Harmine (DB07919): A Comprehensive Pharmacological and Therapeutic Review

1. Introduction to Harmine

Harmine is a naturally occurring β-carboline alkaloid, a class of compounds known for their diverse biological activities, including psychoactive effects.[1] It is a prominent member of the harmala alkaloids. First isolated and named by Fritsch in 1848 from the seeds of

Peganum harmala (Syrian rue), harmine was subsequently identified in other botanical sources, most notably Banisteriopsis caapi, a key ingredient in the traditional Amazonian psychoactive brew, Ayahuasca.[1] Its chemical structure was elucidated in 1927.[1]

Harmine is identified by the DrugBank ID DB07919 and CAS Number 442-51-3.[1] Over its history, it has been known by various alternative names, including banisterin, banisterine, telopathin, telepathine, leucoharmine, yagin, and yageine.[1] These multiple designations often reflect its independent discovery from different plant sources and allude to the profound psychoactive effects observed by traditional users. For instance, the name 'telepathine' was coined due to the purported telepathic experiences reported by indigenous Amazonian peoples using Ayahuasca.[2]

The compound has a long history of both traditional and early pharmacological use, notably as an antiparkinsonian medication from the late 1920s to the early 1950s, although it was later abandoned for this purpose.[1] This early application, despite its discontinuation, hinted at neuroactive properties that are now being re-explored with modern scientific understanding. Harmine's journey from traditional ethnobotanical use to contemporary pharmacological investigation reveals a molecule with a complex, multi-target profile, presenting both significant therapeutic potential and notable safety considerations that continue to be areas of active research.

2. Chemical Properties

The chemical identity and physicochemical characteristics of harmine are fundamental to understanding its biological activity and disposition.

Chemical Structure and Formula:

Harmine's preferred IUPAC name is 7-Methoxy-1-methyl-9H-pyrido[3,4-b]indole.1 Its molecular formula is

C13​H12​N2​O.[1] As a β-carboline, harmine possesses a tricyclic ring system where a pyridine ring is fused to an indole moiety; specifically, it is a derivative of harman, methoxy-substituted at position C-7.[2] This planar tricyclic structure is a key determinant of some of its biological activities, such as its ability to intercalate into DNA.[14]

Molecular Weight:

The molecular weight of harmine is consistently reported as approximately 212.2 g/mol, with slight variations depending on the source (e.g., 212.2 g/mol 4, 212.25 g/mol 1). This relatively small molecular size can influence its diffusion across biological membranes.

Physical State and Appearance:

Harmine exists as a solid at room temperature.5 Its appearance can vary, described as a white to orange to green powder or crystal.5 This variation may depend on the purity of the sample and its source.

Solubility:

Harmine exhibits differential solubility in various solvents, a critical factor for experimental work and potential pharmaceutical formulations.

• Dimethylformamide (DMF): 2 mg/mL.[4]
• Dimethyl sulfoxide (DMSO): Reported as 1.5 mg/mL [4] and also as soluble up to 100 mM.[12]
• Ethanol: Reported as 1.5 mg/mL [4] and soluble up to 5 mM with gentle warming.[12]
• Phosphate-buffered saline (PBS, pH 7.2): 0.25 mg/mL.[4]
• Water: Generally considered insoluble [1], with a predicted solubility of 0.0613 mg/mL (ALOGPS).[6]
• Hot Methanol: Almost transparent solubility.[5]

The observed variability in reported solubility values, for instance, between [4] and [12]/[13] for DMSO and ethanol, underscores the importance of specifying experimental conditions (e.g., temperature, solvent grade) and compound purity when reporting such data. A concentration of 100 mM harmine (MW 212.25 g/mol) translates to 21.225 mg/mL, which is substantially different from 1.5 mg/mL for DMSO, highlighting potential discrepancies that researchers must consider.

Other Physicochemical Properties:

Additional properties that influence harmine's behavior include:

• Density: Reported as 1.326 g/cm³ [1] and predicted as 1.65±0.1 g/cm³.[5]
• Melting Point: 321 °C (for harmine hydrochloride); 262 °C (for harmine hydrochloride dihydrate).[1]
• LogP (octanol-water partition coefficient): Values vary depending on the prediction method, e.g., 3.05 (ALOGPS) [6], 1.85 (Chemaxon) [6], and 3.6 (XLogP3).[11] These values suggest moderate lipophilicity.
• pKa: Strongest acidic pKa predicted at 13.54; strongest basic pKa predicted at 6.15 (Chemaxon).[6]
• Polar Surface Area (PSA): 37.91 Ų.[6]

The poor aqueous solubility of harmine [1] is a significant characteristic, likely contributing to its low oral bioavailability observed in some studies.[43] This presents a common challenge in the development of oral drug formulations. Strategies to overcome this include salt formation (e.g., harmine hydrochloride, which is more soluble [1]) or the exploration of alternative delivery routes.

Table 1: Summary of Harmine Chemical and Physical Properties

Property	Value	Reference(s)
IUPAC Name	7-Methoxy-1-methyl-9H-pyrido[3,4-b]indole	1
CAS Number	442-51-3	1
Molecular Formula	C13​H12​N2​O	1
Molecular Weight	~212.25 g/mol	1
Appearance	White to Orange to Green powder/crystal	5
Melting Point	321 °C (HCl salt); 262 °C (HCl·2H₂O salt)	1
Solubility (Water)	Insoluble; 0.0613 mg/mL (predicted)	1
Solubility (DMSO)	1.5 mg/mL; up to 100 mM	4
Solubility (Ethanol)	1.5 mg/mL; up to 5 mM (with warming)	4
LogP	1.85 - 3.6 (prediction dependent)	6
pKa (Strongest Basic)	6.15 (predicted)	6
Polar Surface Area	37.91 Ų	6

3. Pharmacology

Harmine exhibits a complex pharmacological profile, interacting with multiple biological targets, which underpins its diverse range of observed effects.

