Pao pereira

Pao Pereira (Geissospermum vellosii)

1. Identity: Botanical Classification, Names, and Natural Source

Pao pereira (Geissospermum vellosii, or Geissospermum laeve Velloso, sometimes historically referenced as Tabernaemontana), also spelled Pau pereira, is a well-known tree native to South America. It belongs to the plant family Apocynaceae and is native to the northern part of South America.

Pao pereira is a common name for several closely related South American trees in the Geissospermum genus, especially Geissospermum vellosii (sometimes also called G. laeve). The trees are native to the Amazon and other Brazilian biomes, where their bark has a long history of use in folk medicine.

The species carries a variety of common and trade synonyms. These include Bergibita, Pao, Pao-Pereira, Pau Pereira, and Poirier du Brésil. The extract is also known by the names Bergibita, Geissospermum vellosii, Geissospermum laeve, Pau Pereira, and Brazilian Pear.

Pao pereira extract is an herbal extract derived from the bark of the Amazon rainforest tree, Geissospermum vellosii, that has been used historically as a medicine by South American Indian tribes. This unique tree, primarily found in the Amazon, is valued for its bark and leaves, which are used in herbal preparations.

Common Forms and Preparations

Traditional healers prepare bitter teas, decoctions, or macerated bark to address a wide set of complaints. In many regions, the tree is simply known as a very bitter "quina" type bark, similar in reputation to cinchona. The intense bitterness reflects a dense content of indole alkaloids, a class of plant compounds that can have strong effects on the nervous system, immune system, and parasites.

In the contemporary supplement market, Pao pereira is available in several standardized forms. Commercial preparations include a powdered extract made from the bark of Geissospermum vellosii, which is well-suited for use in capsules, tablets, or functional supplement blends. One commercial product specifies that each vegetarian capsule contains 350 mg Pao pereira extract, with capsules containing 40 mg of alkaloids. Alcohol-based tinctures are also widely sold.

2. Traditional and Historical Use

Pao Pereira boasts a rich history rooted in Brazilian folk medicine. Indigenous tribes of the Amazon rainforest have long valued this tree for its healing properties, with knowledge of its uses passed down through generations.

The first official monograph on the benefits of Pao pereira dates to 1848, when Ezequiel Correa Dos Santos presented his thesis "Monographia do Geissospermum vellosii vulgo Pao pereira" to the Faculty of Medicine of Rio de Janeiro. This document served as the first comprehensive account of the benefits of Pao pereira.

Long before modern supplementation, folk preparations made from the tree bark were used for centuries by Indian tribes, particularly when support for the immune system was needed. Pao pereira's traditional use is well-recognized as an excellent tonic and powerful remedy against intermittent fevers.

Decoctions of Pao pereira and Quassia amara have been used for centuries by the people of the Amazon, and their traditional use is well documented.

Documented traditional applications include:

• A significant traditional application was in managing malaria, a prevalent disease in tropical regions.
• Traditional healers utilized Geissospermum vellosii to address digestive problems, including stomach discomfort and diarrhea.
• The herb was also used as a natural analgesic, particularly for headaches and body pains, and was traditionally used for liver pain as well.
• Historical accounts document its use in folk remedies, primarily as a natural tonic to boost overall vitality, and as a treatment for common ailments such as fevers, digestive disturbances, and infections.
• Some traditional uses include its use to support sexual health.

In many Amazonian communities, Pao Pereira held not only medicinal but also spiritual significance. Shamans and traditional healers often incorporated the herb into rituals and ceremonies.

Pao pereira entered Western alternative medicine largely through the work of Mirko Beljanski, a French biologist who studied certain alkaloid-rich extracts in experimental cancer models.

3. Phytochemistry: Key Constituents and Active Compounds

Phytochemical studies of the species Geissospermum vellosii Allemão (Apocynaceae) led to the isolation of several compounds. The medicinal properties of Pao Pereira are attributed to its rich composition of bioactive compounds, particularly indole alkaloids.

