Mulungu

Mulungu (Erythrina mulungu / Erythrina velutina): A Comprehensive Reference

1. Identity and Botanical Description

1.1 Scientific Names and Taxonomy

Mulungu belongs to the family Fabaceae, genus Erythrina, and is principally represented by two species: Erythrina mulungu and, as a widely used synonym, Erythrina verna. A third synonym recognized in older botanical literature is Corallodendron mulungu. The mulungu tree was first recorded in 1829 and is known under these two botanical names, Erythrina mulungu and Erythrina verna.

A closely related species, Erythrina velutina Willd., is also widely known in Brazil as "mulungu" and shares an overlapping traditional use profile and similar chemical constituents. Erythrina velutina Willd. is commonly known as "mulungu" in Brazil and is a leguminous tree with traditional medicinal uses including the treatment of insomnia, central nervous system disorders, convulsions, nervous cough, and inflammation. Another closely related species, E. crista-galli, is used interchangeably in South American herbal medicine systems and is found farther south on the South American continent. These species are not always distinguished in commerce, which creates significant variability in commercial preparations.

Alkaloids have been found in 78 of 107 species in the genus Erythrina; mulungu is documented with 20 isoquinoline alkaloids. The Erythrina L. genus (Fabaceae) comprises about 115 species, and it has been extensively studied, mainly because of its alkaloids, which have pharmacological properties.

1.2 Common Names

Common names include mulungu, corticeira, murungu, muchocho, murungo, totocero, flor-de-coral, árvore-de-coral, amerikadeigo, ceibo, chilichi, chopo, hosoba deiko, pau-imortal, mulungu-coral, capa-homem, and suiná-suiná. Since its flowers are the same red color as coral, the plant is sometimes also called flor de coral and in English literature "coral tree."

1.3 Physical Description and Habitat

Erythrina mulungu is a Brazilian ornamental tree and medicinal plant native to the cerrado and caatinga ecoregions in Brazil and Bolivia, South America. Commercial preparations of mulungu are available in Brazil. This tree reaches up to 15 meters in height. It produces a profusion of reddish-orange flowers (pollinated by hummingbirds) at the ends of the tree's many branches. The tree is sometimes called "coral flower," as the flowers resemble the color of orange coral. It produces black seed pods containing large, red-and-black seeds, which are sometimes used by indigenous peoples to make necklaces and jewelry.

Mulungu is indigenous to Brazil, parts of Peru, and tropical areas in Latin America and, typically, is found in marshes and along riverbanks. E. velutina is indigenous to Brazil, Peru, Ecuador, Colombia, Venezuela, and Hispaniola.

An important toxicological note regarding the seeds: The seeds of E. mulungu are considered very toxic. Ingestion should be avoided and there is a danger of death. The medicinal parts used are the bark and root, not the seeds.

1.4 Botanical Parts Used and Commercial Forms

The parts used medicinally are the bark and root. Tinctures and decoctions made from the leaves or barks of mulungu are often used in Brazilian traditional medicine as a sedative, to calm an overexcited nervous system, to lower blood pressure, and for insomnia and depression.

Commercial preparations include:

• Dried bark / shredded bark for preparation of teas, decoctions, or infusions
• Powdered bark in loose or encapsulated form
• Hydroalcoholic tinctures (water–alcohol extracts)
• Standardized dry extracts (e.g., 4:1 concentration preparations)
• Capsules containing powdered or standardized bark extract

The label "mulungu" also applies to related species (e.g., Erythrina verna, E. velutina) in commerce. While these species share similar alkaloids, their profiles and strengths differ. Responsible manufacturers specify the exact species and the part used (commonly stem bark) and may standardize to total alkaloids. Because mislabeled or non-standardized products can under- or overshoot expected effects, quality control is important for consistent outcomes.

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2. Traditional and Historical Use

2.1 Indigenous Use in the Amazon and Brazil

Several Erythrina tree species are used by indigenous peoples in the Amazon as medicines, insecticides, and fish poisons. Mulungu has long been used in Brazil by indigenous peoples as a natural sedative: it has been used to calm an overexcited nervous system and promote a restful sleep.

