Nutmeg

Myristica fragrans (of the family Myristicaceae) is a plant which bears seeds, and said seeds are ground into a powder and commonly referred to as Nutmeg. The tree which bears these seeds grows up to 10-20m tall and is indigenous to India, Indonesia, and Srilanka.^[1]

Nutmeg seeds have been used in traditional medicine as a general tonix and nervous system stimulant, but also for the purposes of treating paralysis, respiratory ailments, and sickness or improving the libido, appetite, and blood circulation; it also bears the properties of being a stomachic and carminative agent.^[1][2]

Nutmeg refers to the seeds of the plant Myristica fragrans, and these seeds appear to have general aphrodisiac properties and are said to interact with the nervous system, digestive system, and blood circulation

Components of the overall seed (unless otherwise specified) include:

• Macelignan ((8R, 8′S)-7-(3,4-methylene-dioxyphenyl)-7′-(4-hydroxy-3-methoxyphenyl)-8,8′-dimethylbutane^[3]) in the rhizome.^[4]
• Myrislignan, an acylic neolignan^[5]

The fatty acid component of nutmeg includes:

• Trimyristin (triglyceride composed of three myristic acids) at 20-25% total dehydrated seed weight

The essential oil component (5-10% dry seed weight^[6]) of the nutmeg seeds includes:

• Sabinene (21.38%^[6])
• Myristicin (5-allyl-1-methoxy-2,3-methylenodioxybenzene), seen as the main bioactive of nutmeg^[7] present at 13.57%^[6] and also present in dill to a limited degree
• Elemicin (1-allyl-3,4,5-trimethoxybenzene) at 1.42%^[6]
• 4-terpineol (13.92%^[6]) and α-terpineol (3.11%^[6])
• Safrole (4.28%^[6])
• Methyl eugeunol (0.77%), Isoeugeunol (1.74%), and Methoxyeugeunol (0.10%)^[6]
• α-pinene (10.23%^[6])
• α-thujene (0.78%^[6])
• α-myrcena (2.38%^[6])
• β-asarone (0.03%^[6])
• α-terpinene (2.72%) and γ-terpinene (3.98%) as well as Terpinolene (1.62%)^[6]
• Limonene (5.57%)^[6]
• β-ocimene (0.03%)^[6]
• Linalool (0.75%)^[6]
• Citronellol (0.77%)^[6]

Keep in mind that Myristicin (phenolic), Myristin/Myristic acid (fatty acids), and the flavonoid Myricetin are all different but similarly named molecules

Following inhalation of nutmeg essential oil (1mL per rat cage) for two hours, detectable serum concentrations have been reported for myristicin (3.8-7.1μg/mL), safrole (1.3μg/mL after two hours only), and 4-terpineol (1.5-6.3μg/mL) showing time dependent accumulation.^[6]

Following administration to the rat and in vitro analysis in liver microsomes, myristicin (100mg/kg orally) has been noted to be enzymatically hydroxylated (1'-hydroxymyristicin) and enzymatically formed 5-allyl-1-methoxy-2,3-dihydroxybenzene (oxidation of the methylenedioxy group).^[8]

Myrislignan (acyclic neolignan in the seeds) has been noted to form seven metabolites referred to as myrislignanometins A-G in liver microsomes, whereas C/D and E/F were isomers pairs.^[5]

Myriscitin appears to form two metabolites in the rat, one of which is a hydroxylated variant (similar to other phenolics such as safrole and elemicin) and the other is simply oxidation of the methylenedioxy group

It was initially hypothesized that elemicin and myristicin can form known hallucinogenic drugs in the brain following amination processes (formation of 3,4-methylenedioxy-5-methoxyamphetamine from myricitin and mescaline from elemicin^[9]) since the only structural modification is said amination; this pathway was initially doubted to occur^[10] and has not been demonstrated in vivo.

Other studies on the metabolism of myriscitin or elemicin, either in vitro or in vivo, have failed to detect either mescaline or amphetamine-like compounds^[8] and measuring human urine following nutmeg ingestion has failed to find the aforementioned amphetamine derivative.^[11]

Currently no evidence to support conversion of nutmeg bioactives into known amphetamines (3,4-methylenedioxy-5-methoxyamphetamine) or phenethylamines (mescaline) following oral consumption

In human urine following ingestion of nutmeg neither parent myristicin nor elemicin could be detected and instead the metabolites of O-demethylelemicin, O-demethyldihydroxyelemicin, demethylenylmyristicin, dihydroxymyristicin, and demethylenylsafrole have been detected.^[11]

In the rat given 100mg/kg myristicin, urinary metabolites include 1'-hydroxymyristicin and 5-allyl-1-methoxy-2,3-dihydroxybenzene (oxidation of the methylenedioxy group).^[8]

4-terpineol (as well as α-terpineol) have been noted to augment signalling at the GABA_A in a manner somewhat antagonistic to citral and/or cineol coincubation, albeit at high concentrations of 610µM.^[12][13] Despite serum levels reaching less than 10µM via aromatherapy, pure 4-terpineol has reduced locomotion^[6] implying an interaction with the GABAergic signalling system.

