Harmaline

At pharmacological doses used for the tremor model (20 mg/kg i.p. in rats), harmaline produces significant cerebellar neurotoxicity at 24 hours: granule cell loss, Purkinje cell apoptosis (caspase-3-mediated), and inferior olivary neuron damagesupported

Harmaline 20 mg/kg i.p. in rats causes tremor plus cerebellar granule/Purkinje cell loss and inferior olivary neuron apoptosis via caspase-3. j.neuropharm.2011.05.015

Claim in safety — inconclusiveinconclusiveworking →

Harmaline possesses vasorelaxant properties that may moderate the pressor response.supported

Review of harmaline pharmacological effects: antileishmanial, antimicrobial, antiplatelet, antiplasmodial, antitumoral, hypothermic, vasorelaxant. j.ejphar.2013.05.003

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

The anxiolytic properties demonstrated at low doses in animal models (2 mg/kg i.p.) suggest a dose-dependent bidirectional effect on anxiety, with anxiolysis at lower doses and potential anxiogenesis at higher doses.partially supported

Harmaline 2 mg/kg shows anxiolytic-like effects in elevated plus maze; synergistic with mGluR group III antagonist CPPG. j.neulet.2025.138157

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

The emetic properties of ayahuasca preparations (serotonergic vagal stimulation producing nausea and vomiting at elevated doses) function as an intrinsic dose-limiting mechanism that reduces compulsive escalation.supported

Ritualistic use minimizes overdose risk via vomiting/diarrhea. 02791072.2015.1013202

Yu reviewed β-carboline drug-drug interactions and concluded that interactions with indolealkylamine agents could occur additively at the pharmacokinetic and dynamic levels, leading to severe or even fatal serotonin toxicitysupported

Beta-carboline MAOIs can cause fatal serotonin toxicity in DDIs. s12248-008-9028-5

Claim in safety — inconclusiveinconclusiveworking →

CYP2D6 pharmacokinetic interaction: Harmaline's high-affinity CYP2D6 metabolism (Km = 1.4 µM) means that CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine, haloperidol) would significantly increase harmaline plasma levels and prolong its duration of actionsupported

CYP2D6 (50%) and CYP1A2 (20%) are major isozymes for harmaline O-demethylation. CYP2D6 Km = 1.4 uM. CYP2D6 polymorphism affects harmaline pharmacology and toxicology. pmid:12649384

CYP2D6 pharmacokinetic interaction: Harmaline's high-affinity CYP2D6 metabolism (Km = 1.4 µM) means that CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine, haloperidol) would significantly increase harmaline plasma levels and prolong its duration of actionsupported

CYP2D6 important in IAA metabolism. Beta-carboline MAOIs can cause fatal serotonin toxicity in DDIs. s12248-008-9028-5

Tryptamine potentiation: Harmaline potentiates the oral bioavailability and psychoactive intensity of DMT and likely other orally administered tryptamines (5-MeO-DMT, bufotenin, psilocybin/psilocin) by inhibiting first-pass MAO-A degradationsupported

Beta-carbolines are reversible MAO inhibitors enabling oral DMT activity. pmid:6587171

Tryptamine potentiation: Harmaline potentiates the oral bioavailability and psychoactive intensity of DMT and likely other orally administered tryptamines (5-MeO-DMT, bufotenin, psilocybin/psilocin) by inhibiting first-pass MAO-A degradationsupported

Predominantly peripheral MAO inhibition. pmid:12660312

Claim in safety — inconclusiveinconclusiveworking →

CYP2D6 poor metabolizer status — substantially elevated harmaline exposure; effect amplification and prolonged duration expected.supported

CYP2D6 polymorphism affects harmaline pharmacology and toxicology. pmid:12649384

Cardiovascular disease — although harmaline's cardiovascular effects appear modest in healthy volunteers, the absence of safety data in cardiovascular-compromised populations warrants caution.supported

Double-blind placebo-controlled trial. Ayahuasca contains harmaline, harmine, tetrahydroharmine plus DMT. pmid:12660312

