Case of Levodopa Toxicity from Ingestion of Mucuna gigantea

Abstract

Hawai‘i is home to 1000 native species of flowering plants. Mucuna gigantea is one such Hawaiian species which has been studied as affordable sustenance and as a cover crop in developing countries. Mucuna gigantea and other Mucuna species (spp.) in general, are known to contain natural levodopa and its utility in the treatment of Parkinson's Disease has also been evaluated. Levodopa is converted in the periphery into dopamine which can then act on dopamine receptors to cause nausea, vomiting, arrhythmias, and hypotension. We describe a case in which a patient presents with abdominal pain, nausea, and vomiting after legume ingestion. The bean was ultimately identified as Mucuna gigantea and the patient was diagnosed with levodopa-induced gastrointestinal toxicity from consumption of the legume. A literature review was conducted using the database search engines, Biological Abstracts and PubMed, with a broad combination of keywords of which include “mucuna, “gigantean,” “levodopa,” “l-dopa,” “toxicity,” and the association between Mucuna gigantea ingestion and levodopa toxicity is discussed. These findings expand the differential diagnosis of abdominal pain associated with nausea and vomiting in the correct clinical context.

Introduction

Hawai‘i has approximately 1000 native species of flowering plants of which 90% are unique to the Hawaiian islands.¹ Mucuna genus is a legume in the family Fabaceae with around 100 different species found in tropical areas around the world, including Hawai‘i.^1,2 Various Mucuna species have been studied in developing countries as cover crops for food self-sufficiency development and soil fertility improvement; furthermore, their bioactive substances have been thoroughly evaluated, particularly levodopa (L-DOPA).^3,4 Mucuna varieties grow natively in Hawai‘i and inadvertent ingestion may produce signs and symptoms consistent with the pro-drug L-DOPA used in Parkinson's Disease (PD) treatment. The conversion of L-DOPA into Dopamine (DA) in the periphery and subsequent receptor binding lead to gastrointestinal (GI) symptoms of nausea, vomiting, cramping, as well as neurological side effects. Here we present a case of Mucuna gigantea ingestion, also known as Seabean, with subsequent L-DOPA toxicity and review the biochemical mechanisms of its side effects. A literature review was conducted using the database search engines, Biological Abstracts and PubMed, with a broad combination of keywords of which include “mucuna”, “gigantea”, “levodopa”, “l-dopa”, “toxicity”, and the association between Mucuna gigantea ingestion and levodopa toxicity is discussed.

Case Report

A 27-year-old non-pregnant woman, with no significant past medical history, presented to the Emergency Department (ED) with acute onset abdominal pain, nausea, vomiting, and cramping. One hour prior to presentation, the patient was touring local farms and tried fruit from a tomato plant and beans from a green pod. Within 1 hour of consumption, patient became symptomatic with the aforementioned as well as dizziness and confusion. She denied any other symptoms. In the ED, patient's vital signs were stable and she appeared uncomfortable with active vomiting and a diffusely tender abdominal exam without peritoneal signs. The rest of the physical exam was unremarkable. Her laboratory analyses were all within normal limits and a urine drug screen was negative. While the patient could not tolerate oral contrast, a limited abdominal/pelvic CT with only IV contrast was unremarkable. After consultation with poison control, the patient was treated with anti-emetics, IV fluids and activated charcoal before admission to telemetry and monitoring with serial chemistry profiles and liver function tests. She progressively improved over 48 hours. Later, a botanist confirmed that the legume she had consumed was of the genus species Mucuna gigantea.

