Some science behind the scenes

Nutmeg – myristica fragrans

Nutmeg is a spice.  It is used in cooking and at normal quantities does no harm.  But it has gained an unjustified reputation for being ‘hallucinogenic’ and as a consequence has been taken in overdose proportions.

The spice of life: an analysis of nutmeg exposures in California - Carstairs SD, Cantrell FL; 

Department of Emergency Medicine, Naval Medical Center, San Diego, CA 92134-5000, USA.

BACKGROUND:
Nutmeg is widely used as a household spice. Numerous citations in the medical literature report its abuse as a psychoactive agent, primarily for its purported hallucinogenic effects.

METHODS:
We performed a retrospective review of the California Poison Control System database for the years 1997-2008 for all cases of single-substance human exposure to nutmeg.

RESULTS:
There were a total of 119 single-substance exposures to nutmeg. Eighty-six (72.3%) exposures were intentional. Patients intentionally abusing nutmeg were more likely to be between the ages of 13 and 20 than those with unintentional exposure to the spice (80.2% vs. 9.1%). Abusers were significantly more likely to require medical evaluation than nonabusers (61.6% vs. 33.3%). Patients who abused nutmeg were significantly more likely to experience tachycardia and agitation than those whose exposure was unintentional. No major effects and no deaths were reported to occur in either group.

CONCLUSIONS:
Although nutmeg exposure is uncommonly encountered, clinical effects from ingestion can be significant and can require medical intervention. While clinically significant effects were common, life-threatening toxicity and death did not occur in this series.

Metabolism

We will first take a look at how nutmeg is metabolised in the body.

Reporting in the Drug Monitor [Beyer J et al; The Drug Monitor 28 (4): 568-75 (2006)] scientists wrote that:

Metabolites of elemicin, myristicin, and safrole were identified using gas chromatography-mass spectrometry …… and their presence in the human urine of a nutmeg abuser was confirmed. The identified metabolites indicated that elemicin, myristicin and safrole are once and twice hydroxylated at the side chain. ... myristicin and safrole are demethylenated and subsequently methylated. In the human urine sample, the following metabolites could be identified:

  • O-demethyl elemicin
  • O-demethyl dihydroxy elemicin
  • demethylenyl myristicin
  • dihydroxy myristicin
  • and demethylenyl safrole

Neither amphetamine derivatives nor the main nutmeg ingredients could be detected in the urine samples.”

So, no conversion takes place, if anything happens at all, it is conversion to these metabolites.

Myristicin [1-allyl-3,4-methylenedioxy-5-methoxybenzene ] is metabolised in the liver to a number of metabolites, but the major metabolite is actually , 5-allyl-1-methoxy-2,3-dihydroxybenzene.  The transformation is performed by a liver cytochrome P450 (CYP), more specifically CYP3A4 and possibly other CYP3A enzymes.  [Ref:  Yun CH et al; Toxicol Lett 137 (3): 143-50 (2003)].

It doesn’t  particularly matter which enzyme because the result is not an alkaloid, nor does it have any hallucinogenic potential.  I don’t even need to go into the chemistry because the very name ‘benzene’ should be enough to demonstrate this.

The chemicals in nutmeg

Nutmeg actually contains quite a range of chemicals.  Most of these  provide flavour and smell to the nutmeg or protect the plant against predators.  They are not alkaloids nor do they have any receptor ability.  We can divide these chemicals into three basic groups;

  • Monoterpenes - A number are Monoterpenes derived from the molecular formula C10H16. Examples of monoterpenes in nutmeg include: sabinene, pinene, phellandrine and limonene and  shown in blue in the lists below. These act as natural insecticides

Toxicity of Myristica fagrans seed compounds against Blattella germanica (Dictyoptera: Blattellidae). - Jung WC, Jang YS, Hieu TT, Lee CK, Ahn YJ; School of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.

The insecticidal activity of 13 Myristica seed compounds against female B. germanica was examined …. Results were compared with those of the other 23 known compounds of Myristica seed and currently used insecticides:

  • Dichlorvos
  • Deltamethrin
  • Permethrin
  • and propoxur.