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Using kynuramine as substrate, Herraiz reported an IC₅₀ of 20 nM for harmaline at MAO-A — placing it among the most potent reversible MAO-A inhibitors characterized, more potent than toloxatone and moclobemide, and approximately comparable to the irreversible inhibitor clorgyline (IC₅₀ ~16 nM under identical conditions)partially supported

Harmaline IC50 for MAO-A = 20 nM under experimental conditions; reversible MAO-A inhibitor. More potent than toloxatone and moclobemide. dta.1530

Harmaline exhibits negligible MAO-B inhibitory activity at pharmacologically relevant concentrations.supported

MAO-B poorly inhibited. j.fct.2009.12.019

McKenna et al. established this mechanism as the canonical explanation for ayahuasca's oral psychoactivity: harmaline and harmine inhibit peripheral MAO-A, enabling orally inactive DMT to reach systemic circulation intact.supported

Beta-carbolines are reversible MAO inhibitors enabling oral DMT activity. pmid:6587171

CaV3.1 T-type calcium channel potentiation in inferior olivary neurons produces synchronous 4–10 Hz neuronal oscillations propagating through olivocerebellar circuitry — the established mechanism for harmaline-induced tremorsupported

Harmaline potentiates CaV3.1 T-type Ca2+ channels in inferior olive, causing synchronous 4-10 Hz oscillations that underlie harmaline-induced tremor. pnas.1002995107

Voltage-gated sodium channel Nav1.7 blockade occurs at higher concentrations (IC₅₀ = 35.5 µM for peak current)supported

Harmaline inhibits Nav1.7 channel; IC50 35.5 uM. ijms26104636

Weak 5-HT₂A receptor binding (Ki ≈ 42.5 µM) is orders of magnitude less potent than classical psychedelics but shows functional engagement in in vivo alkylation protection assayssupported

Harmaline 5-HT2A affinity = 42.5 uM (micromolar range - weak). Despite low affinity, harmaline provided significant protection from receptor alkylation. pmid:9476990

Harmaline also attenuates dopamine transporter (DAT) activity and promotes dopamine release in striatal synaptosomes, and fully substitutes for the imidazoline I₂-site ligand 2-BFI in drug discrimination — an activity linked to its MAO-A inhibition rather than direct receptor binding.partially supported

Harmaline inhibits MAO-A and significantly attenuates DAT activity and dopamine uptake; also promotes dopamine release in synaptosomes. acschemneuro.4c00789

Harmaline also attenuates dopamine transporter (DAT) activity and promotes dopamine release in striatal synaptosomes, and fully substitutes for the imidazoline I₂-site ligand 2-BFI in drug discrimination — an activity linked to its MAO-A inhibition rather than direct receptor binding.partially supported

Harmaline substitutes for imidazoline I2 site ligand 2-BFI in drug discrimination studies; associated with reversible MAO-A inhibition rather than MAO-B. pmid:11877331

At low doses (2 mg/kg i.p. in mice), harmaline produces anxiolytic-like effects synergistic with group III metabotropic glutamate receptor (mGluR) antagonismsupported

Harmaline 2 mg/kg shows anxiolytic-like effects in elevated plus maze; synergistic with mGluR group III antagonist CPPG. j.neulet.2025.138157

At 5 mg/kg in mice, it attenuates inflammatory pain and paw edema via COX inhibition, nitric oxide pathway modulation, and Nrf-2 antioxidant signaling, with reductions in IL-1β levels and oxidative stress markers.supported

Harmaline 5 mg/kg reduces pain and inflammation in mice via COX and nitric oxide pathways, antioxidant Nrf-2 activation, IL-1beta reduction. s00210-025-04220-w

Harmaline is absorbed across intestinal epithelium by transcellular passive diffusion, with additional contribution from pH- and Na⁺-dependent OATP and OCT/OCTN-mediated transportsupported