In both North and South American herbal medicine systems, mulungu is considered to be an excellent sedative to calm agitation and nervous coughs and to treat other nervous system problems including insomnia and anxiety.

2.2 Brazilian Folk Medicine

In native herbal medicine, a leaf or bark decoction or tincture from mulungu has long been used in folk medicine due to their tranquilizing effects and as a natural sedative. It is also used as an anxiolytic and antibacterial agent. In both Brazil and Peru, mulungu is used for epilepsy.

In Brazilian folk medicine, mulungu tea is traditionally consumed to promote relaxation, emotional balance, and a sense of inner calm, particularly in the evening. Among rural and indigenous Brazilian communities, mulungu bark tea has been used during periods of rest, reflection, or emotional tension. The bark is gently prepared as an infusion or mild decoction and traditionally consumed later in the day, often as part of practices associated with sleep-inducing herbs and calming evening rituals.

In Brazil, the bark of E. crista-galli is used for the treatment of rheumatism and hepatitis as well as for sedation and hypnogenesis. Broader traditional uses across related species in the genus include the treatment of liver conditions and cardiovascular complaints.

2.3 Traditional Preparations

Across traditional Brazilian practice, several preparation methods were employed:

• Decoction of the bark: Bark pieces boiled in water, consumed as a tea for sedation and sleep promotion.
• Leaf or bark tincture: A leaf or bark decoction or tincture from mulungu has long been used in folk medicine due to their tranquilizing effects and as a natural sedative.
• Multiple plant uses: The natives of the Amazon use several species of Erythrina tree for various purposes, including therapeutic, insecticidal, and as fish poison.

In Brazil, plants such as passionflower (Passiflora spp.), chamomile (Matricaria chamomilla L.) and mulungu (Erythrina spp.) are widely used in folk medicine for their sleep-promoting properties.

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3. Phytochemistry: Key Constituents and Active Compounds

3.1 Overview of Chemical Classes

In mulungu, large amounts of novel flavonoids, triterpenes, and alkaloids have been found. A literature survey showed the presence of flavanones, flavonols, chalcones, cinnamoylphenols, stilbenoids, isoflavones, isoflavans, isoflavanones, pterocarpans, isoflav-3-enes, 3-phenoxychromones, coumastans, 3-phenyl-coumarins, lignans, cinnamate esters, simple phenolics, triterpenes, sesquiterpenes, long-chain carboxylic acids, and long-chain alcohols.

Analyzed studies indicate a complex phytochemical composition characterized primarily by alkaloids, flavonoids, and other phenolic compounds.

3.2 Alkaloids (Primary Bioactive Class)

Alkaloids are considered the most pharmacologically significant class of compounds in mulungu. The most considerable group of biologically active compounds of mulungu are alkaloids. Alkaloids have been found in 78 of 107 species in the genus Erythrina; mulungu is documented with 20 isoquinoline alkaloids.

The principal alkaloids identified in E. mulungu include:

• (+)-Erythravine — the alkaloid most associated with anxiolytic and anticonvulsant effects in preclinical models.
• (+)-11α-Hydroxyerythravine — a hydroxylated derivative of erythravine, also demonstrating potent CNS activity.
• Erysotrine (erysothrine) — among the five major alkaloids isolated from the methanol extract of E. mulungu flowers; erysotrine, erythrartine, and hypaphorine are common constituents of Erythrina species.
• Erythrartine — an alkaloid present in the flowers with documented CNS activity.
• Erysodine — an alkaloid in mulungu and other Erythrina plants that has been documented with neuromuscular effects characteristic of curare arrow poisons.
• Hypaphorine — a tryptophan betaine alkaloid common to the genus.
• Erysotrine-N-oxide and erythrartine-N-oxide — novel N-oxide alkaloids reported from E. mulungu.
• β-Erythroidine — a classical nicotinic antagonist alkaloid of the Erythrina genus.