The principal classes of alkaloids documented in the bark include:

• Beta-carboline alkaloids: The beta-carboline alkaloid flavopereirine has been obtained from the bark of Geissospermum species. Flavopereirine is one of the most extensively studied individual compounds.
• Indole alkaloids: Documented compounds in the bark include beta-carboline alkaloids, geissospermine in stem bark, leuconolam, geissolosimine, geissospermine, geissolaevine, flavopereirine, indole alkaloids vellosimine and vellosiminol, geissoschizoline, and the indole alkaloid geissovelline.
• Geissospermine: The main alkaloid with anticholinesterase activity in the stembark fraction was isolated and identified as geissospermine.
• Geissoschizoline and derivatives: Four indole alkaloids isolated from Pao pereira include geissoschizoline, geissoschizone, geissospermine, and 3′,4′,5′,6′-tetradehydrogeissospermine, an anhydronium base of geissospermine.
• Pereirin (pereirine): Pereirin is isolated from the bark of Geissospermum vellosii, popularly known as "pau pereira."

Studies with isolated indole alkaloids, extracts, and fractions of different parts of Geissospermum spp. have reported antitumor pharmacological, antinociceptive, anti-inflammatory, anticholinesterase, antileishmania, antitrypanosoma, anti-HIV, antimicrobial, cardiovascular, antioxidant, and antimalarial activities.

4. Established Mechanisms of Action

Research has documented several distinct mechanistic pathways through which Pao pereira's alkaloids exert biological effects.

Anticholinesterase Activity

Studies have evaluated the cholinesterase inhibitory activity of an alkaloid-rich fraction of stembark from Geissospermum vellosii. The fraction inhibited rat brain and electric eel acetylcholinesterase, as well as horse serum butyrylcholinesterase, in a concentration-dependent manner with mean IC₅₀ values of 39.3 µg/mL, 2.9 µg/mL, and 1.6 µg/mL, respectively. While geissospermine inhibited only butyrylcholinesterase (BChE), the other alkaloids behaved as non-selective inhibitors of acetylcholinesterase (AChE) and BChE.

Anticancer / Antiproliferative Signaling

Pao extract suppressed castration-resistant prostate cancer (CRPC) PC3 cell growth in a dose- and time-dependent manner, through induction of apoptosis and cell cycle arrest. Pao extract treatment induced cell cycle inhibitors p21 and p27, and repressed PCNA, Cyclin A, and Cyclin D1. Furthermore, Pao extract induced the upregulation of pro-apoptotic Bax, reduction of anti-apoptotic Bcl-2, Bcl-xL, and XIAP expression, which were associated with the cleavage of PARP protein.

Mechanistically, Pao extract suppressed phosphorylation levels of AKT and NFκB/p65, NFκB DNA binding activity, and luciferase reporter activity. Pao inhibited TNFα-induced relocation of NFκB/p65 to the nucleus and NFκB/p65 transcription activity. NFκB/p65 downstream targets involved in proliferation (Cyclin D1), survival (Bcl-2, Bcl-xL, and XIAP), and metastasis (VEGFa, MMP9, and GROα/CXCL1) were also downregulated by Pao extract.

Nuclear β-catenin levels were decreased in pancreatic cancer stem cell studies, suggesting suppression of Wnt/β-catenin signaling pathway.

5α-Reductase Inhibition (Androgen Pathway)

Pao extract treatment reduced the proliferative index in prostate glands and testosterone-induced expression levels of androgen receptor (AR), as well as androgen-associated proteins such as SRD5A1 and PSA. Flavopereirine can suppress the expressions of androgen receptor (AR) and androgen-associated proteins such as steroid 5 alpha-reductase 1 (SRD5A1) and prostate specific antigen (PSA), suggesting that flavopereirine can be used to reduce testosterone-induced BPH development.

Antiplasmodial Activity

The alkaloids isolated from G. vellosii were tested in clones of Plasmodium falciparum chloroquine-sensitive strain, obtaining potential antiplasmodial results for the indole alkaloids geissolosimine (IC₅₀ 0.66 µg/mL), geissospermine (IC₅₀ 0.65 µg/mL), geissoschizoline (IC₅₀ 0.89 µg/mL), geissoschizone (IC₅₀ 1.78 µg/mL), and vellosiminol (IC₅₀ 1.04 µg/mL).