3.1. Mechanism of Action

Harmine's mechanisms of action are multifaceted, involving inhibition of key enzymes and direct interaction with nucleic acids.

3.1.1. Monoamine Oxidase A (MAO-A) Inhibition

A primary and well-characterized action of harmine is its potent, reversible, and selective inhibition of monoamine oxidase A (MAO-A).1 It demonstrates high affinity for MAO-A, with reported

IC50​ values around 4.1 nM (0.0041 µM), and does not significantly inhibit the MAO-B isoform.[1] MAO-A is a critical enzyme in the metabolism of monoamine neurotransmitters, including serotonin, norepinephrine, and dopamine.[16] By inhibiting MAO-A, harmine increases the synaptic availability of these neurotransmitters.

This mechanism is fundamental to several of harmine's effects. It is crucial for the psychoactivity of Ayahuasca, where harmine prevents the first-pass metabolism of co-ingested N,N-dimethyltryptamine (DMT) by MAO-A in the gut and liver, allowing DMT to reach systemic circulation and exert its hallucinogenic effects.[1] Furthermore, MAO-A inhibition is the basis for harmine's potential as an antidepressant agent.[1] The reversibility of harmine's MAO-A inhibition (classifying it as a RIMA) is a significant feature, potentially offering a safer profile concerning dietary tyramine interactions compared to older, irreversible MAOIs.[17]

3.1.2. Dual-specificity Tyrosine-phosphorylation-regulated Kinase 1A (DYRK1A) Inhibition

Harmine is also a potent and selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).12 Reported

IC50​ values are approximately 80 nM for DYRK1A, compared to 800 nM for DYRK3 and 900 nM for DYRK2, indicating a degree of selectivity for DYRK1A.[12] DYRK1A is a serine/threonine kinase implicated in various cellular processes, including neuronal development, tau protein phosphorylation, and cell proliferation.[27]

The inhibition of DYRK1A by harmine has significant therapeutic implications:

• Neurodegenerative Diseases: In conditions like Alzheimer's disease (AD) and Down syndrome (DS), where DYRK1A is often overexpressed, its inhibition by harmine may reduce tau hyperphosphorylation (a pathological hallmark of AD) and mitigate amyloid-beta pathology.[12]
• Diabetes Mellitus: Harmine has been shown to induce the proliferation of pancreatic alpha (α) and beta (β) cells in adult humans, an effect attributed to DYRK1A inhibition.[1] Notably, harmine is currently the only known pharmacological agent reported to elicit this proliferative response in adult human pancreatic islet cells.[1]

3.1.3. DNA Intercalation

The planar, tricyclic structure of harmine allows it to intercalate between the base pairs of DNA.14 This interaction can interfere with crucial DNA-dependent processes, including the activity of DNA topoisomerases and telomerase.14 DNA intercalation is a mechanism utilized by some anticancer drugs; however, it also raises concerns regarding potential mutagenicity and genotoxicity.34 This property is thought to contribute to harmine's observed antitumor effects.14

3.1.4. Other Potential Molecular Targets

Beyond MAO-A and DYRK1A, harmine may interact with other molecular targets, albeit often with lower affinity. It shows inhibitory activity against DYRK2 and DYRK3, though at higher concentrations than for DYRK1A.12 There is also suggestion that β-carbolines, including harmine, may bind to benzodiazepine, imidazoline, serotonin, and opiate receptors, which could contribute to their wide range of psychopharmacological effects.36 While direct evidence for harmine's interaction with 5-HT2A and 5-HT2C receptors is not explicitly detailed in the provided materials, the structural similarity to harmaline, which does interact with these receptors 26, makes such interactions plausible. The capacity to engage multiple targets contributes to harmine's complex pharmacological profile, offering potential for diverse therapeutic applications but also increasing the likelihood of varied side effects.

The dual inhibition of MAO-A and DYRK1A at pharmacologically relevant concentrations presents a unique therapeutic profile. MAO-A inhibition primarily affects neurotransmitter levels, influencing mood and psychoactivity, while DYRK1A inhibition impacts cellular processes like proliferation and tau phosphorylation. The interplay between these mechanisms in vivo is a critical area for further research, as it could lead to synergistic benefits in certain conditions (e.g., neurodegenerative diseases involving both neurotransmitter imbalances and protein pathology) or result in a complex array of desired and undesired effects that are challenging to manage. For example, while DYRK1A inhibition may be sought for pancreatic β-cell regeneration, the concurrent MAO-A inhibition could lead to unwanted psychoactive effects or drug interactions.

Furthermore, the DNA intercalating property, while potentially beneficial for anticancer activity, raises significant concerns about genotoxicity. This could limit the suitability of harmine for chronic use in non-oncological conditions unless derivatives can be developed that separate the desired pharmacological activities from DNA binding.

3.2. Pharmacodynamics

The mechanisms of action translate into observable pharmacodynamic effects on various physiological systems.

Effects on Neurotransmitter Systems:

As a consequence of MAO-A inhibition, harmine leads to increased synaptic concentrations of serotonin, norepinephrine, and dopamine.1 This neurochemical modulation is believed to underlie its psychoactive properties, its potential antidepressant effects, and its capacity for significant interactions with other psychotropic medications.24

Cellular Effects:

Harmine exerts several notable effects at the cellular level:

• It induces the proliferation of pancreatic β-cells, a key finding for diabetes research.[1]
• In cancer cell lines, harmine inhibits proliferation, migration, and angiogenesis, and induces apoptosis.[35]
• It inhibits telomerase activity in MCF-7 breast cancer cells, leading to an accelerated senescent phenotype.[34]
• Harmine also regulates the expression of PPARγ (peroxisome proliferator-activated receptor gamma).[12]

An interesting, non-pharmacological property of harmine is its utility as a fluorescent pH indicator; its fluorescence emission characteristics change in response to alterations in the local pH environment.[1] This suggests intrinsic physicochemical properties that could be exploited for developing analytical tools or sensors, independent of its direct pharmacological actions.