Discussion

Mucuna was first described in Ayurvedic texts as early as 1500 BC as a treatment for Kampavata (paralysis agitans), a neurologic disease with similar symptoms to PD.⁵ Moreover, Mucuna extract is still used in modern India as a complementary treatment of PD. In contemporary medicine, Mucuna remains a plant of interest since its L-DOPA content and use in treatment of PD continues to be evaluated in biochemical research. One small randomized, controlled, double blind study of 8 PD patients comparing Mucuna pruriens seed extract versus synthetic L-DOPA/Carbidopa showed that natural L-DOPA had a more rapid onset of action and longer effect without increases in dyskinesias, when compared to synthetic L-DOPA formulations.⁶ Although interesting, this study was limited by the small sample size and a heterogeneous treatment population since many of the patients were taking concomitant dopamine agonists and NMDA receptor antagonists. Mucuna gigantea, similar to other Mucuna spp., also contains L-DOPA and has been shown to induce mesenchymal stem cell expression of neural protein and genetic markers, similar to studies involving synthetic L-DOPA.^7,8

Mucuna gigantea, also known commonly as Seabean, or in Hawaiian as Kāe‘e, is indigenous to the Hawaiian Islands. It is a vine plant that grows perennially and can extend up to 15 meters long, growing near the coast at lower elevations (Figures 1 through 3). The plant flowers range in color from green-yellow, and white-green; individual flowers are pendent, round-topped, and grow in clusters.² The plant also has bean pods that range in color from green to brown and are covered with brown hairs called trichomes (Figure 4). Leaflets are trifoliolate, hairless, and broadly elliptic in shape. The Mucuna gigantea seeds have a hamburger-like appearance and can be brown to black in color (Figure 5). These seeds have high amounts of crude protein, crude fat, total free phenols and tannins when compared to other legumes.⁷ In one study, 1.5 grams of L-DOPA was isolated from 100 grams of seed flour, lower than values reported in other species of Mucuna described in the region.⁷ From studies investigating Mucuna gigantea as a cover crop, researchers have showed that L-DOPA can be sufficiently reduced from being 4.93% of the content of unprocessed whole seeds to 0.04%, if seeds are cracked and rinsed under running water for 72 hours.⁴ Although their conclusions are useful in the context of Mucuna as a cover crop, their findings could be criticized because they did not control for the shelf life of each batch of seeds prior to study analysis, did not discuss the natural half-life of L-DOPA within Mucuna beans, and did not correct for the risk of sampling error in the samples chosen for analysis.

Figure 1.

Mucuna gigantea, flowers are pendent, round-topped, and umbel-like clusters.

(Plant images are reprinted with permission of wildlifeofhawaii.com)

Figure 2.

Mucuna gigantea, leaves are trifoliolate, broadly elliptic in shape, mostly hairless.

(Plant images are reprinted with permission of wildlifeofhawaii.com)

Figure 3.

Mucuna gigantea, vines hang from trees and stems are slender and intertwine.

(Plant images are reprinted with permission of wildlifeofhawaii.com)

Figure 4.

Mucuna gigantea, drying green to brown legume pods with dark orange-brown.

(Plant images are reprinted with permission of wildlifeofhawaii.com)

Figure 5.

Mucuna gigantea, disk-like seeds with black hilum which are almost hamburger-like in appearance, are approximately 1 inch wide and can range from brown to black in color.

(Plant images are reprinted with permission of wildlifeofhawaii.com)

Endogenous L-DOPA is formed from the amino acid tyrosine by the enzyme tyrosine hydroxylase (Figure 6). L-DOPA in the peripheral vascular system can be transported across the blood brain barrier (BBB) by a neutral amino acid transporter where it can then be decarboxylated by L-aromatic amino acid decarboxylase (AADC) into DA within the brain.⁶ Since DA itself has a catechol moiety, it remains ionized at physiological pH which is the cause for its poor BBB permeability, and therefore the reason why PD cannot be treated directly with DA. This pharmacological and biochemical basis forms the rationale of the combination therapies available for PD. The oral bioavailability of synthetic L-DOPA is approximately 10% because of extensive first pass GI metabolism; only 1%–3% of the original dose is transported across the BBB unchanged.¹⁰

Figure 6.