Antinociceptive / Anti-inflammatory Mechanism

The results of murine studies demonstrate that Geissospermum vellosii stem barks present an anti-inflammatory and antinociceptive activity, similar to that observed with indomethacin, through a mechanism that seems to be unrelated to the opioid system. Results suggest prostanoids such as prostaglandins (PGs) as facilitating agents of the inflammatory process. The mechanism of action of the PPAC fraction differs from that of indomethacin, as the actions are mainly assigned to acetylcholine (ACh), the major vagus nerve neurotransmitter.

Antileishmanial Mechanism

Flavopereirine interacted with residue Tyr-499 of oligopeptidase B during molecular dynamics simulations, giving insights of a possible favorable mechanism of interaction and a possible inhibitory pathway. Flavopereirine proved to be a promising molecule for its antileishmanial activity.

5. Scientific Evidence by Area of Use

Important characterization of evidence base: As of the date of this article, no randomized controlled clinical trials in humans have been conducted with Pao pereira for any indication. Most of the existing research comes from laboratory and animal studies that suggest antimalarial, antiviral, pain-relieving, and anticancer properties. At the same time, there are no clinical trials in humans, and no approved medical indications. All areas below reflect preclinical (in vitro and/or animal) data only unless otherwise specified.

5a. Antimalarial Activity

Evidence level: In vitro and animal only; no human trials.

Lab experiments and animal studies suggest antimalarial activity. Bioactive compounds in Pao pereira known as indole alkaloids showed antiplasmodial activity against a chloroquine-sensitive strain of Plasmodium falciparum, the causative agent of malaria. Of five alkaloids tested, geissolosimine demonstrated the highest activity.

The in vitro antiplasmodial activity of isolated compounds was evaluated in chloroquine-resistant (K1) and chloroquine-sensitive (T9-96) Plasmodium falciparum, and their cytotoxicity was determined in a human (KB) cell line. This research was published in the Journal of Ethnopharmacology in 2012. While the in vitro IC₅₀ values are biologically notable, no progression to human trials has been documented in the peer-reviewed literature.

5b. Prostate Cancer (Preclinical)

Evidence level: In vitro and animal only; no human trials.

Several studies, primarily from Columbia University Medical Center and Nanjing University, have investigated Pao extract against prostate cancer cell lines.

A 2009 study published in the Journal of the Society for Integrative Oncology (Bemis et al.) showed that a beta-carboline alkaloid-enriched extract from the Amazonian rain forest tree Pao pereira suppresses prostate cancer cells.

A subsequent study published in Integrative Cancer Therapies (Chang et al., 2014) examined castration-resistant prostate cancer: Overall, Pao extract induced cell growth arrest and apoptosis, partially through inhibiting NFκB activation in prostate cancer cells. These data suggest that Pao extract may be beneficial for protection against castration-resistant prostate cancer (CRPC).

Although this study supports the idea that a Pao pereira bark extract has activity against human prostate cancer, in vivo results suggest that its potential effectiveness in prostate cancer treatment may be limited to a narrow dose range.

5c. Benign Prostatic Hyperplasia (BPH) — Animal Model

Evidence level: Animal model only; no human trials.

A 2019 study published in Scientific Reports (Nature Publishing Group) investigated Pao extract in a testosterone-induced BPH rat model: The study investigated the therapeutic potential of Pao extract against BPH development in a testosterone-induced BPH rat model. The administration of testosterone induced prostate enlargement, compared with the sham-operated group with vehicle treatment. The BPH/Pao group showed reduced prostate weight comparable with the BPH/finasteride group. Notably, Pao treatment did not significantly reduce body weights or sperm number of rats compared with the control group. Pao extract treatment reduced the proliferative index in prostate glands and testosterone-induced expression levels of AR, as well as androgen-associated proteins such as SRD5A1 and PSA. The study was conducted at Nanjing University. No human studies have followed.

5d. Pancreatic Cancer (Preclinical)

Evidence level: In vitro and animal only; no human trials.