Erythrina species are rich in tetracyclic alkaloids with curare-like activity, capable of inducing muscle paralysis. Compounds such as erythrartine, erythravine, and their derivatives exhibited anxiolytic effects comparable to benzodiazepines in preclinical research.

3.3 Flavonoids and Isoflavonoids

The genus Erythrina is very rich in secondary metabolites, particularly of the flavonoids class. Flavonoids represent a group of very active chemicals with various properties and are almost always present in Erythrina species.

In phytochemical investigation of non-alkaloidal secondary metabolites of species from the genus Erythrina, several isoflavonoids were found, some of which exhibiting anti-inflammatory activity. The chemical fractionation of the stem bark from E. velutina gave homohesperetin and phaseollidin.

The Erythrina genus produces a wide range of secondary metabolites including flavanones, isoflavones, and pterocarpans, characterized by antioxidant activity. Phenolic compounds have demonstrated ability to suppress pro-oxidants and inhibit inflammatory signaling pathways such as MAPK, AP1, and NF-κB.

3.4 Other Constituents

Many alkaloids identified in the genus have demonstrated anti-inflammatory, cardioactive, narcotic, and sedative activities. Mulungu's hypotensive and heart-regulatory activities have been studied and attributed to its alkaloids.

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4. Mechanisms of Action

4.1 Inhibition of Neuronal Nicotinic Acetylcholine Receptors

The most well-characterized molecular mechanism of mulungu's CNS effects involves inhibition of neuronal nicotinic acetylcholine receptors (nAChRs). Crude extracts and three isolated alkaloids from E. mulungu plants have shown anxiolytic effects in different animal models. Researchers investigated whether these alkaloids could affect nicotinic acetylcholine receptors and their selectivity for different CNS subtypes, using whole cell patch-clamp recordings in three cell models: PC12 cells expressing α3* nicotinic acetylcholine receptors; cultured hippocampal neurons expressing α7* receptors; and HEK 293 cells expressing α4β2 receptors.

The IC₅₀ values obtained with (+)-erythravine and (+)-11α-hydroxyerythravine were 6 µM and 5 µM for the α7* receptors, and 13 nM and 4 nM for the α4β2 receptors, respectively. These data suggest that these Erythrina alkaloids may exert their behavioral effects through inhibition of CNS nicotinic acetylcholine receptors, particularly the α4β2 subtype.

Unlike (+)-11-α-hydroxy-erythravine, which presented little effect, (+)-erythravine produced a significant inhibitory modulation on α4β2, α4β4, and α7 isoforms of nicotinic acetylcholine receptors, which could explain at least partially its anxiolytic and anticonvulsant properties.

Since (+)-11-α-hydroxy-erythravine and (+)-erythravine modulated nicotinic acetylcholine receptors to different extents, it is possible that small differences between the chemical structure of these alkaloids affect the selectivity and affinity of target-ligand interactions, conferring distinct potency and/or pharmacological properties to them.

4.2 Non-GABAergic Mechanisms

Oral administration of (+)-erythravine and (+)-11α-hydroxyerythravine induced anxiolytic-like effects comparable to that of diazepam in mice, while (+)-11α-hydroxyerysotrine was only effective in some tests. Because these alkaloids were effective at low oral doses (3–10 mg/kg p.o.) that did not disrupt locomotion or exploratory activity, the authors suggested that the mechanism was non-GABAergic.

Based on negative results in binding and uptake assays in synaptosomes, researchers excluded mechanisms involving GABA or glutamate signaling for the erysotrine alkaloid specifically, further supporting that the primary anxiolytic mechanism operates through cholinergic (nAChR) rather than GABAergic pathways.

