Indirect modulation of the endocannabinoid system by specific fractions of nutmeg total extract

[downwardsfromzero]

Perhaps this rightfully belongs in the 'Other Psychoactives' section, but what the heck, it's about the endocannabinoid system...

It looks as though we missed this a little while back:

Pharmaceutical Biology

Indirect modulation of the endocannabinoid system by specific fractions of nutmeg total extract

Abir T. El-Alfy, Sharon Josepha, Akshar Brahmbhatta, Setor Akatia & Ehab A. Abourasheda

Published online: 14 Jun 2016

Abstract

Context: Nutmeg [Myristica fragrans Houtt. (Myristicaceae)] has a long-standing reputation of psychoactivity. Anecdotal reports of nutmeg use as a cheap marijuana substitute, coupled to previous studies reporting a cannabimimetic-like action, suggest that nutmeg may interact with the endocannabinoid system.

Objective: The study evaluates nutmeg fractions for binding capacity with various CNS receptors and their potential interaction with the endocannabinoid system.

Materials and methods: Dichloromethane (DF) and ethyl acetate (EF) fractions were prepared from the methanol extract of powdered whole nutmeg. The HPLC-profiled fractions were assayed by the NIMH Psychoactive Drug Screening Program (PDSP) in a panel of CNS targets at a 10 μg/mL concentration. The fractions were also screened for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition, initially at a concentration of 500 μg/mL, then by concentration-dependent inhibition studies.

Results: None of the tested fractions showed significant binding to CNS receptors included in the PDSP panel. However, both fractions exerted significant inhibition of the FAAH and MAGL enzymes [emphasis added]. The DF fraction inhibited FAAH and MAGL enzymes at IC50 values of 21.06 ± 3.16 and 15.34 ± 1.61 μg/mL, respectively. Similarly, the EF fraction demonstrated FAAH and MAGL inhibition with IC50 values of 15.42 ± 3.09 and 11.37 ± 6.15 μg/mL, respectively.

Discussion and conclusion: The study provides the first piece of evidence that nutmeg interacts with the endocannabinoid system via inhibition of the endocannabinoid catabolizing enzymes. This mechanism provides insight into reported cannabis-like action as well as expands the potential therapeutic utility of nutmeg.

 

[entheogenic-gnosis]

Very interesting! Thank you!

I've been doing a good deal of work with compounds related to the phenylpropene constituents of nutmeg as well as other spices...

...cannabis like intoxication is also frequently reported concerning nutmeg intoxication.


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This is an unrelated excerpt from PIHKAL, however it relates to shulgin experimenting with the amphetamine counterparts of the phenylpropene components of the essential oil of nutmeg, namely safrole, elemicin and myristicin. Shulgin combines 1 part MDA, 5 parts MMDA, and 2 parts TMA, mimicking the ratios of the phenylpropene compounds found in the essential oil of nutmeg.

There were a few interesting experimental trials that were based on these natural oils. Methoxyeugenol was assayed up to a 10 milligram level, and asarone at up to a 70 milligram level, and neither had any effects at all. And, in an attempt to challenge the "oil-to-amphetamine" concept, I made up a mixture of 1 part MDA, 2 parts TMA and 5 parts MMDA. A total of 100 milligrams of this combination (which I had named the "Pseunut Cocktail" for pseudo-nutmeg) should be equivalent to the safrole, elemicin and myristicin that would be in 5 grams of nutmeg. And 100 milligrams indeed produced quite a sparkle and considerable eye-dilation. But then, I have never taken 5 grams of nutmeg, so I cannot make any comparisons.
-shulgin;PIHKAL

-eg

 

[downwardsfromzero]

While Shulgin may have carried out a nice experiment there, there is no evidence of in vivo phenylpropene-to-amphetamine conversion. The one example where Ulrich Braun at the University of Bonn reported MDA from a mixture of rabbit (rat?) liver homogenate and safrole has not been replicated and is typically regarded as spurious.

Current thinking, based on real evidence, is that the allylbenzenes are oxidised at the 1-position (next to the benzene ring) to form a phenylvinylketone which undergoes Michael addition with an amine to form, in the case of the product formed with piperidine, an aminopropiophenone derivative (with the nitrogen attached at the third carbon of the chain) with activity at certain of the dopamine receptors.

