Tetrahydroharmine

Tetrahydroharmine at a Glance

Tetrahydroharmine (THH) is a β-carboline (harmala) alkaloid and, together with harmine and harmaline, one of the three principal alkaloids of the ayahuasca vine Banisteriopsis caapi and of Syrian rue (Peganum harmala) ^{1,6Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 6Santos BWL et al. · 2020Biodiversity of β-carboline profile of Banisteriopsis caapi and ayahuasca, a plant and a brew with neuropharmacological potentialView study →}. Structurally it is the fully reduced form of harmine — the same skeleton with its pyridine ring saturated — which softens the pharmacology that harmine’s flat, aromatic ring gives it.

That single structural difference produces THH’s most distinctive feature: a dual mechanism. It is a weaker MAO-A inhibitor than harmine, but it is also a serotonin-reuptake inhibitor ^{1,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}. In the ayahuasca context THH therefore does two jobs at once — it adds to the monoamine-oxidase inhibition that protects orally ingested DMT from first-pass breakdown, and it independently raises serotonergic tone in an SSRI-like way ^{1,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}.

Because it is one of the more abundant and slowly-cleared caapi alkaloids, THH also draws its own research interest — in the neurogenesis and antidepressant work on B. caapi β-carbolines ^{4Reference 4Morales-García JA et al. · 2017In vitroThe alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitroView study →}. The honest caveat runs through all of it: almost every human measurement of THH comes from whole ayahuasca, not the isolated molecule, so its independent effects in people are inferred rather than directly demonstrated.

Tetrahydroharmine vs. Harmine

The clearest way to understand THH is by contrast with harmine, the alkaloid it is derived from.

Harmine is a fully aromatic β-carboline. Its flat, conjugated ring system lets it bind monoamine oxidase A tightly — a reversible, competitive MAO-A inhibitor of nanomolar potency (IC₅₀ ≈ 0.004 µM) ^{7Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}. That potent MAO-A inhibition is the main reason harmine (and the caapi vine and Syrian rue that carry it) can shield oral DMT from being deaminated in the gut and liver ^{1,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}.

Tetrahydroharmine is harmine with that ring reduced. Saturating the pyridine ring makes the molecule less planar and markedly weakens its grip on MAO-A, so gram for gram THH is a much poorer MAO inhibitor than harmine ^{1,7Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}. But the same reduction hands THH a second activity harmine largely lacks: inhibition of serotonin re-uptake ^{1,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}. As the classic characterisation put it, THH’s contribution in ayahuasca “is apparently more a function of its inhibition of serotonin uptake than of its action as an MAO inhibitor” ^{1Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →}.

Practically:

Harmine — the potent MAO-A inhibitor; the main DMT-protecting lever.
Tetrahydroharmine — a weaker MAO-A inhibitor but an added serotonin-reuptake inhibitor; a supporting, more serotonergic role.
Harmaline — the dihydro (partly reduced) intermediate; an intermediate MAO-A inhibitor.

The three sit on a reduction ladder — harmine (aromatic) → harmaline (dihydro) → tetrahydroharmine (tetrahydro) — and MAO-A potency falls as saturation rises.

What It's Used For

THH’s pharmacology is inseparable from ayahuasca in the human literature: it is one of four alkaloids measured together in the vine and the brew, and almost no controlled human study has given the isolated molecule on its own ^{1,3,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}.

A genuine but secondary MAO-A inhibitor:THH inhibits MAO-A far more weakly than harmine, so within ayahuasca it is a supporting contributor to the MAOI effect that lets oral DMT act, not the primary one ^{1,7Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}.

A serotonin-reuptake inhibitor (SSRI-like):its more distinctive action is weak inhibition of serotonin uptake, which raises serotonergic tone independently of MAO inhibition — the mechanistic root of both its research interest and its interaction risk ^{1,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}.

Neurogenesis / antidepressant research:with harmine and harmaline, THH stimulates adult neural-stem-cell proliferation and differentiation in vitro, a proposed contributor to the antidepressant signal seen with B. caapi preparations ^{4Reference 4Morales-García JA et al. · 2017In vitroThe alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitroView study →}.