A 2013 study published in Oncology Reports (Yu, Drisko, and Chen; University of Kansas Medical Center) examined Pao extract in pancreatic cancer: The study investigated the extract of Pao Pereira for its anti-pancreatic cancer effect in vitro and in vivo, either alone or in combination with the first-line chemotherapeutic drug gemcitabine. Pao induced dose-dependent apoptosis to all five tested pancreatic cancer cell lines. The combination of Pao and gemcitabine had a synergistic effect in the inhibition of cell growth, with combination indices (CIs) <1 by Chou-Talalay's median effect analysis based on the isobologram principle.

A 2018 study in Integrative Cancer Therapies (Dong, Chen, and Chen) focused on pancreatic cancer stem-like cells: Pao inhibited overall proliferation of human pancreatic cancer cell lines with IC₅₀ ranging from 125 to 325 µg/mL and had limited cytotoxicity to normal epithelial cells. Pancreatic cancer stem cell population was significantly reduced, with IC₅₀s of approximately 100 µg/mL for 48 hours treatment, and approximately 27 µg/mL for long-term treatment. In vivo, Pao at 20 mg/kg, 5 times/week gavage, significantly reduced tumorigenicity of PANC-1 cells in immunocompromised mice, indicating inhibition of cancer stem cells in vivo. No toxic side effects were observed in mice at this dosage.

5e. Ovarian Cancer (Preclinical)

Evidence level: In vitro only; no human trials.

In preclinical studies, the bark extracts demonstrated antitumor activity and enhanced carboplatin effects in ovarian cancer cells. Investigation of Pao Pereira for its activities against ovarian cancer stem cells (CSCs) showed that Pao inhibited ovarian cancer stem cells, probably in preference to the bulk of tumor cells.

5f. Cognitive Function / Anticholinesterase — Potential Alzheimer's Relevance

Evidence level: In vitro and animal only; no human trials.

A 2009 study published in Pharmacology Biochemistry and Behavior (Lima et al.) examined G. vellosii stembark in mice: The study evaluated the cholinesterase inhibitory activity of an alkaloid-rich fraction of stembark from Geissospermum vellosii (PP), and its effect on memory tests in mice. PP inhibited rat brain and electric eel acetylcholinesterase, as well as horse serum butyrylcholinesterase, in a concentration-dependent manner with mean IC₅₀ values of 39.3 µg/mL, 2.9 µg/mL, and 1.6 µg/mL, respectively. PP significantly reduced scopolamine-induced amnesia in the passive avoidance and Morris water maze tests, at 30 mg/kg i.p. (given 45 min before the test sessions). At the highest effective dose (60 mg/kg), administration of PP did not result in noticeable peripheral or central cholinergic side effects.

A 2020 study in Bioorganic Chemistry (Lima et al.) focused specifically on geissoschizoline: In cell viability tests, only geissoschizoline was not cytotoxic. Therefore, geissoschizoline actions were also evaluated in human cholinesterases, where it was twice as potent an inhibitor of hBChE (IC₅₀ = 10.21 ± 0.01 µM) than hAChE (IC₅₀ = 20.40 ± 0.93 µM). This was reported as the first report showing the anticholinesterase activity of these alkaloids and the multi-target actions of geissoschizoline, highlighting this alkaloid as a possible therapeutic prototype to treat Alzheimer's disease.

This anticholinesterase property is being explored as a potential treatment for Alzheimer's disease. All evidence remains preclinical.

5g. Pain and Inflammation — Animal Models

Evidence level: Animal model only; no human trials.

A study published in Anais da Academia Brasileira de Ciências (Lima et al., 2016) evaluated the stembark fraction and ethanolic extract of Pao pereira in murine models: The ethanolic extract and PPAC fraction, both at a dose of 30 mg/kg, significantly reduced mice abdominal constriction induced by acetic acid by 34.8% and 47.5%, respectively. In the formalin test, the ethanolic extract (30 mg/kg) and PPAC fraction (30 and 60 mg/kg) inhibited only the second phase, by 82.8%, 84.9%, and 100%, respectively. Compared with indomethacin, similar doses of ethanolic extract or PPAC fraction were approximately twice as effective in causing antinociception. PPAC fraction was not effective in the hot plate test but reduced the inflammatory response at the second (50.6%) and third (57.8%) hours of rat paw edema induced by carrageenan.