Harmaline absorbed by transcellular passive diffusion and pH/Na+-dependent mechanism via OATPs/OCTs. fphar.2017.00541

Unlike harmine, harmaline is not a substrate for the efflux transporter MRP2, contributing to its higher oral bioavailability and greater metabolic stability (CLint approximately 1.49-fold lower than harmine)partially supported

More metabolically stable than harmine. Not an MRP2 substrate. fphar.2017.00541

Bioaccessibility after simulated gastrointestinal digestion has been confirmed without cytotoxicity at tested concentrations.supported

Harmaline bioaccessible after in vitro digestion and bioavailable in Caco-2 model. No cytotoxicity at tested concentrations. molecules26185555

The principal metabolic pathway is O-demethylation to harmalol, mediated by CYP2D6 (~50% contribution; Km = 1.4 µM, Kcat = 39.9 min⁻¹) and CYP1A2 (~20% contribution; Km = 13.3 µM), with minor contributions from CYP1A1, CYP2C9, and CYP2C19partially supported

CYP2D6 (50%) and CYP1A2 (20%) are major isozymes for harmaline O-demethylation to harmalol in human liver microsomes. CYP2D6 Km = 1.4 uM for harmaline (among highest turnover ever reported). pmid:12649384

Claim in pharmacology — inconclusiveinconclusiveworking →

In the ayahuasca context, Riba et al. reported DMT Tmax at approximately 1.5 hours with subjective effects peaking at 1.5–2 hours and lasting 4–5 hours total, though these parameters reflect the combined brew pharmacology rather than isolated harmaline.partially supported

Subjective effects peaked 1.5-2h. pmid:12660312

In the ayahuasca context, Riba et al. reported DMT Tmax at approximately 1.5 hours with subjective effects peaking at 1.5–2 hours and lasting 4–5 hours total, though these parameters reflect the combined brew pharmacology rather than isolated harmaline.partially supported

DMT+harmine combinations induced dose-dependent effects lasting 4-5h in 16 healthy volunteers. j.biopha.2025.117908

Harmaline (7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole) is a naturally occurring β-carboline alkaloid and potent reversible inhibitor of monoamine oxidase A (RIMA), with an in vitro IC₅₀ of 20 nM at MAO-A — comparable to clorgyline and substantially more potent than clinical RIMAs such as moclobemidepartially supported

Harmaline IC50 for MAO-A = 20 nM under experimental conditions; reversible MAO-A inhibitor. More potent than toloxatone and moclobemide. dta.1530

Claim in summary — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

Harmaline's primary action is reversible competitive inhibition of MAO-A (IC₅₀ = 20 nM), with negligible MAO-B activitypartially supported

Seed extracts potently inhibit MAO-A (IC50 27 ug/L), predominantly attributed to harmaline and harmine. Competitive/reversible MAO-A inhibition. MAO-B poorly inhibited. j.fct.2009.12.019

Secondary mechanisms include potentiation of CaV3.1 T-type calcium channels in inferior olivary neurons — the established substrate for harmaline-induced tremor — and weak binding at 5-HT₂A receptors (Ki ≈ 42.5 µM)partially supported

Harmaline potentiates CaV3.1 T-type Ca2+ channels in inferior olive, causing synchronous 4-10 Hz oscillations that underlie harmaline-induced tremor. pnas.1002995107

Secondary mechanisms include potentiation of CaV3.1 T-type calcium channels in inferior olivary neurons — the established substrate for harmaline-induced tremor — and weak binding at 5-HT₂A receptors (Ki ≈ 42.5 µM)supported

Harmaline 5-HT2A affinity = 42.5 uM (micromolar range - weak). Despite low affinity, harmaline provided significant protection from receptor alkylation. pmid:9476990

Metabolism proceeds primarily via CYP2D6-mediated O-demethylation to harmalol (Km = 1.4 µM), with CYP1A2 contributing approximately 20% of clearance.supported