4. Pharmacokinetics (PK)

The absorption, distribution, metabolism, and excretion (ADME) profile of harmine dictates its concentration at target sites and its duration of action.

4.1. Absorption

Oral bioavailability of harmine is generally reported to be low. One study in rats indicated an absolute bioavailability of 3% for harmine, compared to 19% for the related β-carboline, harmane.43 Another source also cites a low oral bioavailability of 3% for harmine.44 This limited oral absorption is a significant consideration for therapeutic development and is likely attributable to extensive first-pass metabolism, primarily by MAO-A in the gut and liver 25, and potentially its poor aqueous solubility.

The time to reach maximum plasma concentration (Tmax​) varies with the route of administration and co-administered substances. When co-administered with DMT, Tmax​ for harmine increased with dose escalation.[25] Buccal administration of harmine has been shown to produce sustained-release pharmacokinetic profiles, with one study reporting a

Cmax​ of 32.5 ng/mL and a Tmax​ of 1.6 hours.[47] The exploration of alternative delivery routes such as buccal administration aims to bypass the issues of first-pass metabolism and improve systemic exposure.

4.2. Distribution

Harmine appears to distribute well into tissues. Animal studies suggest a larger volume of distribution (Vd) for harmine (3.9 L/kg in rats) compared to harmane, indicating better tissue penetration.43 Specific data on protein binding for harmine were not detailed in the provided materials, though this is a key parameter influencing drug distribution and availability. Harmine is known to cross the blood-brain barrier, which is consistent with its observed central nervous system effects and its use in PET imaging to quantify brain MAO-A levels.1 Good tissue distribution, including CNS penetration, is crucial for its potential applications in neurological and psychiatric disorders.

4.3. Metabolism

Harmine undergoes extensive metabolism. Identified metabolites include harmol and 6-OH-harmaline.6 One study in rats identified seven metabolites of harmine in urine and bile, formed through pathways including O-demethylation, hydroxylation, O-glucuronide conjugation, and O-sulphate conjugation. This study also noted the transformation of harmaline to harmine via oxidative dehydrogenation in rats, highlighting the interconversion potential among harmala alkaloids.49

Cytochrome P450 (CYP) enzymes are involved in the metabolism of β-carbolines. Specifically, CYP2D6 and CYP1A2 have been implicated in the O-demethylation of harmaline, a closely related compound often co-occurring with harmine.[50] While direct studies on harmine's specific CYP interactions are less detailed in the provided snippets, similar pathways are likely involved. Studies have shown that harmaline and harmine are metabolized at different rates across various mammalian species, with rapid metabolism in rats, mice, and rabbits, moderate metabolism in humans and dogs, and weak metabolism in sheep.[51] This species-specific metabolic profiling is critical for the appropriate selection and interpretation of animal models in preclinical studies.

A noteworthy pharmacokinetic interaction occurs between harmine and DMT; harmine reduces the metabolism of DMT, but DMT also appears to alter the pharmacokinetics of harmine.[25] This bidirectional interaction suggests a more complex relationship than simple enzyme inhibition by harmine, possibly involving competition for the same metabolic enzymes or transporters, or other physiological feedback mechanisms. This complexity contributes to the variability in effects observed with traditional Ayahuasca preparations.

4.4. Excretion

The metabolites of harmine are excreted primarily through renal and fecal routes.6 Understanding these excretion pathways is important for considering dose adjustments in individuals with impaired kidney or liver function.

4.5. Elimination Half-Life

The plasma elimination half-life of harmine in humans is reported to be relatively short, generally in the order of 1 to 3 hours.1 Studies involving buccal administration of harmine have reported a half-life (

t1/2​) of approximately 1.4 to 1.5 hours.[47] In rats, a much shorter elimination

t1/2β​ of 26 minutes was observed after intravenous administration.[43] The short half-life suggests that for sustained therapeutic effects with harmine, frequent dosing regimens or modified-release formulations would likely be necessary. This contrasts with the longer duration of psychoactive effects observed with Ayahuasca, which is attributed to the complex interplay of multiple compounds and the sustained inhibition of MAO-A.

Table 2: Key Pharmacokinetic Parameters of Harmine in Humans (Data from provided sources)

Parameter	Value	Route/Condition	Reference(s)
Oral Bioavailability	Low (e.g., 3% reported in animals)	Oral	43
Tmax​ (Time to Peak)	~1.4 - 1.6 hours	Buccal (100 mg)	47
	Increases with dose (oral with DMT)	Oral (with DMT)	25
Cmax​ (Peak Concentration)	~32.5 - 33.5 ng/mL	Buccal (100 mg)	47
	Up to 49 ng/mL	Oral (up to 180 mg, with DMT)	25
Volume of Distribution (Vd​)	3.9 L/kg (rats)	IV (rats)	43
Protein Binding	Not specified for harmine	-	-
Elimination Half-life (t1/2​)	~1 - 3 hours	Oral/IV	1
	~1.4 - 1.5 hours	Buccal	47
Major Metabolites	Harmol, 6-OH-harmaline, glucuronides, sulfates	-	6
Primary Excretion Route	Renal and fecal (metabolites)	-	6
Known CYP Involvement	Likely (CYP2D6, CYP1A2 for harmaline)	-	50

Note: Human pharmacokinetic data for harmine alone is limited in the provided sources; some parameters are inferred from animal studies or studies involving co-administration.

5. Therapeutic Potential and Research Applications

Harmine's diverse pharmacological activities have spurred research into its therapeutic potential across a range of conditions, alongside its utility as a research tool.