In a murine model, the crude extract and dichloromethane fraction exerted antinociceptive effects against acetic acid and formalin-induced nociception via stimulation of the 5-HT_1A receptor, which is involved in neuromodulation.

5h. Leishmaniasis

Evidence level: In vitro only; no human trials.

The study assessing Pao pereira assessed the in vitro activity of flavopereirine on promastigote cultures of Leishmania amazonensis and performed an in silico evaluation of the physicochemical characteristics of this alkaloid. A greater inhibitory effect of flavopereirine was observed at 24 h and 72 h (IC₅₀ of 0.23 and 0.15 µg/mL, respectively). The extract, fractions, and flavopereirine presented low toxicity, with high selectivity for the alkaloid. Flavopereirine derived from Pao pereira demonstrated activity against leishmaniasis in vitro.

6. Body Systems and Health Areas of Association

Based on the available preclinical literature, Pao pereira has been studied in relation to the following body systems and health areas:

• Immune system: Traditionally, Geissospermum vellosii has been employed to support immune function.
• Oncology / Cell biology: Previous studies on the extract of Pao showed the inhibitory effect on proliferation in pancreatic, ovarian, and prostate cancers.
• Urological / Prostate health: Studied in models of prostate cancer and benign prostatic hyperplasia; a beta-carboline alkaloid-enriched Pao extract has been shown to have inhibitory effects on two prostate cancer lines, LNCaP and PC3, by inhibiting cell proliferation and survival.
• Nervous system / Cognitive health: The stem barks are rich in indole alkaloids that present intense anticholinesterase activity.
• Infectious disease / Parasitology: The bark of Pao pereira shows anti-plasmodial, antinociceptive, and anti-inflammatory activities.
• Gastrointestinal system: Used for stomach disorders in folk medicine, although scientific research in humans has not been conducted.
• Musculoskeletal / Pain: Studied in murine models of acute and inflammatory pain with evidence of antinociceptive effects.

7. Dosage Forms and Dosages Reported in Studies

At this time there is not enough scientific information to determine an appropriate range of doses for Pao pereira in humans. No randomized or even small open-label clinical trials in humans exist for any indication, and there are no standardized dosing guidelines based on pharmacokinetics, target engagement, or toxicity thresholds.

The following dosages appear specifically in the reviewed preclinical studies:

• Anticholinesterase / Memory (murine): The alkaloid-rich stembark fraction (PP) significantly reduced scopolamine-induced amnesia at 30 mg/kg i.p. in mice (given 45 min before test sessions).
• Anti-inflammatory / Antinociceptive (murine): At a dose of 30 mg/kg, the ethanolic extract and PPAC fraction significantly reduced abdominal constriction. In the formalin test, the ethanolic extract at 30 mg/kg and PPAC fraction at 30 and 60 mg/kg inhibited the second phase by 82.8%, 84.9%, and 100%, respectively.
• Pancreatic cancer stem cell inhibition (murine): Pao at 20 mg/kg, 5 times/week gavage, significantly reduced tumorigenicity of PANC-1 cells in immunocompromised mice.
• Commercial supplement (as labeled): One commercial product contains 350 mg of Pao pereira extract per capsule, equal to 40 mg of alkaloids, with one daily serving equaling 6 capsules. Because there are no robust safety data, some practitioners begin at the lower end of label dosing, sometimes 50–100 mg once daily, and gradually increase only if well tolerated and if there is a clear rationale.

8. Safety, Toxicology, and Potential Interactions

When taken by mouth, there is not enough reliable information to know if Pao pereira is safe or what the side effects might be.

Preclinical Toxicology Signals

At the highest effective therapeutic dose (60 mg/kg) in mice, administration of the stembark fraction (PP) did not result in noticeable peripheral or central cholinergic side effects. Only after administration of 200 mg/kg did mice show convulsions affecting the whole body followed by death. This represents a critical animal-model toxicity finding: the lethal dose in mice was approximately 3.3-fold higher than the highest effective dose in that study; however, these figures cannot be directly extrapolated to human dosing.

High doses of Pao Pereira extracts have shown anticholinergic activity and caused convulsions and death in animals.