CYP2D6 (50%) and CYP1A2 (20%) are major isozymes for harmaline O-demethylation to harmalol in human liver microsomes. CYP2D6 Km = 1.4 uM for harmaline. pmid:12649384

Claim in summary — inconclusiveinconclusiveworking →

High-dose rodent studies (20 mg/kg i.p.) demonstrate cerebellar neurotoxicity including Purkinje cell apoptosis, though relevance to human doses is unestablishedsupported

Harmaline 20 mg/kg i.p. in rats causes tremor plus cerebellar granule/Purkinje cell loss and inferior olivary neuron apoptosis via caspase-3. j.neuropharm.2011.05.015

As a RIMA, harmaline poses serotonin syndrome risk when combined with serotonergic medications — a class-level inference not confirmed by harmaline-specific case reportssupported

Beta-carboline MAOIs can cause fatal serotonin toxicity in DDIs. s12248-008-9028-5

Harmaline's discriminative stimulus (3.0 mg/kg i.p.) showed partial substitution with the 5-HT₂A agonist DOM (76% harmaline-appropriate responding at 1.25 mg/kg DOM), suggesting a 5-HT₂A component to its pharmacological profile at higher doses.partially supported

Harmaline used as training drug in drug discrimination at 3.0 mg/kg i.p. in rats. Stimulus similarity to DOM (hallucinogen) demonstrated. pmid:9649961

Harmaline potentiates CaV3.1 T-type calcium channels in inferior olivary neurons, shifting the voltage dependence of activation in a hyperpolarizing direction and amplifying subthreshold oscillations to produce synchronous 4–10 Hz tremorsupported

Harmaline potentiates CaV3.1 T-type Ca2+ channels in inferior olive, causing synchronous 4-10 Hz oscillations that underlie harmaline-induced tremor. pnas.1002995107

Harmaline inhibits MAO-A with an IC₅₀ of 20 nM under in vitro conditions using kynuramine as substratesupported

Harmaline IC50 for MAO-A = 20 nM under experimental conditions; reversible MAO-A inhibitor. dta.1530

Harmaline displays weak affinity at 5-HT₂A receptors: Helsley et al. measured Ki ≈ 42.5 µM in rat brain tissue — orders of magnitude less potent than classical psychedelics such as LSD (Ki ~1–3 nM) or psilocin (Ki ~100–300 nM)supported

Harmaline 5-HT2A affinity = 42.5 uM (micromolar range - weak). pmid:9476990

CaV3.1 knockout mice lack harmaline-induced tremor entirely, and selective CaV3.1 knockdown via shRNA in the inferior olive suppresses the tremor phenotype.partially supported

CaV3.1 knockout mice lack harmaline tremor. pnas.1002995107

This activity provides a mechanistic rationale for harmaline's traditional use in pain medicine.supported

Potential anti-nociceptive implications. ijms26104636

Harmaline fully substitutes for the selective imidazoline I₂-site ligand 2-BFI in drug discrimination studies in rats, while irreversible MAO inhibitors do not consistently substitutesupported

Harmaline substitutes for imidazoline I2 site ligand 2-BFI in drug discrimination studies; associated with reversible MAO-A inhibition rather than MAO-B. pmid:11877331

Harmaline potentiates CaV3.1 T-type calcium channels in neurons of the inferior olive, generating synchronous 4–10 Hz oscillations that propagate via climbing fibers to cerebellar Purkinje cells, producing the characteristic harmaline tremorsupported

Harmaline potentiates CaV3.1 T-type Ca2+ channels in inferior olive, causing synchronous 4-10 Hz oscillations that underlie harmaline-induced tremor. CaV3.1 knockout mice lack harmaline tremor. pnas.1002995107

This mechanism has made harmaline the standard pharmacological model for essential tremor research for over five decades.supported

Comprehensive review of harmaline-induced tremor model. Harmaline and harmine are tremorigenic beta-carbolines inducing acute postural/kinetic tremor in animals. d8td9w2p