4.3 Glycinergic and CNS-Depressant Activity

While E. velutina and E. mulungu did not exhibit any protective effect in PTZ-induced seizures at any dose, an increase in the latency of convulsion and in the death time was observed with both doses in strychnine-induced seizures. The sleeping time was increased with both plants as compared to control. The hydroalcoholic extracts of E. velutina and E. mulungu have anticonvulsant effects only in the strychnine-induced seizure model, suggesting their possible action in the glycine system, and a potentiation of pentobarbital sleeping time, suggesting depressant action in the central nervous system.

4.4 Antinociceptive Mechanism

The antinociceptive effects of the hydroalcoholic extracts from E. velutina and E. mulungu were studied in three experimental models of nociception in mice. The extract was administered intraperitoneally at doses of 200 and 400 mg/kg. Inhibitions of abdominal contractions were observed with doses of 200 (88.6%; 86.8%) and 400 (95.5%; 83.5%) mg/kg of E. velutina and E. mulungu respectively, compared to controls. Both species reduced nociception produced by formalin in the 1st and 2nd phases. This effect was not reversed by naloxone, and the authors concluded that E. velutina and E. mulungu present antinociceptive effects that are independent of the opioid system.

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5. Scientific Evidence by Area of Use

5.1 Anxiety — Preclinical Evidence

The anxiolytic properties of mulungu are the most extensively studied area. Aqueous alcoholic extracts of E. mulungu produce anxiolytic-like effects in rats submitted to elevated T-maze and light/dark transition tests, as well as antinociceptive and anticonvulsant effects in mice, raising interest in the discovery of neuroactive compounds in the plant.

The effects of acute oral administration of erythrinian alkaloids — (+)-11α-hydroxy-erysotrine, erythravine, and (+)-11α-hydroxy-erythravine isolated from the flowers of E. mulungu — were investigated in the light-dark transition model (LDTM) and the elevated plus-maze (EPM) in mice. In the LDTM, erythravine (3, 10 mg/kg) and (+)-11α-hydroxy-erythravine (10 mg/kg) increased the time spent by the animals in the illuminated compartment, and (+)-11α-hydroxy-erythravine (3 mg/kg) increased the number of transitions between compartments, suggesting an anxiolytic-like effect of these erythrinian alkaloids. The third alkaloid studied, (+)-11α-hydroxy-erysotrine, did not change any behavioral response within the dose range used (3–10 mg/kg).

Both E. velutina and E. mulungu, popularly used in Brazil as tranquilizing agents, were studied. The effects of acute and chronic oral treatment with a water:alcohol extract of E. velutina (7:3, plant grounded stem bark; acute = 100, 200, 400 mg/kg; chronic = 50, 100, 200 mg/kg) were evaluated in rats submitted to the elevated T-maze. This model was selected for its capacity to elicit specific subtypes of anxiety disorders recognized in clinical practice: avoidance has been related to generalized anxiety and escape to panic. Animals were also treated with the same doses and submitted to the forced swim test for evaluation of antidepressant activity.

Evidence strength (anxiolytic, preclinical): Moderately robust in rodent models. Multiple independent laboratories have replicated anxiolytic-like effects using both crude extracts and isolated alkaloids across standard behavioral test batteries (elevated plus-maze, light/dark transition, elevated T-maze). The effects of the two key alkaloids, (+)-erythravine and (+)-11α-hydroxyerythravine, were characterized as comparable in magnitude to diazepam in certain test paradigms, at low oral doses. All this evidence, however, derives from animal studies; it cannot be directly extrapolated to human clinical outcomes.

5.2 Anxiety — Human / Clinical Evidence

Human clinical evidence for mulungu is limited but exists in the context of procedural dental anxiety.

Study 1 (Silveira-Souto et al., 2014 — published in Medicina Oral Patología Oral y Cirugía Bucal, PMC): The aim was to evaluate the effect of E. mulungu on the control of dental anxiety in patients who had undergone bilateral extraction of asymptomatic, impacted mandibular third molars. In a randomized, double-blind, crossover study, 30 healthy volunteers (5 men and 25 women, over 18 years of age) received either 500 mg of E. mulungu (Mulungu Matusa®) or 500 mg of placebo, orally, one hour before the surgical procedure. The level of anxiety was assessed through questionnaires and physical parameters such as blood pressure, heart rate, and oxygen saturation. Data were analyzed by Chi-square test, ANOVA (Tukey test), and Friedman with significance level of 5%. Erythrina mulungu showed an anxiolytic effect without significant changes in physiological parameters, and could be considered as an alternative to control anxiety in adult patients undergoing mandibular third molar surgery.