Reported Side Effects

While Pao Pereira is generally considered safe when used as traditionally recommended, gastrointestinal issues including stomach upset, nausea, or diarrhea are possible.

Allergy and Hypersensitivity

Individuals with allergies to plants in the Apocynaceae family should exercise caution. Avoiding Pao pereira with a known allergy or hypersensitivity to Pao pereira, its constituents, or other members of the Apocynaceae family is advised.

Pregnancy and Lactation

Not enough is known about the use of Pao pereira during pregnancy and breast-feeding, and staying on the safe side to avoid use during these periods is generally recommended.

Potential Drug Interactions

As studies have not been conducted in humans, there are no reports of drug interactions with Pao pereira. However, mechanistic considerations identified in preclinical research raise interaction concerns:

• While no known drug interactions have been definitively established, Pao Pereira could potentially interact with anticancer and antimalarial drugs, and it may interact with medications affecting the liver.
• The documented NFκB inhibition and chemosensitization effects in cancer cell lines (Pao extract can chemosensitize ovarian cancer cells to carboplatin and pancreatic cancer cells to gemcitabine) raise the theoretical possibility of interaction with chemotherapy agents, though this has not been evaluated in humans.
• The potent anticholinesterase activity of the stembark alkaloids theoretically raises caution regarding concomitant use with cholinergic or anticholinergic medications.

Product Variability

Limited information exists about long-term safety, especially regarding liver health, heart rhythm, and interactions with complex cancer regimens. There is also variability between commercial products in terms of alkaloid profile, potency, and contaminants.

9. Current Research Status and Evidence Summary

Studies in vitro and in animal models using the bark extracts indicate antimalarial, antinociceptive, and anti-inflammatory effects, as well as anticholinesterase activity resulting in reversal of cognitive defects. The anticancer potential of Pao pereira has also been investigated. In preclinical studies, the bark extracts demonstrated antitumor activity and enhanced carboplatin effects in ovarian cancer cells. They also suppressed the growth of prostate cancer and pancreatic cancer cells along with potentiating gemcitabine effects, and inhibited pancreatic cancer stem-like cells. However, clinical trials have not yet been conducted.

Despite these promising observations, robust clinical data in humans remains limited. Only a few small-scale studies and anecdotal reports are currently available, and more rigorous research is needed to conclusively validate health claims.

The inhibition of tumorigenicity in animal models implies a possible role of Pao in the prevention of cancer, in addition to data indicating a treatment role. Given that extracts of Pao Pereira are consumed by the American public as a health supplement, the safety, toxicity, and effects of Pao as an anticancer agent should be further investigated clinically.

References

• Liu J, et al. "Pao Pereira Extract Attenuates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by inhibiting 5α-Reductase." Scientific Reports 9, 19703 (2019) — Nature.com
• Chang C, et al. "Pao Pereira Extract Suppresses Castration-Resistant Prostate Cancer Cell Growth, Survival, and Invasion Through Inhibition of NFκB Signaling." Integrative Cancer Therapies (2014) — PubMed
• Yu J, Drisko J, Chen Q. "Inhibition of pancreatic cancer and potentiation of gemcitabine effects by the extract of Pao Pereira." Oncology Reports (2013) — PubMed
• Dong R, Chen P, Chen Q. "Extract of the Medicinal Plant Pao Pereira Inhibits Pancreatic Cancer Stem-Like Cell In Vitro and In Vivo." Integrative Cancer Therapies (2018) — SAGE Journals
• da Silva ESJV, et al. "Flavopereirine—An Alkaloid Derived from Geissospermum vellosii—Presents Leishmanicidal Activity In Vitro." Molecules 24(4):785 (2019) — PMC/PubMed
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• Lima JA, et al. "Antinociceptive and anti-inflammatory effects of a Geissospermum vellosii stem bark fraction." Anais da Academia Brasileira de Ciências (2016) — PubMed
• Lima JA, et al. "Geissoschizoline, a promising alkaloid for Alzheimer's disease: Inhibition of human cholinesterases, anti-inflammatory effects and molecular docking." Bioorganic Chemistry (2020) — ScienceDirect
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