SPECT neuroimaging following ayahuasca administration (which contains harmaline) revealed increased cerebral blood flow in frontal and paralimbic regions — including anterior cingulate cortex, insular cortex, and frontal polesupported

Ayahuasca (containing harmaline) produces increased frontal and paralimbic brain activation as measured by neuroimaging. s00213-006-0358-7

Harmaline also demonstrates neuroprotective antioxidant activity, protecting brain mitochondria and synaptosomes against dopamine- and 6-hydroxydopamine (6-OHDA)-induced oxidative damage via reactive oxygen species scavenging and inhibition of thiol oxidationsupported

Harmaline protects brain mitochondria and synaptosomes against dopamine/6-OHDA oxidative damage via ROS scavenging and thiol oxidation inhibition. pmid:11403679

Ayahuasca administration modulates REM and slow-wave sleep architecture in healthy volunteers — consistent with serotonergic modulation of brainstem sleep-wake circuitrysupported

Ayahuasca (containing harmaline) modulates REM and slow-wave sleep in healthy volunteers; serotonergic mechanism via 5-HT1A and 5-HT2A activity. pmid:18030450

Quantitative analysis of ayahuasca beverages reported harmaline concentrations ranging from 27.5 to 181.3 µg/mL, with substantial batch-to-batch variability.supported

Harmaline concentrations in ayahuasca: 27.5-181.3 ug/mL. 02791072.2015.1013202

Harmine — the fully aromatic β-carboline (1-methyl-7-methoxy-β-carboline). A comparably potent MAO-A inhibitor in vitro but with lower oral bioavailability than harmaline due to MRP2 efflux and faster hepatic clearance.supported

More metabolically stable than harmine. Not an MRP2 substrate. fphar.2017.00541

In P. harmala seeds, harmaline and harmine together account for virtually all MAO-A inhibitory activity, with negligible MAO-B inhibition from any alkaloid fractionsupported

Seed extracts potently inhibit MAO-A (IC50 27 ug/L), predominantly attributed to harmaline and harmine. MAO-B poorly inhibited. j.fct.2009.12.019

Claim in alkaloid-profile — inconclusiveinconclusiveworking →

The seeds are the richest natural source: harmaline and harmine together account for virtually all MAO-A inhibitory activity in P. harmala seed extracts (combined IC₅₀ ~27 µg/L)supported

Seed extracts potently inhibit MAO-A (IC50 27 ug/L), predominantly attributed to harmaline and harmine. Competitive/reversible MAO-A inhibition. j.fct.2009.12.019

McKenna et al. identified harmaline alongside harmine and tetrahydroharmine as the principal β-carboline alkaloids in B. caapi bark preparationssupported

B. caapi contains harmine, harmaline, and tetrahydroharmine. pmid:6587171

Harmaline has also been identified at trace levels in tobacco (Nicotiana tabacum), where it functions as an endogenous MAO-A inhibitor contributing to the dopaminergic effects of tobacco smokesupported

Harmaline inhibits MAO-A and significantly attenuates DAT activity and dopamine uptake; also promotes dopamine release in synaptosomes. acschemneuro.4c00789

Multianalytical investigation of a Ptolemaic Egyptian ritual Bes-vase dated to the 2nd century BCE identified P. harmala residues alongside Nymphaea nouchali var. caerulea, indicating deliberate psychoactive use of harmaline-containing plant material in ritual contexts predating Islamic traditional medicine by over a millennium.supported

Peganum harmala identified in 2nd century BCE Egyptian ritual vase alongside Nymphaea and Cleome. Suggests ancient psychotropic ritual use of P. harmala. s41598-024-78721-8

Tanasi et al. identified P. harmala residues in a Ptolemaic Egyptian ritual vessel dated to the 2nd century BCE, representing the earliest confirmed archaeological evidence of deliberate usesupported

Peganum harmala identified in 2nd century BCE Egyptian ritual vase alongside Nymphaea and Cleome. s41598-024-78721-8