Schematic showing biosynthesis of dopamine from tyrosine with corresponding enzymes and co-factors.

L-DOPA, whether synthetic or natural from a Mucuna bean, is readily converted by AADC into DA in the GI tract (Figure 6). In fact, dopamine is found to be significantly abundant in the intestinal mucosal cell layer and these same epithelial cells, particularly those localized to the jejunum, are rich in AADC.^11–13 Using brain tissue for controls, Eaker, et al, showed that dopamine is indeed abundant and localized in the intestinal mucosal layer by treating gut tissue with neurotoxin 6-OHDA to decrease dopamine extraction and elution versus controls, and that DOPAC (a DA metabolite) could be directly extracted from gut tissue, suggesting that gut DA acts independently as a neurotransmitter rather than as a norepinephrine precursor. It is well known that endogenously catecholamines play an important role in the regulation of body fluid and electrolyte homeostasis in the intestinal tract. Therefore, conversion of exogenous L-DOPA to DA by mucosal epithelial cell AADC, such as in our patient with ingestion of Mucuna gigantea seeds, leads to aberrantly elevated DA levels and subsequent manifestation of GI and cardiovascular symptoms due to concomitant fluid and electrolyte dysregulation.

All five classes of DA receptors (D1–D5) are expressed in the proximodistal axis of the bowel.¹⁴ Moreover, Li, et al, showed, using both RT-PCR and in situ hybridization, that DA receptors are present in the gut smooth muscle, myenteric plexus, and mucosa as early as embryonic day 10, even before the appearance of neurons. Exogenously converted DA will then act predominately on D1 dopaminergic receptors, activating adenylyl cyclase in smooth muscle cells, increasing cAMP and creating vasodilatation in coronary, mesenteric, and renal vascular beds.¹⁵ Vasodilatation in the mesenteric vasculature can lead to the abdominal pain and cramping as the mucosal wall can become edematous. Dopamine also acts as an indirect anti-cholinergic in the GI tract through D2 receptors that are prominent on the processes of myenteric and submucosal neurons. DA binds to axonal D2 receptors within the ganglia, decreasing acetylcholine release from post-ganglionic nerve terminals as well as de-sensitizing muscarinic receptors of GI smooth muscles, which effectively decreases prokinetic signals.^11,12,14 This leads to loss of peristalsis, decreased gastric motility, and dysregulation of prokinetic GI secretions which contributes to abdominal pain, nausea, and vomiting associated with an ileus. Decreasing cholinergic tone in the GI tract also leads to decreased esophageal sphincter tone, further mediating emesis. Dopamine also stimulates D2 receptors in the area postrema which directly induces nausea and vomiting.⁹ This is actually the basis for some drugs that treat nausea and vomiting such as the D2 antagonist, Metoclopramide.¹⁶ These same mechanisms that lead to change in intra and extracellular signaling can cause cardiovascular side effects such as arrhythmias and hypotension. Excess DA from L-DOPA in Mucuna gigantea seeds that do reach the CNS may mediate neurologic side effects; DA involvement in the nigrostriatal and tubero-infundibular pathway may lead to altered mental status, confusion, and even hallucinations if ingested in high concentrations.

This case adds to the differential for patients presenting with abdominal pain, nausea, and vomiting with unremarkable labs and imaging, as well as reviews the biochemical mechanisms behind L-DOPA toxicity. The differential remains broad for such nonspecific GI complaints and may include GI ova and parasites, bacterial or viral gastroenteritis, bacterial toxin (food) poisoning, mesenteric ischemia, trauma, anatomical or pathological obstruction, among others. Yet in the appropriate clinical scenario legume ingestion with or without neurologic symptoms in the context of normal stool studies and unremarkable imaging, L-DOPA toxicity should be considered.

Disclosure Statement/Conflict of Interest

This study used resources provide by NIH (U54MD007584). The authors report no conflict of interest.