazepine receptor as a site of action. European Journal of Pharmacology. https://pubmed.ncbi.nlm.nih.gov/6252023/
5. Di Giorgio C, Delmas F, Ollivier E, Elias R, Balansard G, Timon-David P (2004). In vitro activity of the beta-carboline alkaloids harmane, harmine, and harmaline toward parasites of the species Leishmania infantum. Experimental Parasitology. https://pubmed.ncbi.nlm.nih.gov/15172213/
6. Rahimi-Moghaddam P, Ebrahimi SA, Ourmazdi H, et al. (2011). In vitro and in vivo activities of Peganum harmala extract against Leishmania major. Journal of Research in Medical Sciences. https://pubmed.ncbi.nlm.nih.gov/22279479/
7. Callaway JC, Raymon LP, Hearn WL, et al. (1996). Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuasca. Journal of Analytical Toxicology. https://pubmed.ncbi.nlm.nih.gov/8889686/
8. Wu C, Jiang XL, Shen HW, Yu AM (2009). Effects of CYP2D6 status on harmaline metabolism, pharmacokinetics and pharmacodynamics, and a pharmacogenetics-based pharmacokinetic model. Biochemical Pharmacology. https://pubmed.ncbi.nlm.nih.gov/19445902/
9. Yu AM, Idle JR, Krausz KW, Küpfer A, Gonzalez FJ (2003). Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmine. Journal of Pharmacology and Experimental Therapeutics. https://pubmed.ncbi.nlm.nih.gov/12649384/
10. Callaway JC, Grob CS (1998). Ayahuasca preparations and serotonin reuptake inhibitors: a potential combination for severe adverse interactions. Journal of Psychoactive Drugs. https://pubmed.ncbi.nlm.nih.gov/9924842/
11. Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH, Shayegh J (2013). Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids. Pharmacognosy Reviews. https://pubmed.ncbi.nlm.nih.gov/24347928/

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