The honest headline:the human data are whole-ayahuasca measurements (plasma levels, kinetics), not trials of isolated THH; its stand-alone effects in people are inferred ^{1,3,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}.

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. Human data are ayahuasca-brew measurements, not isolated-THH trials, so isolate scores stay modest by design.

Mechanisms

Target / pathway	Effect	Relevant to
Serotonin transporter (SERT)	inhibits serotonin re-uptake (SSRI-like) → raises synaptic serotonin	serotonergic tone; antidepressant-research angle; interaction risk
Monoamine oxidase A (MAO-A)	weak, reversible inhibition (much weaker than harmine)	supporting the brew’s protection of oral DMT
Monoamine oxidase B (MAO-B)	little inhibition	(selectivity note — the harmala β-carbolines are MAO-A-preferring)
Adult neural stem cells	↑ proliferation / migration / neuronal differentiation in vitro (with harmine, harmaline, harmol)	neurogenesis / antidepressant research

The load-bearing point is the combination: a serotonin-reuptake inhibitor stacked on even weak MAO-A inhibition is two serotonin-raising mechanisms at once — the reason THH is pharmacologically interesting and the reason it carries a serotonin-syndrome interaction flag (see Toxicity).

Pharmacokinetics

THH’s kinetics are among the better-characterised of the ayahuasca alkaloids because it is measured in human plasma after ritual dosing. After oral ayahuasca, THH reaches peak plasma levels around 80 ng/mL at roughly 180 minutes and is eliminated slowly, with a half-life near 530 minutes (~9 hours) — far longer than harmine’s ~116 minutes ^{3Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →}. Individual peak concentrations up to ~134 ng/mL have been reported ^{2Reference 2Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →}. In other words, THH lingers well after harmine has cleared, so its serotonergic contribution outlasts the acute MAO-inhibition window — a distinctive feature of this molecule. Metabolically, THH undergoes O-demethylation to tetrahydroharmol followed by conjugation, with the conjugates abundant in urine ^{8Reference 8Riba J et al. · 2012Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuascaView study →}. Its slow clearance and independent serotonergic action are exactly why THH, rather than harmine, is often flagged as the caapi alkaloid with the most drawn-out serotonergic footprint ^{3,5Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}.

Clinical Trials

There are no controlled clinical trials of isolated tetrahydroharmine. The human data are pharmacokinetic and pharmacodynamic measurements taken within whole-ayahuasca studies, where THH is one of four co-administered alkaloids ^{2,3Reference 2Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →}; the neurogenesis and antidepressant-mechanism work is preclinical (cell culture) ^{4Reference 4Morales-García JA et al. · 2017In vitroThe alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitroView study →}.

Completed	Planned	Terminated	Preclinical
Whole-ayahuasca PK/PD (THH as one alkaloid) ^{2,3Reference 2Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →}	—	—	Serotonin-uptake inhibition; MAO-A inhibition; neural-stem-cell neurogenesis ^{1,4,7Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 4Morales-García JA et al. · 2017In vitroThe alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitroView study →Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}

Last checked: July 2026.

Isolate vs. Plant Studies

This molecule sits firmly on the plant/brew side of the isolate-vs-plant line. Every human measurement of THH — plasma concentration, half-life, metabolite profile — comes from people who drank ayahuasca, a mixture of the caapi β-carbolines plus a DMT-bearing admixture ^{2,3Reference 2Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →}. The biochemical findings that define THH’s character (serotonin-uptake inhibition, weak MAO-A inhibition) are isolate-level pharmacology ^{1,7Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}, and the neurogenesis work tested the isolated caapi alkaloids in cell culture ^{4Reference 4Morales-García JA et al. · 2017In vitroThe alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitroView study →} — but there is no controlled human trial of THH on its own. So its independent effects in people are reconstructed from the brew and from in-vitro data, not demonstrated directly. When THH’s serotonergic or antidepressant potential is discussed, that inference should be kept explicit.