5.1. Neurological and Psychiatric Disorders

5.1.1. Depression

The MAO-A inhibitory properties of harmine form the primary basis for its investigation in depression.1 By increasing synaptic levels of key neurotransmitters like serotonin, norepinephrine, and dopamine, harmine could exert antidepressant effects. Some reports also suggest anti-inflammatory properties that might contribute to its potential in mood disorders.16 While MAOIs are an established class of antidepressants, the specific clinical development of harmine for depression is in early stages. A Phase 1 dose-escalation study of harmine in healthy volunteers has been documented, focusing on determining the maximum tolerated dose and safety, rather than efficacy in depressed patients.54 Another study on pure oral harmine in healthy volunteers assessed mood and side effects but was not designed as a depression treatment trial.22 The psychoactive effects and overall side effect profile of harmine require careful consideration if it is to be developed as a mainstream antidepressant.

5.1.2. Parkinson's Disease (PD)

Harmine has a historical connection to Parkinson's disease, having been used as an antiparkinsonian medication from the late 1920s to the early 1950s.1 There is renewed interest in reconsidering harmine as a potential rapidly acting agent for PD.7 Its mechanism in PD could involve MAO-A inhibition (as MAO-B inhibitors are standard PD treatments, and MAO-A also metabolizes dopamine) and possibly DYRK1A inhibition, though the latter's role in PD is less clearly defined in the provided materials compared to its role in Alzheimer's disease.57 Early clinical trials yielded mixed results, and harmine was eventually abandoned for PD due to perceived weaker efficacy compared to other available treatments and its side effect profile.10

5.1.3. Alzheimer's Disease (AD) and Neuroprotection

The inhibition of DYRK1A by harmine is a key focus for AD research.27 DYRK1A is overexpressed in Down syndrome (DS) and AD, and is implicated in the hyperphosphorylation of tau protein (a hallmark of AD pathology) and the processing of amyloid precursor protein, which leads to amyloid-beta plaque formation.27 Harmine and its derivatives are being investigated for their potential to inhibit DYRK1A and thereby prevent or slow age-associated neurodegeneration. Given harmine's potent MAO-A inhibitory activity, it is often used as a chemical scaffold for developing new, more selective DYRK1A inhibitors that lack significant MAO-A effects, aiming to improve the therapeutic window for AD treatment.27

5.2. Diabetes Mellitus

A particularly notable and unique therapeutic potential of harmine lies in its ability to induce the proliferation of pancreatic alpha (α) and beta (β) cells in adult humans.[1] This effect is attributed to its inhibition of DYRK1A. Harmine is currently the only pharmacological agent known to elicit this regenerative response in adult human pancreatic islet cells.[1] Animal studies using high-fat diet-induced diabetic mice have further demonstrated harmine's antidiabetic and anti-adipogenic properties, showing improvements in glycemic control, insulin sensitivity, lipid profiles, and a reduction in oxidative stress.[33] The prospect of regenerating insulin-producing cells offers a potentially transformative approach to diabetes treatment. However, the systemic administration of a compound with such broad activity as harmine to achieve this localized pancreatic effect presents a significant benefit-risk assessment challenge, given DYRK1A's widespread expression and roles in other tissues.[27]

5.3. Oncology

Harmine has demonstrated a broad spectrum of antitumor effects in preclinical research.[35] Its anticancer activity is attributed to multiple mechanisms:

• Inhibition of Epithelial-to-Mesenchymal Transition (EMT): Reducing cancer cell invasiveness and metastasis.[35]
• Inhibition of Angiogenesis: Limiting tumor blood supply.[35]
• Induction of Tumor Cell Apoptosis: Triggering programmed cell death in cancer cells, partly via the PI3K/Akt/mTOR pathway and modulation of Bcl-2 family proteins.[35]
• Regulation of the Cell Cycle: Causing cell cycle arrest at various phases (G0/G1, S, or G2/M) depending on the cancer type.[35]
• Inhibition of DNA Topoisomerases and Telomerase: Resulting from its DNA intercalating properties.[14]

Furthermore, harmine has shown synergistic effects when combined with conventional chemotherapeutic drugs and has potential as a radiosensitizer.[35] It may also enhance the efficacy of immunotherapy by modulating the tumor immune microenvironment.[35] Despite these promising activities, the clinical application of harmine in oncology is currently limited by its poor solubility and significant neurotoxicity. Consequently, research efforts are directed towards developing harmine derivatives with improved pharmacokinetic profiles and reduced toxicity.[35] The DNA intercalation mechanism, while contributing to anticancer effects, also brings the risk of genotoxicity, which needs careful evaluation.

5.4. Other Investigated Uses

Harmine's utility extends beyond direct therapeutic applications into various research roles:

• Fluorescent pH Indicator: Its fluorescence emission is sensitive to changes in pH, making it a useful laboratory tool.[1]
• PET Imaging Ligand: Carbon-11 labeled harmine ($[^{11}C]$harmine) is employed in positron emission tomography (PET) studies to visualize and quantify MAO-A levels in the human brain, aiding research into psychiatric and neurological disorders characterized by MAO-A dysregulation.[1]
• Antimicrobial, anti-inflammatory, antifungal, and antiplasmodial activities have also been reported for harmine or harmala alkaloids, reflecting the broad biological screening these natural products have undergone.[2]

The polypharmacology of harmine, while offering multiple avenues for therapeutic exploration, also presents a significant challenge. Developing it as a targeted therapy for a single condition is complicated by potential off-target effects and a complex side-effect profile stemming from its interactions with MAO-A, DYRK1A, and DNA, among others. The ethnobotanical uses of harmine-containing plants for a wide array of ailments may offer clues for further investigation but require rigorous scientific validation, as traditional preparations often involve complex mixtures and different administration routes, and perceived benefits may not always align with modern safety and efficacy standards.

6. Ethnobotanical Significance and Natural Sources

Harmine's history is deeply rooted in traditional medicine and ethnobotany, primarily due to its presence in several psychoactive and medicinal plants.