In contact toxicity tests using female B. germanica,

  • beta-pinene (0.06 mg/cm2) was the most toxic insecticide.  The insecticidal activity of this compound was comparable with that of permethrin
  • Camphor, dipentene [limonene], -3-pinene, and alpha-terpineol were more toxic than propoxur
  • Sabinene hydrate and propoxur were almost equitoxic

Potent insecticidal activity also was observed with citronellal, alpha-phellandrene, alpha-pinene, and safrole.

 Myristica seed compounds described merit further study as potential insecticides or as leads for the control of cockroaches.

  • Sesquiterpenes  - Some are Sesquiterpenes. Sesquiterpenes are found naturally in plants and insects, as semiochemicals, e.g. defensive agents or pheromones.  These are shown in red in the lists below [and above]
  • Phenylpropenes -  are produced by plants as defense compounds against animals and microorganisms and as floral attractants of pollinators. Humans have used phenylpropenes since antiquity for food preservation and flavouring and as medicinal agentsThey are natural anti-bacterial agents .  Some are anti-viral and anti-inflammatory agents.  Phenylpropenes include Anethole, Chavibetol, Chavicol, Elemicin,  Estragole, Eugenol, Isoeugenol, Isosafrole, Methyl eugenol, Myristicin and  Safrole

Antibacterial principles from Myristica fragrans seeds - Narasimhan B, Dhake AS.
Department of Pharmaceutical Sciences, Guru Jambheshwar University, Hisar, Haryana, India.

Antibacterial activity of these isolated constituents was evaluated by determination of minimum inhibitory concentration against selected Gram-positive and Gram-negative organisms. All the constituents isolated from nutmeg exhibited good antibacterial activity. This study shows the potential of natural compounds in replacement of synthetic preservatives.

Anti-inflammatory effect of myristicin on RAW 264.7 macrophages stimulated with polyinosinic-polycytidylic acid - Lee JY, Park W.

Myristicin …. is an active aromatic compound found in nutmeg (the seed of Myristica fragrans), carrot, basil,cinnamon, and parsley. Myristicin has been known to have anti-cholinergic, antibacterial,and hepatoprotective effects, however, the effects of myristicin on virus-stimulated macrophages are not fully reported. In this study, the anti-inflammatory effect of myristicin on double-stranded RNA (dsRNA)-stimulated macrophages was examined. ……..myristicin has anti-inflammatory properties related with its inhibition of NO, cytokines, chemokines, and growth factors in dsRNA-stimulated macrophages via the calcium pathway.

Remember they have no receptor capability.

The actual chemical constituents vary widely according to where the plant has been grown , the soil and the climate.  It can also be affected by adulterants – in lower quality nutmeg powder, other varieties of myristica may be used – such as Papuan nutmeg M. argentea from New Guinea, and Bombay nutmeg M. malabarica from India, called jaiphal in Hindi.  These have different properties and chemicals.  So in reality you don’t know what you are getting, nor do you know in what quantities you may be getting them – this partly accounts for the widely different reports you get on sites such as EROWID.

For example, Christian Rasch [Encyclopedia  of Psychoactive plants] indicates that the essential oil of the nutmeg consists of

  • 4%  - Myristicin - Myristicin is a phenylpropene, a natural organic compound present in small amounts in the essential oil of nutmeg and to a lesser extent in other spices such as parsley and dill.
  • 39%   - Sabinene is one of the chemical compounds that contributes to the spiciness of black pepper and is a major constituent of carrot seed oil. It also occurs in tea tree oil at a low concentration..
  • 13%  -  alpha-Pinene is found in the oils of many species of many coniferous trees, notably the pine. It is also found in the essential oil of rosemary (Rosmarinus officinalis).. The racemic mixture is present in some oils such as eucalyptus oil
  • 9% - beta-Pinene (?-pinene) is soluble in alcohol, but not water. It has a woody-green pine-like smell. It occurs naturally in rosemary, parsley, dill, basil, yarrow, and rose. It is also a major constituent of hop aroma and flavor.
  • 4% - alpha-Phellandrene was named after Eucalyptus phellandra,  from which it can be isolated. It is insoluble in water but can be isolated in ether.  The phellandrenes are used in fragrances because of their pleasing aromas..
  • 4% - Limonene is the main odor constituent of citrus.  It is in food manufacturing, as a flavoring,  a fragrant in perfumery; and it is also used as botanical insecticide.  Limonene is increasingly being used as a solvent for cleaning purposes. It has even served as a paint stripper when applied to painted wood. Limonene is also used as a solvent in some model airplane glues
  • ?% - Elemicin is a phenylpropene, a constituent of the essential oil of nutmeg and a minor constituent of the oleoresin and essential oil of Manila elemi (Canarium luzonicum).  Although Rasch mentioned it, no percentage was specified. 