It was reported that E. mulungu Mart. ex Benth. had shown an anxiolytic effect without significant changes in physiological parameters (Silveira-Souto et al., 2014).

Study 2 (randomized controlled clinical trial, published in Clinical Oral Investigations, 2020): This study aimed to compare the effects of Passiflora incarnata, Erythrina mulungu, and midazolam in controlling anxiety in patients undergoing mandibular third molar extraction. The volunteers underwent extraction of their third mandibular molars in a randomized, placebo-controlled, triple-blind, and parallel clinical trial. Passiflora incarnata (500 mg), Erythrina mulungu (500 mg), or midazolam (15 mg) was orally administered 60 min before the surgery. Anxiety level was evaluated using questionnaires and measurements of physical parameters, including heart rate, blood pressure, and oxygen saturation. A total of 200 volunteers were included in this clinical trial.

Small human trials have explored mulungu for short-term anxiety around dental procedures, usually given as a single capsule dose about an hour before surgery. Results are mixed: some studies report a perceived calming effect, while a larger randomized trial did not find clear benefit compared with placebo.

The use of this natural anxiolytic in anxious patients may be advantageous, as it does not cause respiratory depression and motor abnormalities. However, as there is a lack of studies in humans, it is not possible to confirm the results found. It is important to confirm results so that optimal dosages can be tested and research models refined to assess clinically the anxiety during dental treatment.

Evidence strength (anxiolytic, clinical): Preliminary and mixed. Only a very small number of human clinical trials have been conducted, all in the specific context of pre-procedural dental anxiety, and all using a single oral dose. The crossover study (n=30) showed a statistically significant patient preference for mulungu over placebo. The larger parallel trial (n=200) produced mixed results. No trials have examined mulungu for chronic anxiety disorders, generalized anxiety disorder, or other anxiety indications. Human evidence is insufficient to establish clinical efficacy at this time.

5.3 Insomnia and Sedation

The anticonvulsant effects and the potentiation of pentobarbital-induced sleeping time in mice with E. velutina and E. mulungu hydroalcoholic extracts from the stem bark were examined. No alteration was observed in sleeping latency at both doses as compared to control; however, the sleeping time was increased in both plants as compared to control. This indicates a CNS-depressant effect that prolongs sedation duration in animal models, consistent with traditional use for sleep promotion.

Preclinical evidence demonstrates anxiolytic, sedative, anticonvulsant, antioxidant, neuroprotective, and anticholinesterase activities associated with modulation of GABAergic and cholinergic neurotransmission.

Evidence strength (insomnia/sedation): Preclinical only. No human clinical trials specifically addressing insomnia have been published. The sedative mechanism is supported by animal pharmacology data showing prolonged pentobarbital sleeping time, but this has not been validated in human sleep studies.

5.4 Anticonvulsant Activity

Results showed that the administration of different doses of (+)-erythravine inhibited seizures evoked by bicuculline, pentylenetetrazole, and kainic acid at a maximum of 80, 100, and 100%, respectively, whereas different doses of (+)-11-α-hydroxy-erythravine inhibited seizures at a maximum of 100% when induced by bicuculline, NMDA, and kainic acid, and, to a lesser extent, PTZ (60%).

Researchers isolated the alkaloid erysothrine from the hydroalcoholic extract of flowers from E. mulungu and screened for its anticonvulsant and anxiolytic actions. Results showed that the administration of erysothrine inhibited seizures evoked by bicuculline, PTZ, NMDA, and most remarkably, kainic acid. In preliminary neurochemistry tests, erysothrine (0.001–10 μg/mL) did not alter GABA or glutamate synaptosomal uptake and binding. Altogether, these results describe an alkaloid with anticonvulsant activity and mild anxiolytic activity that might be considered well tolerated as it does not alter the general behavior of the animals at the used doses.