Principal Plant Sources:

Harmine is found in a variety of plant species, with notable concentrations in:

• Peganum harmala (Syrian Rue or Harmal): The seeds of this plant are a primary source of harmine and other harmala alkaloids.[1] The concentration of total harmala alkaloids in P. harmala seeds is reported to be around 3% by dry weight, although this can vary significantly (from 2–7% or even higher) depending on the specific plant material and environmental conditions.[2]
• Banisteriopsis caapi (Ayahuasca Vine): This Amazonian liana is a fundamental ingredient in the psychoactive brew known as Ayahuasca.[1] The concentration of harmine in B. caapi stems has been reported to range from 0.31% to 8.43%.[2]
• Other Sources: Harmine has also been identified in various species of Passiflora (passionflower), lemon balm (Melissa officinalis), and even tobacco (Nicotiana species).[1] Its presence in such diverse and geographically widespread plants partly explains its independent discovery and varied traditional applications across different cultures.

The considerable variability in harmine and other harmala alkaloid concentrations within natural plant sources [2] is a critical factor contributing to the inconsistent potency and psychoactive effects of traditional preparations like Ayahuasca. This lack of standardization presents challenges for consistent traditional use and for modern scientific research attempting to study these complex botanical preparations.[47]

Traditional Medicinal Uses of Source Plants:

The plants containing harmine have a rich history of use in traditional medicine systems:

• Peganum harmala has been traditionally employed for a wide array of ailments, including as an analgesic, anti-inflammatory agent, emmenagogue (to promote menstruation), and abortifacient. It has also been used to treat conditions such as depression, infections, rheumatism, and various skin disorders.[2] The smoke from burning P. harmala seeds has been used for ritual purification and protection against the "evil eye" in some cultures.[58] The traditional use of P. harmala smoke suggests that inhalation might be an effective route for administering harmala alkaloids, potentially bypassing first-pass metabolism and leading to different pharmacokinetic and pharmacodynamic profiles compared to oral ingestion—an area that appears underexplored in modern research based on the provided information.
• Banisteriopsis caapi is central to Amazonian shamanistic practices, primarily due to its role as the base ingredient for Ayahuasca.[2] Historically, there are also accounts of its use in the treatment of Parkinson's disease.[2]

Role in Ayahuasca:

Harmine, along with other β-carbolines like harmaline found in B. caapi, plays a crucial role in the pharmacology of Ayahuasca. Its primary function in this context is as an MAO-A inhibitor.1 Ayahuasca is typically prepared by combining

B. caapi with leaves of plants like Psychotria viridis, which contain the potent psychedelic compound N,N-dimethyltryptamine (DMT). DMT is not orally active on its own because it is rapidly metabolized by MAO-A in the gastrointestinal tract and liver. Harmine inhibits this enzyme, allowing DMT to be absorbed into the bloodstream, cross the blood-brain barrier, and exert its characteristic psychoactive effects.[1] Ayahuasca is traditionally used for spiritual, divinatory, social, and medicinal purposes within indigenous Amazonian cultures.[2] The synergistic interaction between harmine and DMT in Ayahuasca is a classic example of ethnopharmacological knowledge.

It is important to recognize that the co-occurrence of multiple harmala alkaloids (harmine, harmaline, tetrahydroharmine, etc.) in these source plants [2] means that the observed effects of traditional preparations are likely due to the complex interplay of these compounds, rather than harmine acting in isolation. Modern research focusing solely on isolated harmine may not fully replicate the ethnobotanical reality or the complete therapeutic and psychoactive profile of these traditional medicines.

7. Safety Profile and Toxicology

The therapeutic application of harmine is significantly influenced by its safety profile, which includes a range of adverse effects and potential drug interactions.

7.1. Adverse Effects

Harmine administration can lead to several adverse effects, particularly at higher doses:

• Common Effects: The most frequently reported adverse effects are gastrointestinal, including nausea and vomiting.[1] Central nervous system effects such as drowsiness, dizziness, and impaired concentration are also common.[1]
• Neurological/Psychiatric Effects: Agitation and paresthesias have been reported.[1] While some sources suggest hallucinogenic effects at high doses [7], a Phase 1 study with pure oral harmine hydrochloride up to 500 mg in healthy adults did not report major psychoactive effects or hallucinations, though drowsiness was noted in some participants.[22] This discrepancy may be attributable to differences in dose, compound purity, individual sensitivity, or the specific definition of "psychoactive."
• Cardiovascular Effects: Both bradycardia and tachycardia have been observed, as well as transient hypotension, which may occur particularly during episodes of vomiting.[1]
• Dose-Dependent Toxicity: Adverse effects are generally dose-dependent. A Phase 1 clinical trial established a Maximum Tolerated Dose (MTD) for single oral doses of pharmaceutical-grade harmine hydrochloride in healthy adults at approximately 2.7 mg/kg body weight.[1] The study also noted that adverse effects were more common in participants with lower body weight when given fixed doses, suggesting that weight-based dosing is more appropriate for defining tolerance thresholds.[1]

The adverse effect profile, particularly the gastrointestinal and central nervous system disturbances, requires careful consideration in the development of harmine for therapeutic purposes. The MTD of 2.7 mg/kg established in a controlled clinical setting [1] provides crucial modern safety data. However, this contrasts with the traditional use of Ayahuasca, which often involves unquantified doses of harmine and co-administration with DMT and other harmala alkaloids. The perceived safety in traditional contexts might be influenced by lower effective doses of harmine, different absorption profiles from crude plant preparations, or cultural frameworks for interpreting and managing what would be considered adverse effects in a clinical trial setting (e.g., nausea and vomiting are often considered part of the Ayahuasca purging experience [23]).

7.2. Drug Interactions

Harmine's potent MAO-A inhibitory activity is the primary driver of its clinically significant drug interactions.