Its Role in Plants

In Banisteriopsis caapi and Peganum harmala, tetrahydroharmine is one of a family of β-carboline alkaloids built on the tryptophan/tryptamine backbone — the same indole-amine chemistry that gives rise to serotonin and the tryptamine alkaloids. THH is the most reduced member of the harmine → harmaline → tetrahydroharmine series found in the vine, and the relative amounts of the three vary widely between plants, populations and growing conditions ^{6Reference 6Santos BWL et al. · 2020Biodiversity of β-carboline profile of Banisteriopsis caapi and ayahuasca, a plant and a brew with neuropharmacological potentialView study →}. These β-carbolines are generally regarded as defensive secondary metabolites; their striking bioactivity in animals (MAO inhibition, serotonergic effects) is a consequence of that chemistry rather than evidence of a function the plant “intends” pharmacologically. The plant-chemistry role should not be read as human pharmacology.

Prevalence in Nature

Tetrahydroharmine is a harmala β-carboline, concentrated in the two classic sources of these alkaloids:

Ayahuasca vine (Banisteriopsis caapi) — THH is typically the second-most-abundant β-carboline after harmine. In a large survey of Brazilian material, mean concentrations were harmine ~4.79 mg/g, tetrahydroharmine ~2.18 mg/g and harmaline ~0.45 mg/g of plant, with very high sample-to-sample variability (relative standard deviations of ~79–170%) ^{6Reference 6Santos BWL et al. · 2020Biodiversity of β-carboline profile of Banisteriopsis caapi and ayahuasca, a plant and a brew with neuropharmacological potentialView study →}.
Syrian rue (Peganum harmala) — THH is one of the main β-carbolines of the seed, reported accumulating around 0.1% (w/v/w) of dry seed, alongside the more abundant harmine and harmaline ^{7Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}.
Passionflower (Passiflora spp.) — carries the harmala β-carbolines (harman-type and harmine-group alkaloids) at much lower, trace levels than caapi or rue.

Because these are the same species that carry harmine and harmaline, THH’s occurrence tracks theirs; it is essentially always found as part of a β-carboline mixture, not on its own.

Major Natural Sources

Source	Plant part	Reported THH content
Ayahuasca vine (Banisteriopsis caapi)	stem / liana	~2.18 mg/g (mean; highly variable) ^{6Reference 6Santos BWL et al. · 2020Biodiversity of β-carboline profile of Banisteriopsis caapi and ayahuasca, a plant and a brew with neuropharmacological potentialView study →}
Syrian rue (Peganum harmala)	seed	~0.1% dry weight ^{7Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}
Passionflower (Passiflora spp.)	aerial parts	trace

These are content figures from surveyed plant material and vary enormously with species, region and growing conditions ^{6Reference 6Santos BWL et al. · 2020Biodiversity of β-carboline profile of Banisteriopsis caapi and ayahuasca, a plant and a brew with neuropharmacological potentialView study →}.

Discovery & Synthesis

Tetrahydroharmine was characterised as one of the three principal β-carbolines of Banisteriopsis caapi, isolated alongside harmine and harmaline in the mid-20th-century alkaloid chemistry of the ayahuasca vine (it also carries the older botanical name leptaflorine, from its occurrence in other genera). Chemically it is simply harmine with its pyridine ring fully reduced (tetrahydro), so it is readily obtained by chemical reduction of harmine or harmaline as well as by extraction from caapi or Syrian rue. Modern interest in the molecule is pharmacological rather than synthetic — it is studied as a constituent of ayahuasca and of the harmala-alkaloid set, not manufactured as a stand-alone product.

Patents: not yet researched.