Nutmeg is actually far more complex than the list above implies – see the list below. Source:  Production, handling and processing of nutmeg and mace and their culinary uses  - FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS; Guido B. Marcelle; Grenada Produce Chemist Laboratory; FAO REGIONAL OFFICE FOR LATIN AMERICA AND THE CARIBBEAN

  • Bergamotene alpha;
  • Bisabolene;
  • Borneol;
  • Cadinene;
  • Camphene;
  • Camphor;
  • Caryophyllene beta;
  • Caryophyllene;
  • Cineole or eucalyptol;
  • Citronellol;
  • Copanene;
  • Cubebene alpha
  • Cymen-8-OL;
  • Eugenol;
  • Ether;
  • Farnesene alpha;
  • Fenchol – alpha;
  • Geraniol;
  • Germacrene;
  • Humulene;
  • Linalool;
  • Myrcene;
  • Nerol;
  • Piperitone;
  • Terpinen-4-OL;
  • Terpinene;
  • Terpineol alpha and beta;
  • Terpinolene;
  • Thujene;
  • And Trimyristin 

Bergamottin is a natural furanocoumarin found principally in grapefruit juice. Along with the chemically related compound 6’,7’-dihydroxybergamottin, it is believed to be responsible for the grapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.

Trimyristin is an ester with the chemical formula C45H86O6. It is a saturated fat which is the triglyceride of myristic acid. Nutmeg oil generally consists of over eighty percent trimyristin. Trimyristin makes up between 20-25% of the overall mass of dried, ground nutmeg. It is the trimyristin that contains the myristicin.

Antibacterial principles from Myristica fragrans seeds - Narasimhan B, Dhake AS.

Department of Pharmaceutical Sciences, Guru Jambheshwar University, Hisar, Haryana, India.

Nutmeg (Myristica fragrans) is used in food preparations for its aromatic flavour. The present investigation was undertaken to evaluate the antibacterial activity of constituents of M. fragrans seeds.

Seeds of M. fragrans were powdered and extracted with chloroform to obtain trimyristin, which on saponification yielded myristic acid. The mother liquor remaining after separation of trimyristin was concentrated and column-chromatographed with petroleum ether to separate myristicin.

I hope you can see from this list that there is nothing here that would give you a spiritual experience – nothing.

Nutmeg poisoning

“Several intoxications have been reported after an ingestion of approximately 5 g of nutmeg, corresponding to 1-2 mg myristicin/kg body weight (b.w.). Although these intoxications may be ascribed to the actions of myristicin, it is likely that other components of nutmeg may also be involved”  [Ref:  Hallstrom H, Thuvander A; Nat Toxins 5 (5): 186-92 (1997)]

Chronic poisoning by oral administration has also caused temporary (up to six months) psychosis in prison inmates. [Ref:  International Programme on Chemical Safety (IPCS); Poisons Information Monograph: Myristica Fragrans Houtt (PIM 355) (1991)]

The effects by inhalation are generally similar to those experienced via oral administration with the exception that onset is faster by 15 minutes. [Ref:  International Programme on Chemical Safety (IPCS); Poisons Information Monograph: Myristica Fragrans Houtt (PIM 355) (1991).One reported case of nutmeg intoxication after drinking nutmeg tea, states that the reaction is immediate.