• Serotonin Syndrome: This is a potentially life-threatening condition that can occur when harmine is co-administered with other serotonergic agents, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), but also other antidepressants or drugs that increase serotonin levels.[24]
• Pathophysiology: Harmine inhibits MAO-A, preventing the breakdown of serotonin. SSRIs block the reuptake of serotonin from the synaptic cleft. The combination leads to a synergistic and excessive accumulation of serotonin in the central nervous system, overstimulating postsynaptic 5-HT1A and 5-HT2A receptors.[41]
• Clinical Presentation: Symptoms typically include a triad of mental status changes (e.g., agitation, confusion, delirium), autonomic hyperactivity (e.g., tachycardia, hypertension, hyperthermia, diaphoresis, diarrhea), and neuromuscular abnormalities (e.g., tremor, myoclonus, hyperreflexia, rigidity).[36] Severe cases can be fatal.
• Tyramine-Induced Hypertensive Crisis (the "Cheese Reaction"): This adverse reaction can occur when MAO-A inhibitors like harmine are taken concomitantly with tyramine-rich foods or beverages (e.g., aged cheeses, cured meats, fermented products, certain beers and wines).[18]
• Mechanism: MAO-A enzymes in the gastrointestinal tract and liver are responsible for metabolizing dietary tyramine. Harmine inhibits these enzymes, allowing tyramine to be absorbed systemically. Tyramine acts as an indirect sympathomimetic, causing the release of large amounts of norepinephrine from sympathetic nerve endings, leading to vasoconstriction and a rapid, potentially dangerous increase in blood pressure.[64]
• Clinical Implication for RIMAs: Harmine is a reversible inhibitor of MAO-A (RIMA). RIMAs generally pose a lower risk of the tyramine pressor response compared to older, irreversible MAOIs. This is because the inhibition by RIMAs can be overcome by high concentrations of substrate (like tyramine) or as the RIMA is cleared from the system.[17] However, the risk is not entirely eliminated, and dietary caution is still warranted, especially with higher or sustained doses of harmine. Given harmine's relatively short half-life (1-3 hours), MAO-A inhibition might fluctuate if used chronically, and consumption of tyramine-rich food during peak harmine levels could still precipitate a reaction.
• Interactions with N,N-Dimethyltryptamine (DMT): As previously discussed, harmine's MAO-A inhibition is essential for the oral activity of DMT in Ayahuasca by preventing its first-pass metabolism [multiple snippets, see section 6.3]. Studies also suggest that DMT may, in turn, alter the pharmacokinetics of harmine, indicating a bidirectional interaction.[25]
• CYP450-Mediated Interactions: Since harmine's metabolism likely involves cytochrome P450 enzymes [49], co-administration with potent inhibitors or inducers of these enzymes could significantly alter harmine's plasma concentrations and, consequently, its efficacy and toxicity. [70] lists numerous potential drug interactions for harmaline (a related β-carboline with MAOI properties), many of which involve CYP enzyme modulation or additive pharmacodynamic effects; similar precautions would apply to harmine.

The primary safety concerns associated with harmine—Serotonin Syndrome and Hypertensive Crisis—are direct consequences of its MAO-A inhibitory mechanism. This implies that any therapeutic application leveraging this mechanism must inherently address these risks through careful patient selection, comprehensive patient education regarding dietary and drug restrictions, and diligent monitoring. For indications where MAO-A inhibition is not the desired therapeutic effect (e.g., DYRK1A inhibition for diabetes), the development of harmine derivatives that minimize MAO-A activity would be a crucial strategy to enhance the safety profile.

7.3. Toxicology

Beyond acute adverse effects and drug interactions, potential longer-term toxicities are also a concern:

• Neurotoxicity: This has been noted as a concern, particularly at higher doses, though the specific manifestations are not extensively detailed in the provided snippets beyond general CNS effects.[35]
• Genotoxicity: Harmine's ability to intercalate into DNA raises concerns about potential mutagenicity and carcinogenicity, especially with chronic exposure.[14] This is a significant hurdle for the development of harmine for non-oncological chronic conditions.

7.4. Clinical Implications of Reversible MAO-A Inhibition

The reversibility of MAO-A inhibition by harmine distinguishes it from older, irreversible MAOIs and has important clinical implications:

• Tyramine Interaction: RIMAs are generally associated with a reduced risk of tyramine-induced hypertensive crisis compared to irreversible MAOIs. This is because the enzyme inhibition can be surmounted by high concentrations of tyramine or recovers as the RIMA is eliminated from the body.[17] Nonetheless, dietary caution is still advisable.
• Serotonergic Drug Interactions: The risk of Serotonin Syndrome remains significant even with RIMAs when combined with other serotonergic drugs.[24]
• Washout Periods: When switching between antidepressants, the washout period required for RIMAs may be shorter than for irreversible MAOIs due to the faster recovery of enzyme activity. However, caution and adherence to specific guidelines are still paramount to avoid adverse interactions.[18]

Table 3: Clinically Significant Drug and Food Interactions with Harmine

Interacting Agent/Class	Mechanism of Interaction	Potential Clinical Consequence	Management/Precaution	Reference(s)
Selective Serotonin Reuptake Inhibitors (SSRIs) and other Serotonergic Agents (e.g., SNRIs, TCAs, other MAOIs, triptans, opioids like tramadol, St. John's Wort)	Additive serotonergic effects due to MAO-A inhibition by harmine and inhibition of serotonin reuptake or increased serotonin release/activity by the other agent.	Serotonin Syndrome (potentially life-threatening): mental status changes, autonomic hyperactivity, neuromuscular abnormalities.	Contraindicated or use with extreme caution and close monitoring. Avoid co-administration, especially with other MAOIs. Ensure adequate washout periods when switching.	24
Tyramine-Rich Foods (e.g., aged cheeses, cured meats, fermented products, some beers/wines)	Inhibition of MAO-A in the gut and liver by harmine prevents breakdown of dietary tyramine. Tyramine displaces norepinephrine from sympathetic nerve endings.	Hypertensive Crisis ("Cheese Reaction"): severe headache, rapid heartbeat, chest pain, dangerously high blood pressure, potential for stroke.	Dietary restrictions are necessary. Patients should avoid or strictly limit tyramine-rich foods. Risk is lower with RIMAs than irreversible MAOIs but still present.	18
Sympathomimetic Drugs (e.g., pseudoephedrine, phenylephrine, stimulants)	Harmine's MAO-A inhibition can potentiate the effects of sympathomimetic drugs by reducing their metabolism or enhancing norepinephrine release.	Hypertensive crisis, tachycardia, agitation.	Avoid concomitant use.	65
N,N-Dimethyltryptamine (DMT)	Harmine inhibits MAO-A, preventing first-pass metabolism of orally ingested DMT. DMT may also alter harmine PK.	Enables oral psychoactivity of DMT; potential for intensified or prolonged psychedelic effects.	This interaction is the basis of Ayahuasca. Uncontrolled co-ingestion outside of traditional/ritual contexts carries risks.	1
CYP450 Enzyme Inducers/Inhibitors	Potential for altering harmine's metabolism if harmine is a substrate for specific CYP enzymes.	Altered plasma concentrations of harmine, leading to increased toxicity or reduced efficacy.	Caution with potent CYP modulators; specific interacting CYPs for harmine need full elucidation.	49