The antidepressive effects of nutmeg (10mg/kg of the n-hexane extract) appear to be attenuated with p-chlorophenylalanine, an inhibitor of serotonin synthesis.^[14]

The antidepressive effects of nutmeg (10mg/kg of the n-hexane extract) appear to be attenuated with prazosin, an antagonist of the α1-adrenergic receptors.^[14]

The antidepressive effects of nutmeg (10mg/kg of the n-hexane extract) appear to be attenuated with coadministration of the D2 receptor antagonist sulpiride.^[14]

500mg/kg of the extract appears to be more effective than imipramine (15mg/kg) in reducing haloperidol induced catalepsy after 3 hours of monitoring.^[15]

In mice, 5-20mg/kg of myristica fragrans (n-hexane extract) for three days was able to reduce depressive symptoms with peak efficacy at 10mg/kg with a potency comparable to injections of imipramine (15mg/kg) and fluoxetine (20mg/kg) in the forced swim and tail suspension tests.^[14]

A 500mg/kg basic extract of myristica fragrans was later found to be comparable to imipramine (15mg/kg) again in rats subject to a forced swim test and also reduced reserpineinduced immobility.^[15]

Inhalation of nutmeg essential oil (0.1-0.5mL per rat cage) reduced locomotion by 62.81-68.62% relative to control with time dependence but weak dose dependence.^[6] This was due to three components detected in the blood (Myristicin at 3.7-7.1μg/mL, Safrole at 1.3μg/mL, and 4-terpineol at 1.49-6.28μg/mL) When comparing the aromatherapeutic potency of nutmeg against Lavender oil, nutmeg appeared to be more potent.^[6]

Myristica fragrans (500mg/kg) has failed to potentiate phenobarbitone induced sleep time.^[15]

Injections of trimyristin (10-100mg/kg) in rats was able to cause an anxiogenic response in various tests, and when anxiolytic drugs (buspirone, diazepam, ondansetron) were coadministreted trimyristin was able to attenuate their effects.^[16]

Injections of the major fatty acid in nutmeg seeds appears to cause anxiety in research rodents

In mice, 500mg/kg of the alkaloids failed to cause analgesia in an acetic-acid induced writhing model while in female mice only 1,000mg/kg exerted analgesic properties (23%) but significantly less potent than diclofenac.^[2]

Myristicin appears to be a potential drug of abuse at 20g or more due to it being a hallucinogen,^[17] which has been confirmed to occur in a series of case studies (see toxicology section) albeit with questionable safety.

Antigen induced allergic inflammation in the lungs appears to be reduced with macelignan to mice (400-800mg/kg orally alongside the antigen), due to a relative reduction in the activity of GATA3 (transcription factor needed for IL-4 production^[18]) in Th2 cells and subsequently less IL-4 production,^[4] which would reduce the mucus secretion IL-4 stimulates^[19] which was noted in the lungs following macelignan treatment.^[4] IFN-γ and IL-17 (both secreted by T-cells) were unaffected, and there were only alterations in eosinophil content of the lungs (macrophage, neutrophils, and total leukocytes unaffected).^[4]

Myristica fragrans 50% ethanolic extract at 500mg/kg to male rats was able to increase mounting frequency within one hour (331%) and three hours (642%) post treatment, a potency greater than an equal dose of Clove and while it was lesser than the refers of Viagra (5mg/kg) at the one hour point it was equal after three hours.^[1]

Isolated myristicin appears to be safe up to 10mg/kg oral intake in rats.^[20]

500mg/kg of nutmeg (50% ethanolic extract) to rats does not cause any acute toxicological changes within 24 hours of a single oral dose.^[1] Isolated injections of trimyristin (up to 1g/kg in rats) and the acetone-insoluble part of the n-hexane extract (up to 3g/kg) were note acutely toxic.^[16]

In mice, 5,100mg/kg of the extract (pure alkaloids) appears to be the LD₅₀ value with clinical side-effects of dizziness and hypoactivity being seen at 4,000mg/kg.^[2] 3,000mg/kg was deemed the NOAEL for mice.^[2]

Myristicin has been noted to not be genotoxic in rat hepatocytes up to 1mM,^[21] and while elemicin is inherently genotoxic (at 100µM to a lesser degree than α-asarone and β-asarone from Acorus calamus).^[21]

Myristicin is sometimes abused due it being a hallucinogen, leading to 'myristicin' or 'nutmeg' toxicity due to an overdose,^[17][22] which are almost always associated with the intent to induce hallucinations.^[23][24]

The doses of which toxicity have been reported include 50g in a shake of which 2/3^rds was reportedly drank in a teenage girl (nonlethal),^[22] 14g in an 8 year old (lethal),^[25] a 55 year old women with an unknown oral dose (lethal but used alongside flunitrazepam; hypothesized dose based on serum values of myricitin being around 30-40g)^[24], a 13 year old female with 15-24g nutmeg (alongside marijuana; nonlethal)^[26], . In doing an analysis of past reports there have been reports of 80g (nonlethal), 133g (nonlethal), 40g with alcohol (nonlethal), and 14-21g (nonlethal).^[24]

Cardiovascular symptoms that have been reported include tachycardia, sinus arrythmia, and increased respiratory rate while both mild hypotension and hypertension have been reported.^[22][24][26] Neurological symptoms that have been reported include giddiness, nausea, delirium and hallucinations, anxiety, restlessness, (general) algesia, blurred vision, and feelings of impending doom.^[22][23][26] Symptoms occur about 4-6 hours after ingestion and may persist for up to 72 hours at worst^[23][24][26] and case studies have noted dissipation in 16^[22] or 48 hours (some dizziness after the third day remained).^[26]

Nutmeg toxicity has been reported numerous times associated with persons who are using the spice in an attempt to induce cheap hallucinations. The toxicology reports are highly variable, and while some persons tolerate or have mild adverse effects to high doses there have been fatalities associated with more moderate dosages