Toxicity & Safety

Tetrahydroharmine carries a moderate flag — higher than an inert plant metabolite — for a specific, mechanistic reason: it is doubly serotonergic. It inhibits serotonin re-uptake and (weakly) inhibits MAO-A ^{1,5Reference 1McKenna DJ et al. · 1984Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuascaView study →Reference 5Brito-da-Costa AM et al. · 2020Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impactView study →}, and stacking a reuptake inhibitor on an MAO inhibitor is precisely the drug combination that produces serotonin toxicity. That makes THH’s headline risk an interaction risk, not an intrinsic-toxicity one, and it applies to the whole harmala-alkaloid class it belongs to.

Safety at a Glance

Moderate toxicitySerotonin risk

Serotonin-syndrome interaction risk. As a serotonin-reuptake inhibitor and MAO-A inhibitor, THH can add dangerously to SSRIs, SNRIs, MAOIs, triptans, tramadol, St John’s wort and other serotonergic drugs — the combination that causes serotonin toxicity.
MAOI dietary and drug cautions. The MAO-A-inhibiting side of its activity carries the classic hypertensive concern with tyramine-rich foods and sympathomimetics, shared with harmine and harmaline.
Almost always consumed in a mixture. Real-world exposure is via ayahuasca or Syrian rue, where THH acts together with harmine, harmaline and (in the brew) DMT — its effects and risks are not separable from that combination.
Isolate safety data are thin. There is no dedicated human toxicology of isolated THH; the cautions here are class-level (harmala β-carboline / serotonergic) rather than THH-specific.

Reproductive and developmental data for isolated THH are not established; harmala alkaloids as a class are generally cautioned in pregnancy at the plant level. Pregnancy and lactation decisions belong to the herb or product page where intake is decided, not to this molecule page.

Dosage

There is no established or recommended human dose for isolated tetrahydroharmine — it is not used as a stand-alone drug. The only human figures are measurements from ayahuasca research: after a ritual dose of the brew, THH reaches plasma concentrations of roughly 80–135 ng/mL, peaking near three hours and clearing slowly (half-life ~9 hours) ^{2,3Reference 2Callaway JC et al. · 1996Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuascaView study →Reference 3Callaway JC et al. · 1999Pharmacokinetics of Hoasca alkaloids in healthy humansView study →}. In the plant, THH is present at roughly 2 mg/g in caapi stem and ~0.1% of Syrian rue seed, always as one member of a β-carboline mixture ^{6,7Reference 6Santos BWL et al. · 2020Biodiversity of β-carboline profile of Banisteriopsis caapi and ayahuasca, a plant and a brew with neuropharmacological potentialView study →Reference 7Herraiz T et al. · 2010Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)View study →}. These are research and content measurements, not a personal recommendation.

References

McKenna DJ, Towers GH, Abbott F (1984). Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuasca. Journal of Ethnopharmacology. https://pubmed.ncbi.nlm.nih.gov/6587171/
Callaway JC, Raymon LP, Hearn WL, McKenna DJ, Grob CS, Brito GS, Mash DC (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/
Callaway JC, McKenna DJ, Grob CS, et al. (1999). Pharmacokinetics of Hoasca alkaloids in healthy humans. Journal of Ethnopharmacology. https://pubmed.ncbi.nlm.nih.gov/10404423/
Morales-García JA, de la Fuente Revenga M, Alonso-Gil S, et al. (2017). The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro. Scientific Reports. https://pubmed.ncbi.nlm.nih.gov/28706205/
Brito-da-Costa AM, Dias-da-Silva D, Gomes NGM, Dinis-Oliveira RJ, Madureira-Carvalho Á (2020). Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: clinical and forensic impact. Pharmaceuticals (Basel). https://pubmed.ncbi.nlm.nih.gov/33114119/
Santos BWL, Oliveira RC, Sonsin-Oliveira J, Fagg CW, Barbosa JBF, Caldas ED (2020). Biodiversity of β-carboline profile of Banisteriopsis caapi and ayahuasca, a plant and a brew with neuropharmacological potential. Plants. https://doi.org/10.3390/plants9070870
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/
Riba J, McIlhenny EH, Valle M, Bouso JC, Barker SA (2012). Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca. Drug Testing and Analysis. https://pubmed.ncbi.nlm.nih.gov/22514127/