8. Legal and Regulatory Status

The legal and regulatory status of harmine is multifaceted and varies significantly across jurisdictions. It is often influenced by the legal standing of N,N-dimethyltryptamine (DMT) and Ayahuasca, the traditional brew in which harmine plays a critical role as an MAO-A inhibitor, rather than by regulations pertaining to harmine as an isolated chemical compound.[3]

United States:

• Federal Law: DMT is classified as a Schedule I controlled substance under the Controlled Substances Act (CSA), indicating no currently accepted medical use and a high potential for abuse.[3] Consequently, Ayahuasca, as a preparation containing DMT, is generally considered illegal under federal law.[71] Harmine itself is not explicitly listed as a federally scheduled drug in the provided materials. However, its integral role in enabling the oral activity of DMT in Ayahuasca often brings it under scrutiny in contexts involving Ayahuasca. The Drug Enforcement Administration (DEA) acknowledges the presence of harmala alkaloids (harmine, harmaline) in Ayahuasca as MAOIs but does not specifically schedule harmine in the provided documents.[73] Certain religious groups, such as the União do Vegetal, have obtained exemptions under the Religious Freedom Restoration Act (RFRA) for the sacramental use of Ayahuasca.[72]
• State and Local Laws: The legal status at the state level often mirrors federal law regarding DMT. However, there is a trend towards decriminalization or deprioritization of enforcement for plant-based entheogens in some localities. For example, Colorado has decriminalized natural psychedelics, including DMT, for personal use by adults, and Oregon has decriminalized the possession of small amounts of all drugs, including DMT.[72] Several cities in California, Massachusetts, and Washington have also passed resolutions to decriminalize or deprioritize enforcement against certain plant-based entheogens.[72] These local measures, however, do not supersede federal law, creating a complex and sometimes conflicting legal environment.

European Union:

The legal status of harmine and Ayahuasca varies significantly among EU member states:

• France: Initially, a court case allowed Santo Daime to use Ayahuasca as the plants were not scheduled. However, subsequently, the common ingredients of Ayahuasca, including harmala alkaloids, were declared narcotics, rendering them illegal.[71]
• Germany: DMT and 5-MeO-DMT, active components of some Ayahuasca preparations, are listed in Annex I of the German Narcotics Law, making their handling without a permit illegal.[71]
• Italy: Ayahuasca was declared illegal in 2022.[71]
• Netherlands: Ayahuasca is officially illegal following a 2019 Supreme Court decision, reversing a period where it was more accessible.[71]
• Spain: The sale of Ayahuasca to the public is prohibited due to its toxicity. Its use and marketing are restricted to the manufacture of pharmaceutical specialities, officinal preparations, homeopathic strains, and research.[71]
• United Kingdom: DMT is a Class A drug under the Misuse of Drugs Act. As Ayahuasca contains DMT, it is considered illegal.[71] Interestingly, a UK Home Office report lists harmine and harmaline as "Non-controlled NPS" (New Psychoactive Substances) in the context of forensic early warning systems.[75] This suggests that pure harmine may not be explicitly scheduled in the same manner as DMT, but its inclusion in Ayahuasca would render the preparation illegal.
• European Medicines Agency (EMA): While the EMA sets standards for pharmaceutical products (e.g., European Pharmacopoeia) [11], and new regulations like the EU Health Technology Assessment Regulation (HTAR) aim to harmonize assessments [77], no specific EMA classification for harmine itself as a standalone substance is detailed in the provided snippets. Any medicinal product containing harmine would require authorization through the EMA or national competent authorities.

Australia:

Harmala alkaloids, which include harmine, are generally classified as Schedule 9 prohibited substances under the Poisons Standard.1 This prohibits their manufacture, possession, sale, or use except for approved medical or scientific research, or analytical/teaching purposes. However, exceptions are made for therapeutic preparations containing 0.1% or less of harmala alkaloids, or 2 mg or less per recommended daily dose in divided preparations.1

Canada:

Harmaline and harmalol, closely related harmala alkaloids, are considered Schedule III controlled substances under the Controlled Drugs and Substances Act.26 While the status of harmine itself is not as explicitly stated for Canada in these documents, it would likely be treated similarly due to its classification as a harmala alkaloid.

The primary legal impediment to harmine research and therapeutic development in many Western nations appears to stem not always from the explicit scheduling of harmine as an isolated compound, but rather from its strong association with DMT and Ayahuasca, where DMT is often a highly controlled substance. This "guilt by association" can create significant hurdles for legitimate research into harmine's independent therapeutic potentials, even if pure harmine might be technically unscheduled or subject to less stringent controls than DMT in certain jurisdictions.

Furthermore, the distinction under the 1971 UN Convention on Psychotropic Substances, which does not regulate natural materials containing DMT (like Ayahuasca) in the same way it schedules pure DMT [71], creates an international legal ambiguity. This allows for varied interpretations and enforcement strategies by different countries, contributing to the inconsistent global legal landscape for Ayahuasca and its components, including harmine.

