Pharmacology FAAH inhibition as possible explanation for extreme length of nutmeg high

[nostarmane]

So according to a 2019 research study on PubMed the main component of nutmeg called Licarin A is a significant FAAH / MAGL inhibitor.

Source: https://pubmed.ncbi.nlm.nih.gov/31595522/

Full text:

Phenolic compounds from nutmeg (Myristica fragrans Houtt.) inhibit the endocannabinoid-modulating enzyme fatty acid amide hydrolase - PMC

The study aimed to identify nutmeg compounds that indirectly interact with the endocannabinoid system through inhibition of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes. Thirteen compounds were screened for FAAH ...

pmc.ncbi.nlm.nih.gov

On the figures in the study you can see that the inhibiton lasts well over 12 hours for FAAH. Even after 36 hours there is still some inhibition.

Maybe the FAAH inhibition is irreversible and the encyme need to be replenished completely? So far i couldn't find anything about mechanism of inhibition in that study.

Another thing is that nutmeg has really significant anticholinergic effects on higher dose, at least dry mouth, eyes and no ability to sweat. Especially short term memory loss is very common on nutmeg trip reports.

So back to the FAAH encyme which breaks down endocannabinoids like Anandamine. Besides (partial) agonisn on CB1 receptors it also inhibits alpha7 nicotinic acetylcholine receptor function (alpha7 nAChR). Not clear if it's an indirect effect or simple antagonism at receptor level.

This is completely different to classical deliriants like DPH which antagonist muscarinic acetylcholine receptors (mAChR).

Source: https://pubmed.ncbi.nlm.nih.gov/12766252/

Addendum:

Nutmeg essential oil does not contain either Trimyristin or Licarian A if it's steam distilled oil. Don't know what's the case for CO2 extracted oil though.

 

[daturetard]

You really enjoy the Nutmeg intoxication? I found its hard to achieve a noticeable alteration in consciousness from it, and even if you can the most apparent effect ime is a splitting headache. I'd love to hear your experience and why you take it though. Could try it again I suppose.

 

[Allylbenzene]

If you do try it, find a nutmeg essential oil with good amounts of myristicin (good sellers will include a COA for their current batch). Alternatively use the nutmeg seed covering called mace which usually contains plenty of myristicin.
Using whole nutmeg isn't recommended because it contains a sedative pro-anxiety fat called trimyristin. The FAAH inhibitors just add additional cannabinoid type effects (sedation/stone).

 

[atara]

Impressive find. The licarin A looks to have a MW a little higher than THC, around the limit for distillation. It also has a phenolic OH, which is a risk factor for oxidation and tends to reduce solubility in some solvents.

Also, trimyristin is an ordinary saturated fat. It would be very surprising if it had any central activity.

 

[Allylbenzene]

Regarding trimyristin:

Anxiogenic activity of Myristica fragrans seeds

In the present study, the n-hexane extract of Myristica fragrans (MF) seeds, acetone-insoluble part of the n-hexane extract (AIMF) and trimyristin (TM) were assessed for their anxiogenic activity. The MF (10 and 30 mg/kg), AIMF (30, 100, and 300 mg/kg), and TM (10, 30, and 100 mg/kg) administered intraperitoneally exhibited anxiogenic activity in elevated plus-maze (EPM) paradigm. The open-field test and hole-board test were also used to assess anxiogenic activity of AIMF and TM. In the EPM test, MF, AIMF, and TM decreased the time spent by mice in the open arm and the entries in the open arm. Further, the effect of diazepam (1 mg/kg ip), serotonin 5-HT3 receptor antagonist, ondansetron (1 mg/kg ip), and 5-HT1A receptor agonist, buspirone (1 mg/kg ip), on the occupancy in open arm and entries in open arm was significantly reduced by TM. In the open-field test, AIMF as well as TM reduced the number of rearing and locomotion. Both TM and AIMF reduced the number of head pock in the hole-board test. Inhibition of anxiolytic activity of ondansetron (5-HT3 receptor antagonist), buspirone (5-HT1A receptor agonist), and diazepam [acting on γ-aminobutyric acid (GABAA) receptor] suggests a nonspecific anxiogenic activity of TM and also a link between 5-HT and GABA systems in the anxiogenic activity of TM.

https://www.sciencedirect.com/science/article/abs/pii/S0091305701006608

Depressant Effect of Trimyristin and Its Inhibition by SomeAntidepressants in Mice

The depressant activity of trimyristin and its interaction with antidepressantslike amitryptiline, imipramine, mianserin, and fluoxetine has been studied. In forcedswim tests and tail suspension tests male albino mice were treated intraperitoneallywith 10 mg/kg each of amitryptiline, imipramine, mianserin, and fluoxetine 30 minbefore vehicle or trimyristin (10 or 30 mg/kg i.p.). Some groups received trimyristin(10 or 30 mg/kg i.p.). In reserpine-induced hypothermia, the effect of trimyristin wasobserved on hypothermia induced by reserpine. In forced swim tests and tailsuspension test, trimyristin increased the duration of immobility and pretreatmentwith antidepressants inhibited the effect of trimyristin. Trimyristin significantlylowered the rectal temperature and potentiated the reserpine-induced hypothermia.In the forced swim tests, the depressant effect of trimyristin was inhibited by prioradministration of serotonin 5-HT2A receptor antagonist, saprogrelate suggestinginvolvement of serotonergic and noradrenergic mechanisms in the depressant actionof trimyristin.

https://scispace.com/pdf/depressant-effect-of-trimyristin-and-its-inhibition-by-some-5citciwgvx.pdf

 

[nostarmane]

You really enjoy the Nutmeg intoxication? I found its hard to achieve a noticeable alteration in consciousness from it, and even if you can the most apparent effect ime is a splitting headache. I'd love to hear your experience and why you take it though. Could try it again I suppose.