In both Brazil and Peru, mulungu is used for epilepsy.

Evidence strength (anticonvulsant): Preclinical only. Multiple rodent studies have demonstrated anticonvulsant activity using different chemical convulsant models. The mechanisms appear partially independent of GABA and glutamate pathways. No human trials exist for this indication.

5.5 Antidepressant Activity

Animals were treated with doses of E. velutina and E. mulungu (water:alcohol 7:3, inflorescence extract) and submitted to the forced swim test for the evaluation of antidepressant activity. The forced swim test is a standard preclinical model for detecting antidepressant-like activity in rodents.

The plant and its extracts have exhibited various bioactivities, such as anti-inflammatory, anxiolytic, anticonvulsant, neuroprotective, analgesic, antimicrobial, and antioxidant effects, validating some of its traditional medicinal uses.

Evidence strength (antidepressant): Preliminary preclinical only. Antidepressant-like activity has been observed in forced swim test models in rodents. No human clinical evidence exists for this indication.

5.6 Anti-Inflammatory and Analgesic Activity

Although there is local ethnobotanical data on the use of the genus Erythrina to relieve pain and inflammation, few preclinical studies evaluating the effect have been published, and an even smaller amount describes the biological activity and therapeutic potential of the genus for this purpose.

E. velutina and E. mulungu are among the species studied for their analgesic and anti-inflammatory effects, following E. variegata as the most studied species.

Evidence strength (anti-inflammatory/analgesic): Preliminary preclinical only. Anti-inflammatory and analgesic activity has been demonstrated in animal models, attributable to both alkaloid and isoflavonoid constituents. No human trials for these indications have been published.

5.7 Cardiovascular / Hypotensive Activity

Mulungu's hypotensive and heart-regulatory activities were studied and attributed to its alkaloids. Tinctures and decoctions made from the leaves or barks of mulungu are used in Brazilian traditional medicine as a sedative, to calm an overexcited nervous system, to lower blood pressure, and for insomnia and depression.

Evidence strength (cardiovascular): Traditional use supported by limited preclinical data. No human trials on cardiovascular outcomes have been conducted.

5.8 Antimicrobial Activity

Some isoflavonoids, mainly erycristagallin (3,9-dihydroxy-2,10-di(γ,γ-dimethylallyl)-6a,11a-dehydropterocarpan), isolated from Erythrina variegata, have antibacterial activity against cariogenic oral bacteria. The findings indicate that erycristagallin has potential as a potent phytochemical agent for prevention of dental caries by inhibiting the growth of cariogenic bacteria and by interfering with the incorporation of glucose responsible for production of organic acids. Related isoflavonoids from Erythrina species have also shown activity against methicillin-resistant Staphylococcus aureus.

Activities in the central nervous system have been documented, including neurotransmitter receptor modulation and anticonvulsant, sedative, and amnesic effects. The plant has also demonstrated antibacterial and antinociceptive properties.

Evidence strength (antimicrobial): Preliminary in vitro only. Antimicrobial data are derived from cell culture experiments with isolated compounds from related Erythrina species. No clinical antimicrobial trials have been conducted with mulungu.

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6. Body Systems and Health Areas Associated with Mulungu

• Central Nervous System: Anxiety, sedation, sleep promotion, epilepsy/convulsions, depression — the primary area of traditional use and the most researched domain.
• Cardiovascular System: Blood pressure regulation, heart-rate modulation — supported by traditional use and limited animal pharmacology.
• Musculoskeletal / Pain: Antinociceptive and anti-inflammatory effects observed in animal models; historically used in rheumatism.
• Liver: Hepatitis is listed among traditional uses of related Erythrina species. Some alkaloid fractions showed hepatoprotective activity in the broader genus; however, chronic oral mulungu extract has also raised liver safety concerns in animal toxicology (see Safety section).
• Immune / Infectious: Antibacterial activity in vitro, particularly against oral cariogenic bacteria and methicillin-resistant Staphylococcus aureus, via isoflavonoid constituents.