The recent trend of decriminalization or deprioritization of plant-based entheogens at local levels, particularly in the United States [72], may open new, albeit limited, avenues for research and traditional use of harmine-containing plants. However, these local measures do not override federal laws, thus maintaining a degree of legal uncertainty and precarity for individuals and researchers operating under such ordinances.

Table 4: Summary of Harmine Legal Status in Key Regions (based on provided information)

Region/Country	Legal Status of Harmine (isolated)	Legal Status of Ayahuasca/DMT	Key Regulatory Notes	Reference(s)
USA - Federal	Not explicitly scheduled as a standalone compound in provided snippets.	DMT is Schedule I; Ayahuasca generally illegal due to DMT content.	Religious exemptions for Ayahuasca exist for specific groups.	3
USA - Colorado	Not specified; DMT decriminalized.	Decriminalized for personal use (natural psychedelics including DMT).	Proposition 122 (2022). Regulated access program expected.	72
USA - Oregon	Not specified; DMT decriminalized.	Decriminalized for small amounts (Measure 110).	Psilocybin therapy legalized (Measure 109), does not cover DMT.	72
European Union	Varies by member state; often tied to Ayahuasca/DMT status. Not centrally scheduled by EMA as a standalone substance in snippets.	Varies; DMT generally controlled. Ayahuasca illegal in France, Germany (DMT controlled), Italy, Netherlands. Restricted in Spain.	EU HTAR for harmonizing health technology assessments.	11
United Kingdom	Listed as "Non-controlled NPS" in a Home Office report context, but its presence in Ayahuasca makes the brew illegal.	DMT is Class A drug; Ayahuasca illegal.	Complex status; pure harmine vs. harmine in preparations.	71
Australia	Schedule 9 Prohibited Substance (as a harmala alkaloid).	DMT is Schedule 9; Ayahuasca illegal.	Exceptions for low concentrations in therapeutic preparations.	1
Canada	Likely Schedule III (as harmaline/harmalol are Schedule III).	DMT is Schedule III; Ayahuasca illegal unless for religious exemption.	Religious exemptions granted for Ayahuasca use.	26

9. Conclusion and Future Perspectives

Harmine is a β-carboline alkaloid with a rich ethnobotanical history and a complex pharmacological profile. Its primary mechanisms of action include potent, reversible inhibition of MAO-A and selective inhibition of DYRK1A, alongside an ability to intercalate with DNA. These varied actions underpin its traditional uses, particularly in the Ayahuasca brew, and its investigated therapeutic potential in diverse fields such as neurology (depression, Parkinson's disease, Alzheimer's disease), diabetes (via pancreatic β-cell regeneration), and oncology. Furthermore, its physicochemical properties lend it to applications as a research tool, for instance, as a fluorescent pH indicator and a PET imaging ligand for MAO-A.

Despite its promise, the therapeutic development of harmine faces significant challenges. Its polypharmacology, while offering multiple avenues for intervention, also complicates targeted therapy and contributes to a complex side-effect profile. Key safety concerns include the risk of serotonin syndrome and tyramine-induced hypertensive crises due to MAO-A inhibition, as well as potential neurotoxicity and genotoxicity. Pharmacokinetically, harmine's low oral bioavailability and relatively short half-life necessitate strategies to improve systemic exposure and duration of action. Compounding these scientific and clinical challenges is a complex and often restrictive legal and regulatory landscape, largely stemming from harmine's association with psychoactive substances like DMT and Ayahuasca. The variability in alkaloid content in natural plant sources also poses issues for standardization.

The future of harmine as a therapeutic agent may lie less in the direct use of the natural alkaloid for many systemic indications and more in its role as a crucial lead compound or scaffold for the development of synthetic derivatives. Such derivatives could be engineered for improved selectivity (e.g., potent DYRK1A inhibitors devoid of significant MAO-A activity or DNA-intercalating properties), enhanced pharmacokinetic profiles, and reduced toxicity.[27] The unique ability of harmine to stimulate pancreatic β-cell proliferation is particularly compelling and warrants dedicated efforts to harness this effect safely, perhaps through targeted delivery systems or highly selective analogs.

Recommendations for future research and development include:

1. Rational Drug Design: Continued synthesis and screening of harmine derivatives to optimize target engagement, improve selectivity, and enhance ADME/Tox properties.
2. Advanced Drug Delivery: Investigation of novel drug delivery technologies to improve harmine's bioavailability, achieve targeted tissue distribution (e.g., to the pancreas for diabetes, or across the blood-brain barrier with controlled release for neurological disorders), and minimize systemic side effects.
3. Mechanism Elucidation: Deeper investigation into the interplay of harmine's multiple mechanisms of action in vivo to better predict therapeutic outcomes and potential adverse effects across different pathological contexts.
4. Rigorous Clinical Evaluation: Well-designed clinical trials are essential, beginning with comprehensive Phase 1 studies for pure harmine or its optimized derivatives to meticulously characterize safety, tolerability, MTD, and human pharmacokinetics.[1] Subsequent efficacy trials should be indication-specific and placebo-controlled.
5. Regulatory Engagement and Harmonization: Proactive dialogue with regulatory agencies is needed to navigate the complex legal status of harmine, advocating for pathways that facilitate legitimate research and therapeutic development, particularly for non-psychoactive indications, and distinguishing it from illicit or unregulated preparations.
6. Ethnobotanical Exploration: Systematic and scientific validation of traditional uses of harmine-containing plants can continue to provide valuable leads for novel therapeutic applications, provided such investigations are coupled with rigorous assessments of efficacy and safety according to modern standards.

In conclusion, harmine stands as a molecule of significant scientific interest, bridging ancient traditional medicine with modern pharmacology. While its direct clinical utility may be constrained by its inherent complexities, its value as a research tool and a template for future drug discovery is undeniable. Successfully translating harmine's therapeutic potential into approved medicines will require innovative chemical and pharmaceutical approaches, alongside careful navigation of the regulatory environment.

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