I really get good effects and the dry mouth does only last 15 minutes. But there is definitely significant sedation 6 hours after ingestion. The best effects are 9 to 12 hours after 1 teaspoon nutmeg powder for me, as long as it's consumed before 10 am.

 

[nostarmane]

Regarding trimyristin:

https://www.sciencedirect.com/science/article/abs/pii/S0091305701006608

https://scispace.com/pdf/depressant-effect-of-trimyristin-and-its-inhibition-by-some-5citciwgvx.pdf

I wonder if Trimyristin is responsible for some anxiogenic effects 6 hours after ingestion. But after 9 to 12 hours it wears off and the FAAH inhibition by Licarin A seems to still be ik effect.

 

[Allylbenzene]

I wonder if Trimyristin is responsible for some anxiogenic effects 6 hours after ingestion. But after 9 to 12 hours it wears off and the FAAH inhibition by Licarin A seems to still be ik effect.

Yes, Trimyristin is an anxiogenic sedative.
Nutmeg / mace essential oils contains zero trimyristin. If you're interested in the allylbenzene (myristicin, elemicin, safrole) effects, use the essential oil.
Mace is a better alternative to nutmeg. Both are part of the same fruit.

I would really hate to find out that trimyristin is the key to activating the allylbenzenes in nutmeg. This is not the healthiest thing to be ingesting.
Whole nutmeg contains about 20-30% trimyristin. The nuts are typically less than 1% myristicin. So the ratio of trimyristin to active allylbenzenes is at least 20:1

Mace should have less trimyristin so that means mace is healthier if you ingest the whole herb gram for gram.
People, if you're going to be megging powder, mace is the way to go because these figures show its about twice as potent and healthier (trimyristin).
But if you're going to be megging oil, nutmeg oil is a bit stronger.

A study on the psychoactive effects of myristicin:

The pharmacologic and toxic effects of myristicin have been examined in laboratory animals in order to estimate its safety in man. Myristicin is assumed to be the principal active ingredient of nutmeg powder. In 400mg doses, myristicin produced mild cerebral stimulation in human subjects. This effect is much less than that produced by 15g of nutmeg powder, which was taken by one of the authors in order to describe its psychopharmacologic action. Removal of the volatile components of nutmeg eliminates the psychic action but not all of the side effects. It appears that myristicin does not reproduce the entire activities of whole nutmeg.

https://www.erowid.org/references/texts/show/7158docid6486

After some animal testing, 10 human subjects were given either 400mg of myristicin or a placebo. The administration was orally in capsules. Out of 10 subjects, 4 had confirmed effects from this does. 2 had doubtful but possible effects from myristicin orally. The other 4 either had placebo or no reaction. To see how this differed from actual nutmeg, one of the authors took 15g of nutmeg himself, and reports on the experience. 3 authors then take 10g of nutmeg with the volatile oils removed - they did not get hallucinogenic effects but some did get either sedation or stimulation (suggesting that the fixed oils - i.e. trimyristin - may have some effects which differ in different subjects).
This is the first study on nutmeg that I can find in the literature.
It's not a new phenomenon. According to the study, published in 1961, myristicin - and possibly all allylbenzenes - are active in only about 40% of the population if administered orally as the sole ingredient in a capsule. No wonder so many people think this is BS. Most people don't get effects orally from straight allylbenzenes. But in nutmeg, which contains about 20% trimyristin by weight as well as a lot of other compounds, it is active in almost everyone.

 

[Allylbenzene]

Another thing is that nutmeg has really significant anticholinergic effects on higher dose

So back to the FAAH encyme which breaks down endocannabinoids like Anandamine. Besides (partial) agonisn on CB1 receptors it also inhibits alpha7 nicotinic acetylcholine receptor function (alpha7 nAChR).

This is completely different to classical deliriants like DPH which antagonist muscarinic acetylcholine receptors (mAChR).

Note also that nutmeg contains multiple pro-cholinergic substances, particularly terpenes which are present in the oil. Apart from the toxic sedative trimyristin fat, I'm not aware of any other candidates for anti-cholinergics in nutmeg.

In contrast, the reports of "feeling a cannabis-like high" from nutmeg ingestion can be corroborated by the FAAH inhibitor(s), likely in combination with the other sedatives like trimyristin (assuming use of whole nutmeg).

On the other hand, reports using nutmeg essential oil contain neither FAAH inhibitors not trimyristin.

 

[MedicinalUser247]

Last time I did a high dose of Nutmeg I had lay down in bed because I was so dizzy. I ended up throwing up next to my Bed.