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7. Dosage Forms and Reported Dosages

Dosages reported in scientific studies are given below exactly as stated in the source literature. These are not recommendations.

7.1 Human Clinical Trials

• In a randomized, double-blind, crossover trial (Silveira-Souto et al., 2014), 30 healthy volunteers received either 500 mg of E. mulungu (Mulungu Matusa®) or 500 mg of placebo, orally, one hour before the surgical procedure.
• In the parallel randomized controlled trial published in Clinical Oral Investigations (2020), Erythrina mulungu (500 mg) was orally administered 60 min before the surgery.

7.2 Animal (Preclinical) Study Dosages

• Oral administration of (+)-erythravine and (+)-11α-hydroxyerythravine (isolated alkaloids) induced anxiolytic-like effects comparable to diazepam in mice at low oral doses of 3–10 mg/kg p.o.
• The effects of acute and chronic oral treatment with a water:alcohol extract of E. velutina (7:3, plant grounded stem bark; acute = 100, 200, 400 mg/kg; chronic = 50, 100, 200 mg/kg) were evaluated in rats submitted to the elevated T-maze model of anxiety.
• The extracts of E. velutina (intraperitoneally or orally) and E. mulungu (intraperitoneally) were administered in mice at single doses of 200 or 400 mg/kg.
• In antinociception studies, the extract was administered intraperitoneally to female mice at doses of 200 and 400 mg/kg. Inhibitions of abdominal contractions were observed with doses of 200 (88.6%; 86.8%) and 400 (95.5%; 83.5%) mg/kg for E. velutina and E. mulungu, respectively.

Note: Rodent doses expressed in mg/kg body weight cannot be directly converted to human dosing without validated pharmacokinetic and allometric scaling data. The only human doses documented in peer-reviewed clinical trials are the 500 mg oral doses used in the pre-procedural dental anxiety studies.

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8. Safety Considerations

8.1 Seed Toxicity

The seeds of E. mulungu are considered very toxic. Ingestion should be avoided and there is a danger of death. Medicinal use universally employs the bark or root, not the seeds.

8.2 Chronic Oral Toxicity — Animal Data

Chronic oral toxicity studies of E. mulungu Mart. ex Benth. (synonym = E. verna Vell. or Corallodendron mulungu (Mart. ex Benth.) Kuntze or E. flammea Herzog) stem bark extract in mice at a dose of 1,000 mg/kg BW resulted in alterations of biochemical parameters of the liver and cardiovascular functions. Hematological analysis indicated significant decreases in red blood cells.

Oral daily doses of 500 and 1,000 mg/kg BW of E. mulungu Mart. ex Benth. stem bark extract increased the relative weights of the liver and heart and serum malondialdehyde levels. These findings in animal models raise questions about long-term use at high doses that have not yet been investigated in human subjects.

8.3 Scope of Toxicology Data

The toxicity and clinical studies of Erythrina genus plants are limitedly reported. In fact, there are only very limited toxicity studies on Erythrina genus plants. No long-term human safety studies have been published.

Robust human hepatotoxicity data are lacking; because alkaloids are metabolized by the liver, those with significant liver disease should exercise caution.

8.4 Potential Drug Interactions

Extensive caution should be considered when prescribing botanical drugs for patients simultaneously taking a narrow therapeutic window drug. The botanical drugs may dangerously alter the main drug's activity or cause ineffectiveness.

Extensive caution should be considered when prescribing botanical drugs for patients parallelly taking a narrow therapeutic window drug, as the botanical drugs may dangerously alter the main drug or cause ineffectiveness. A review of the Herb–Drug Interaction Chart (Mills and Bone, 2005; ESCOP, 2023) found that no interactions of the Erythrina genus were recorded in those databases, indicating the paucity rather than absence of interaction data.