Elemecin, in the sort of doses people subject themselves to, is genotoxic.  Genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity. Genotoxic substances are all those with affinity to interact with DNA - which is not proof of their dangerousness to humans, but does render them potentially mutagenic or cancerogenic in quantity.

Genotoxicity of the alkenylbenzenes alpha- and beta-asarone, myristicin and elimicin as determined by the UDS assay in cultured rat hepatocytes - Hasheminejad G, Caldwell J.

Department of Pharmacology and Toxicology, St Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK.

While the alkenylbenzenes alpha- and beta-asarone are hepatocarcinogenic in rodents, myristicin and elimicin, two other alkenylbenzenes, are not…….

The present study investigated the mechanism of genotoxicity of the asarones to elucidate the role of cytochrome P-450 and obtain further information about the relationships between the structure, metabolism and genotoxicity of the alkenylbenzenes. The data on the ability of these compounds to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats are presented in this paper.

Elimicin and alpha- and beta-asarone are genotoxic in the UDS assay but myristicin is not.

…Simple allylbenzenes such as safrole, estragole and methyleugenol are activated by sequential 1-hydroxylation and sulfation, and this is the likely mechanism of the genotoxicity of elimicin.

The overall effect of the chemicals in nutmeg such as Limonene, which will have a partly

Myristicin at high doses is cytotoxic…………………………

Myristicin-induced neurotoxicity in human neuroblastoma SK-N-SH cells.

Lee BK, Kim JH, Jung JW, Choi JW, Han ES, Lee SH, Ko KH, Ryu JH - Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University,  Seoul, Korea.

Myristicin, … is a naturally occurring alkenylbenzene compound found in the nutmeg. The present study was conducted to assess the cytotoxic and apoptotic effects of myristicin on the human neuroblastoma SK-N-SH cells.

We found that a dose-dependent reduction in cell viability occurs at myristicin concentration > or =0.5 mM in SK-N-SH cells…………..

The apoptosis triggered by myristicin was accompanied by an accumulation of cytochrome c and by the activation of caspase-3. The results obtained suggest that myristicin induces cytotoxicity in human neuroblastoma SK-N-SH cells by an apoptotic mechanism.

Apoptosis  is the process of programmed cell death.  Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 new cases per year in the US.  Myristicin may help with fighting cancer.

It is not just the myristicin or safrole or elemecin or limonene that causes the deleriant  reaction – all the chemicals are acting together to produce this effect.

And it must be emphasised Nutmeg poisoning can kill you, although because the problem of abuse is known and hospitals are geared up to handle it, it is rare.

Nutmeg (myristicin) poisoning--report on a fatal case and a series of cases recorded by a poison information centre - Stein U, Greyer H, Hentschel H;  Department of Legal Medicine Erfurt, Institute of Legal Medicine, Friedrich-Schiller University, Jena, Germany.

In literature, cases of nutmeg abuse have been described repeatedly, but only one fatal case of poisoning. In the present case, myristicin (4 microg/ml) was detected for the first time in the postmortal serum of a 55-year-old woman. ….. From 1996 to 1998, in a series of cases, seven poisonings with nutmeg were recorded by the Erfurt Poison Information Centre.

According to one scientific report “ Most patients with accidental nutmeg intoxication experience an impending sense of doom after the initial excitation” [International Programme on Chemical Safety (IPCS); Poisons Information Monograph: Myristica Fragrans Houtt (PIM 355) (1991)]

Well they might.

References

  1. Meyler’s Side Effects of Drugs – Elsevier publishing
  2. A Modern Herbal – Mrs M Grieve
  3. Medical Toxicology of Natural Substances – Foods, Fungi, Medicinal Herbs, Plants and Venomous Animals pub. Wiley
  4.  http://en.hortipedia.com/wiki/Main_Page
  5.  Encyclopedia of Psychoactive plants - Christian Rasch
  6.  http://www.erowid.org/experiences/subs/exp_Nutmeg_General.shtml
  7.  http://www.erowid.org/plants/nutmeg/nutmeg_basics.shtml
  8.  http://www.erowid.org/experiences/subs/exp_Nutmeg.shtml