A Tale of Two Anticholinergics: Nutmeg and Jimson Weed

Published in the March 2024 issue of Clinical & Forensic Toxicology News

The Therapeutic Drug Management (TDM) and Toxicology Division of ADLM is excited to announce a partnership with CFTN on an initiative to bring the Division’s toxin library to CFTN’s readership! The toxin library is a digital resource that happens to be one of the most frequently visited ADLM web pages. At present, the library contains entries for 12 naturally occurring toxins, with plenty of room to grow. As part of the partnership with CFTN, the Division has begun the process of updating the existing toxin library content and adding entries for new toxins. Each upcoming issue of CFTN will include an article on a featured toxin, authored or revised by a member of the Division. If you are interested in volunteering to assist with this project, please contact the TDM/ Toxicology Division. In this first feature article, we present revised entries for two toxins that may cause an anticholinergic toxidrome (the classic red as a beet, dry as a bone, blind as a bat, and mad as a hatter syndrome).

Nutmeg (Myristicin, Elemicin, Safrole)

History

Nutmeg is obtained from the seeds of Myristica fragrans, an evergreen tree native to the South Pacific islands (Figure 1). Nutmeg is commonly available at supermarkets across the globe and may be purchased as an intact seed or as a powder. Nutmeg has a long history of use as a spice for food and drinks and was once the subject of significant trade. Interestingly, nutmeg has long been known to cause physiologic effects when ingested in large amounts. Reports of nutmeg intoxications date back approximately 400 years (1). More recently, nutmeg intoxication has been the focus of a viral social media trend wherein willing participants record themselves ingesting nutmeg. The main participants in this so-called “Nutmeg Challenge” have been teenagers, some of whom ingested enough nutmeg to need medical care (2).

Figure 1. Red aril surrounding a nutmeg seed (Myristica fragrans). The nutmeg seed and the aril, which is also known as mace, are both used as spices. Reproduced with permission from AntanO/Wikimedia Commons/ CC-BY-SA-3.0.

Pharmacology and toxicology

Nutmeg contains volatile terpenes and aromatic ethers and has been used to treat dyspepsia, musculoskeletal disorders, and arthritis. Myristicin, elemicin, and safrole are three of the pharmacologically active compounds found in nutmeg. Myristicin and elemicin produce metabolites with amphetamine-like structures (3). Nutmeg ingestions can produce anticholinergic symptoms as well as altered mental status and hallucinations.

Nutmeg intoxication typically requires 5 to 20 grams (1 to 4 teaspoons) of ground nutmeg, significantly more than required for cooking. In intentional intoxications, nutmeg is often administered as a tea. A typical supermarket container of nutmeg holds approximately 60 to 80 grams of ground nutmeg, which is sufficient for multiple intoxications. The low cost and ease of acquisition makes nutmeg an appealing choice for young people looking for “natural highs.”

Health impacts

The onset of symptoms occurs within 3 to 6 hours and lasts for 12 to 24 hours. Symptoms typically resolve within 48 hours and most patients make a full recovery (3). Toxic symptoms are doserelated and primarily anticholinergic, including dry mouth, GI upset, flushing, palpitations, agitation, blurred vision, miosis, hypotension, hypothermia, hallucinations, as well as coma and death. The scientific literature contains two reports of death attributed to nutmeg ingestion; in one case an 8-year-old boy ingested approximately 14 grams of nutmeg, and the other involves a 55-year-old woman who ingested an unknown amount of nutmeg (3). Treatment for nutmeg intoxication is generally supportive in nature; there is no specific antidote (3). Physostigmine is not typically recommended after a nutmeg exposure.

Laboratory testing

Detection of nutmeg-related compounds is not currently available except through laboratory developed tests. Using chromatography and mass spectrometric methods, metabolites of elemicin, myristicin, and safrole have been detected in the blood and urine of patients who ingested nutmeg (1, 4). Gas chromatography and liquid chromatography have both been used, as have nominal mass and high-resolution mass spectrometers.

Jimson weed (Atropine, Scopolamine)

History

Jimson weed (Datura stramonium) is one of the 3,000-plus members of the Solanaceae family, one of the largest families in the plant kingdom. Included in this family are edible crop species such as the potato, eggplant, and tomato (5). The family also includes ornamental plants including the Datura genus, which produces trumpet-like flowers in a variety of colors. There are more than a dozen species of this naturalized Asian plant that grow in many regions of the world. The plant has stout, much-branched, leafy stems from 2 to 5 feet high and large, smooth, thin, wavy, toothed leaves from 3 to 8 inches long. The flowers, which appear from May to September, are white, funnel-shaped, about 3 inches long, and have a pronounced odor. The plants produce prickly seed pods filled with small brown seeds that are colloquially known as “thorn apples” (Figure 2) (6).

Figure 2. “Thorn apple” (Datura stramonium) seedpods. Mature seedpod (L) and immature seedpod (R). Reproduced with permission from Corin Royal Drummond/ Wikimedia Commons/CC-BY-SA-3.0.