Given its demonstrated CNS-depressant properties in animal models, additive sedation with central nervous system depressants including benzodiazepines, barbiturates, opioids, alcohol, and other sedating herbs represents a theoretically significant pharmacodynamic concern. Sedatives including benzodiazepines, Z-drugs (zolpidem), barbiturates, opioids, and some antihistamines and alcohol can, in combination with sedating botanicals, cause over-sedation and impair breathing or reflexes.

8.5 Neuromuscular / Curare-Like Properties

It was found that Erythrina species are rich in tetracyclic alkaloids with curare-like activity, inducing muscle paralysis. The alkaloid erysodine in mulungu has been documented with neuromuscular effects characteristic of curare arrow poisons. This alkaloid class is recognized for its role as nicotinic receptor antagonists. At typical herbal preparation doses, the clinical significance of this property has not been established in humans.

8.6 Regulatory Status

Mulungu is sold as an herbal product in some countries but is not approved as a drug for anxiety. It is not subject to an official WHO monograph, ESCOP monograph, or German Commission E approval specifically for E. mulungu or E. velutina at the time of the evidence reviewed.

8.7 Populations for Which Data Are Absent

No adequate safety data exist for pregnant or breastfeeding individuals. Data in children and adolescents are also absent.

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9. Summary of Evidence Quality

The overall evidence base for mulungu is characteristic of an under-researched traditional botanical. Preclinical (animal and in vitro) pharmacology is reasonably well developed and has successfully identified key bioactive alkaloids, their molecular targets (particularly α4β2 nAChRs), and biologically plausible mechanisms for the traditionally reported CNS effects. Despite this evidence, the biological activities of E. mulungu remain underexplored, highlighting the need for further studies to better understand its mechanisms of action, safety, and therapeutic applications.

Human clinical trials are extremely limited in number, restricted in scope to procedural dental anxiety, small in sample size, and have produced mixed results. Further research should focus on conducting toxicological studies, clinical trials, and mechanistic investigations. These efforts will enable a comprehensive exploration of its pharmacological properties and potential applications in drug development.

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References

• Silveira-Souto ML et al. (2014). Effect of Erythrina mulungu on anxiety during extraction of third molars. Medicina Oral Patología Oral y Cirugía Bucal. PMC4192578.
• Herbal medicines as anxiolytics prior to third molar surgical extraction: a randomized controlled clinical trial. Clinical Oral Investigations (2020). PubMed PMID: 32951121.
• Setti-Perdigão P et al. (2013). Erythrina mulungu alkaloids are potent inhibitors of neuronal nicotinic receptor currents in mammalian cells. PLoS ONE. PubMed PMID: 24349349.
• Setti-Perdigão P et al. (2013). Erythrina mulungu alkaloids are potent inhibitors of neuronal nicotinic receptor currents in mammalian cells. PLoS ONE. PMC3862643.
• New insights in the mode of action of (+)-erythravine and (+)-11α-hydroxy-erythravine alkaloids. PubMed PMID: 32735983.
• Faggion SA et al. (2011). Anticonvulsant profile of the alkaloids (+)-erythravine and (+)-11-α-hydroxy-erythravine isolated from the flowers of Erythrina mulungu. Epilepsy & Behavior. PubMed PMID: 21277832.
• Erysothrine, an alkaloid extracted from flowers of Erythrina mulungu: evaluating its anticonvulsant and anxiolytic potential. PubMed PMID: 22381390.
• Effect of Erythrina velutina and Erythrina mulungu in rats submitted to animal models of anxiety and depression. PubMed PMID: 16470314.
• Vasconcelos SM et al. (2007). Anticonvulsant activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu. Journal of Ethnopharmacology. PubMed PMID: 17070003.
• Antinociceptive activities of the hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu in mice. PubMed PMID: 12843615.
• Erythrina velutina Willd.: A review of its traditional uses, phytochemistry, pharmacology, and toxicology. PubMed PMID: 37820994.
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