It is clear that the pharmacology of nutmeg is fairly complex - as well as being highly variable both from the variations in the natural components of nutmeg itself, there are also the variations between individuals of metabolic enzyme expression and dietary intake of amine-producing substances.

And another thing, analyses of nutmeg often list 'alkaloids' as being present, presumably on the basis of a positive result with Dragendorff's, but none of these researchers has ever bothered trying to pin down exactly what alkaloids are present :? In a similar vein, it would be interesting to see what the components of the nutmeg extract with FAAH and MAGL inhibition properties turn out to be (and whether any of them are alkaloids).

To optimise the effects of nutmeg, I recommend using a tincture

 

[entheogenic-gnosis]

While Shulgin may have carried out a nice experiment there, there is no evidence of in vivo phenylpropene-to-amphetamine conversion. The one example where Ulrich Braun at the University of Bonn reported MDA from a mixture of rabbit (rat?) liver homogenate and safrole has not been replicated and is typically regarded as spurious.

Current thinking, based on real evidence, is that the allylbenzenes are oxidised at the 1-position (next to the benzene ring) to form a phenylvinylketone which undergoes Michael addition with an amine to form, in the case of the product formed with piperidine, an aminopropiophenone derivative (with the nitrogen attached at the third carbon of the chain) with activity at certain of the dopamine receptors.

It is clear that the pharmacology of nutmeg is fairly complex - as well as being highly variable both from the variations in the natural components of nutmeg itself, there are also the variations between individuals of metabolic enzyme expression and dietary intake of amine-producing substances.

And another thing, analyses of nutmeg often list 'alkaloids' as being present, presumably on the basis of a positive result with Dragendorff's, but none of these researchers has ever bothered trying to pin down exactly what alkaloids are present :? In a similar vein, it would be interesting to see what the components of the nutmeg extract with FAAH and MAGL inhibition properties turn out to be (and whether any of them are alkaloids).

To optimise the effects of nutmeg, I recommend using a tincture

Yeah, I seriously doubt that these compounds are metabolized to amphetamines in vivo, and noted that this excerpt was not necessarily on topic, just an interesting piece of information regarding the substance being discussed.

It's been well known for quite some time that this would not occur...

In 1963, Alexander Shulgin speculated myristicin could be metabolized to MMDA, a psychoactive drug related to MDA, in the liver.[3]

This speculation has never been confirmed and studies with the closely related compounds asarone and safrole demonstrated that the proposed transamination reactions did not take place in humans.[21] However, Alexander Shulgin notes in his book PiHKAL that

"Myristicin and the conjugated isomer isomyristicin are also found in parsley oil, and in dill. This was the oil that was actually shown to be converted to MMDA by the addition of ammonia by passage through an in vitro liver preparation."[22]

As quoted, this transamination was conducted in vitro, and has yet to be proven to occur in vivo.
-Wikipedia

Here was the direct quote from PIHKAL:

The two spices are virtually identical as to their chemical composition. Myristicin and the conjugated isomer isomyristicin are also found in parsley oil, and in dill. This was the oil that was actually shown to be converted to MMDA by the addition of ammonia by passage through an in vitro liver preparation. So here is the major justification for the equation between the essential oils and the essential amphetamines. Care must be taken to make an exact distinction between myristicin (this essential oil) and myristin (the fat) which is really trimyristin or glyceryl trimyristate from nutmeg and coconut. This is the fat from myristic acid, the C-14 fatty acid, and these two similar names are often interchanged even in the scientific literature.
-shulgin / PIHKAL

The carbon skeleton end positional location of the ether oxygen atom in 13 (end in MMDA. 25. below) are identical to that found in elemicin end myristicin. components of the spice nutmeg. These Latter nitrogen-free essential cils have recently been shown capable of being converted into the above mentioned amphetamine analogs under biological conditions (26).] http://www.lycaeum.org/leda/docs/16291.shtml?ID=16291

While this may sound incorrect, these biological conditions could be facilitated in vitro, such as shulgin's in vitro liver preparation.

Phenylpropenes article.
Shulgin, A. T.; Sargent, T.; Naranjo, C. (1967)

I don't feel the use of "shulgin's essential amphetamines" was to speculate in vivo conversion into their amphetamine counter-parts, I feel This was a simple notion shulgin wanted to explore, but that it has little to do with the practical value of this information.

I'll get back to this when I get back to my house...

-eg