Jimson weed has a lengthy history as a medicinal plant, with use recorded as early as the 1500s, but is also frequently associated with accidental and intentional intoxications (5). In the Americas, the first reported account of accidental jimson weed poisoning occurred in 1676 in Jamestown, which gave rise to the common name of jimson weed (5). A recent large-scale poisoning outbreak occurred in Uganda due to accidental contamination of the food supply during harvesting; home gardeners occasionally make similar mistakes (7). Intentional misuse by eating seeds, drinking tea, or smoking cigarettes made of jimson weed is common. The scientific literature contains a plethora of case reports detailing the intentional use of jimson weed by teenagers or other younger people in an effort to experience its psychoactive effects.

Pharmacology and toxicology

Like many Datura species, jimson weed contains alkaloids that possess strong anticholinergic and antimuscarinic properties. These compounds include atropine (d,l hyoscyamine), hyoscine, and scopolamine (l-hyoscine) that act as competitive antagonists to acetylcholine at muscarinic acetylcholine receptors (6). Physiological effects associated with muscarinic receptor stimulation include an impact on sweating, salivation, and smooth muscle tone. As tertiary amines, jimson weed alkaloids also have central nervous system absorption and result in a central anticholinergic syndrome of acute psychosis and delirium. All parts of the jimson weed plant contain potentially toxic compounds; the alkaloids can be ingested, smoked, or topically absorbed from roots, leaves, stems, and flowers. The exact concentration of the alkaloids varies with species, cultivation, environment, temperature, moisture, storage, flower status, and age of the plant. The highest concentration of atropine typically occurs in the seeds (6).

Medicinal uses of the alkaloids are varied. In traditional Chinese medicine, alkaloids have been used to treat asthma, chronic bronchitis, pain, and flu symptoms. Atropine has been used in ophthalmic solutions and is also available in oral and intravenous formulations for use in the treatment of bradycardia and first-degree heart block. Atropine is also an important antidote in organophosphate insecticide poisoning, where it reduces the effects of excess acetylcholine at muscarinic receptors. Scopolamine is used to treat motion sickness and as a pre-anesthetic medication, and is available in a variety of formulations.

Health impacts

Ingestion of jimson weed often results in anticholinergic toxicity as the alkaloids are easily absorbed from the GI tract. The effects manifest as classic anticholinergic poisoning with symptoms initially observed within 30 to 60 minutes. Symptoms may continue for 24 to 48 hours if left untreated. Metabolism of the alkaloids occurs in the liver by hydrolysis that eliminates approximately half of the dose. The remainder is excreted unchanged in the urine.

Fatalities due to jimson weed are relatively rare, making up less than 0.1% of fatal poisonings reported to poison control centers in the United States (8). Physostigmine may be used clinically to reverse the anticholinergic symptoms but many cases are managed supportively. Adolescents account for nearly 50% of the jimson weed exposures reported to United States poison control centers; of these, the vast majority of exposures were intentional (8).

Laboratory testing

Detection of jimson weed alkaloids in human biospecimens is not currently available except through laboratory-developed tests. Using chromatography and mass spectrometric methods, atropine and scopolamine have been detected in a variety of samples, including human hair, blood, and urine (7). Testing for these compounds is available at reference laboratories in the United States.

References

1. Manier SK,Wagmann L,Weber AA, Meyer MR. Abuse of nutmeg seeds: Detectable by means of liquid chromatographymass spectrometry techniques? Drug Test Anal 2021;13:1440–1444.
2. Atherton RR. The ‘Nutmeg Challenge’: a dangerous social media trend. Arch Dis Child 2021;106:517–518.
3. Casale MJ,MacDonald LQL, Mitra A. Nutmeg intoxication: a case report. Cureus Published online September 30, 2023.
4. Beyer J, Ehlers D,Maurer HH. Abuse of nutmeg (Myristica fragrans Houtt.): studies on the metabolism and the toxicologic detection of its ingredients elemicin, myristicin, and safrole in rat and human urine using gas chromatography/mass spectrometry. Ther DrugMonit 2006;28:568–575.
5. Fatur K, Kreft S. Common anticholinergic solanaceaous plants of temperate Europe - a review of intoxications from the literature (1966–2018). Toxicon 2020;177:52–88.
6. Sharma M, Dhaliwal I, Rana K, Delta AK, Kaushik P. Phytochemistry, pharmacology, and toxicology of datura species— a review. Antioxidants 2021;10:1291.
7. Mutebi RR, Ario AR, Nabatanzi M, et al. Large outbreak of Jimsonweed (Datura stramonium) poisoning due to consumption of contaminated humanitarian relief food: Uganda, March–April 2019. BMC Public Health 2022;22:623.
8. Krenzelok EP. Aspects of Datura poisoning and treatment. Clin Toxicol 2010;48:104–110.

Jennifer Colby, PhD, DABCC (CC, TC), F-ABFT is the Scientific Director at Premier Biotech in Minneapolis, MN, and the current Chair of ADLM’s TDM and Toxicology Division.

The author has nothing to disclose.