McKenna et al. published the landmark phytochemical and pharmacological characterization of β-carboline alkaloids in South American ayahuasca preparations in 1984, identifying harmaline in B. caapi and establishing the MAOI mechanism by which these alkaloids enable oral activity of DMTpartially supported

B. caapi contains harmine, harmaline, and tetrahydroharmine. Beta-carbolines are reversible MAO inhibitors enabling oral DMT activity. pmid:6587171

The identification of CaV3.1 T-type calcium channels as the inferior olivary pacemaker substrate for harmaline tremor by Park et al. in 2010 represented the most mechanistically rigorous advance in understanding the phenomenon.partially supported

Harmaline potentiates CaV3.1 T-type Ca2+ channels in inferior olive, causing synchronous 4-10 Hz oscillations that underlie harmaline-induced tremor. pnas.1002995107

Contemporary harmaline research has expanded beyond the tremor model into several domains: neuroplasticity and adult neurogenesis, neuroprotection against oxidative damage, anti-inflammatory and antinociceptive activity, and novel ion channel pharmacology including Nav1.7 sodium channel blockadesupported

Harmaline protects brain mitochondria and synaptosomes against dopamine/6-OHDA oxidative damage via ROS scavenging and thiol oxidation inhibition. pmid:11403679

Harmaline crosses intestinal epithelium via transcellular passive diffusion, supplemented by pH- and Na⁺-dependent uptake through organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs/OCTNs)supported

Harmaline absorbed by transcellular passive diffusion and pH/Na+-dependent mechanism via OATPs/OCTs. fphar.2017.00541

Bioaccessibility following simulated gastrointestinal digestion (oral, gastric, and intestinal phases) has been confirmed, with absorption across Caco-2 cell monolayers proceeding without cytotoxicity.supported

Harmaline bioaccessible after in vitro digestion and bioavailable in Caco-2 model. No cytotoxicity at tested concentrations. molecules26185555

All values from Yu et al..supported

CYP2D6 (50%) and CYP1A2 (20%) are major isozymes for harmaline O-demethylation to harmalol in human liver microsomes. CYP2D6 Km = 1.4 uM. pmid:12649384

This has two important consequences: (1) CYP2D6 genetic polymorphism — poor metabolizer status (5–10% of Europeans, ~1% of East Asians) — will produce disproportionately elevated harmaline plasma levels and prolonged duration; and (2) co-administration of CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) would substantially increase harmaline exposure.partially supported

CYP2D6 important in IAA metabolism. Beta-carboline MAOIs can cause fatal serotonin toxicity in DDIs. s12248-008-9028-5

Egger et al. examined the pharmacokinetic and pharmacodynamic interaction of DMT and harmine (close analog of harmaline) in 16 healthy volunteers in a dose-ranging designsupported

DMT+harmine combinations induced dose-dependent effects lasting 4-5h in 16 healthy volunteers. j.biopha.2025.117908

Palhano-Fontes et al. conducted a randomized, double-blind, placebo-controlled trial (NCT02914769) of ayahuasca in 29 patients with treatment-resistant major depressionsupported

First RCT of ayahuasca (containing harmaline) in treatment-resistant depression (n=29). s0033291718001356

Dos Santos et al. systematically reviewed the evidence for antidepressant and anxiolytic effects of ayahuasca, concluding that the available literature supports therapeutic potential warranting further controlled investigation.supported

Systematic review of ayahuasca (containing harmaline) antidepressant and anxiolytic effects in both animal and human studies. 1516-4446-2015-1701

Claim in chemistry — not_supportednot supportedworking →

Claim in chemistry — inconclusiveinconclusiveworking →

Compared to moclobemide — the only RIMA widely available as a pharmaceutical — harmaline is substantially more potent at MAO-A in vitro (IC₅₀ 20 nM vs. moclobemide IC₅₀ typically 6,000–20,000 nM)supported

Harmaline IC50 for MAO-A = 20 nM under experimental conditions; reversible MAO-A inhibitor. More potent than toloxatone and moclobemide. dta.1530