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Safrole to MDA in the human body

There are no amphetamines in nutmeg or mace. It's unlikely that allylbenzenes are metabolised into amphetamines, as shown by Oswald in 1971 (details below).

This all relates to Shulgins so-called "essential amphetamines" and their corresponding essential oil precursors. Shulgin proposed a possible in-vivo mechanism for the conversion of allylbenzenes to their equivalent amphetamine; elemicin would make TMA. Myristicin (parsley seed oil) would make MMDA. Dillapiole (dill seed oil) would make DMMDA-2. Eugenol (clove oil) would make HMA. Safrole would make MDA, etc.

A few years after Shulgin proposed this, someone called Oswald discovered another possibility. Oswald found aminated metabolites from 5 of the essential oil precursors and wrote several papers about this. (Did Shulgin ever read them I wonder?)

Here's some quotes from Oswalds papers:
The presently reported investigations were undertaken to firmly document the biological formation of amphetamines from the compounds of essential oils. No amphetamine production was detected. Instead, more chemically active tertiary aminoketones were isolated and structurally identified.
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The present study illustrates that allylbenzene derivatives are converted biologically in vivo in the rat and guinea pig to nitrogen-containing tertiary amino substituted propiophenones.
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All of the tertiary aminopropiophenones described presently may very likely be the active metabolites which elicit the psychotropic activity of the allylbenzene derivatives of essential oils. We also find that elemicin, eugenol and other substituted allylbenzene derivatives are metabolized to the same type of nitrogen-containing metabolites.

A possible mechanism for the biosynthesis of the tertiary amino substituted propiophenones from allylbenzene derivatives. This mechanism suggests that the allylbenzene derivative undergoes a biological allylic oxidation first to form the allylic ketone. The allylic ketone could then condense with a secondary amine, piperidine, pyrrolidine or dimethylamine in the presence of the appropriate enzyme systems to yield the final excreted tertiary amino ketone.
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Oswald didn't investigate which enzymes are involved in the biological conversion but recent research implicates ADH, ALDH, SSAO, GST, 17bHSD2, tyrosinase and several SULT, UGT & CYP enzymes. The necessary secondary amines (piperidine, pyrrolidine, dimethylamine) occur naturally in the human body and levels can be influenced by diet.

Re the importance of 17bHSD2
The single most important enzyme to induce is Estradiol 17beta dehydrogenase type 2 (17bHSD2). This enzyme is required. If 17bHSD2 is inhibited by drinking tea or consuming other drinks, supplements, or food items that inhibit 17bHSD2, then allylbenzene activation will not take place.
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Estradiol 17beta dehydrogenase type 2 (17bHSD2) creates phenyl vinyl ketones from allylbenzenes in their 1'-hydroxy form. For example, the phenyl vinyl ketone 1'-oxoestragole is proven to be created from the alcohol 1'-hydroxyestragole (a metabolite of the allylbenzene methyl chavicol) by the action of estradiol-17beta-dehydrogenase Type 2 (17bHSD2).[13] This metabolite is then proven to be capable of forming adducts with glutathione (GSH) leading to inactivation, or forming adducts with endogenous amines.[13] The latter action is believed to be required for the psychedelic effects of methyl chavicol and related allylbenzenes.
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Common 17bHSD2 inhibitors include quercetin and linoleic acid (vegetable oils) which are both very common components of most diets. Things with particularly high quercetin content include tomatoes, tea, onions and grapefruit / grape / orange / lemon juice. Vegetable oils include soy, corn, canola, grape seed, sunflower, cottonseed & safflower.

Torsten from the shaman-australis forum has written a lot about this topic, favouring topical application followed by rigorous physical activity like running or dancing. He told me that he still believes the in-vivo allylbenzene bio-transformation produces amphetamine metabolites - whereas Oswald discovered tertiary aminopropiophenones which look very different.

There's also a recipe from 1991 on erowid that details a mix specifically designed to encourage nutmegs allylbenzenes (myristicin, safrole, elemicin) to become active. Judging by the ingredients, whoever designed it clearly knew about some of the enzymes involved and probably how lysine & arginine are metabolized by gut bacteria into piperidine & pyrrolidine - key secondary amines involved in the bioactivation process.

Oilman from the dmt-nexus forums designed Space Booze based on this 1991 erowid recipe. There's also "Space Cake" iirc. These are all based on the same concept. Fwiw, mace is a safer alternative to nutmeg and usually has a more reliable allylbenzene content.

Based on reports it seems that for ~30% of people the allylbenzenes are active without needing enzyme inhibitors or inducers. Incomplete bioactivation usually causes sedative effects.

Whole nutmeg contains a toxic anxiogenic saturated fat called trymistrin alongside pro-endocannabinoid substances. These sedatives/intoxicants are not present in nutmeg essential oil or mace. Nutmeg oil usually contains pro-cholinergic terpenes (eg cineole) alongside varying allylbenzene content.

Safrole metabolites:
Myristicin metabolites:
Elemicin metabolites:
 
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Yo check this out...


"Yes, it's possible that 3-(3,4,5-trimethoxyphenyl)-propionic acid can be metabolized into trimethoxyphenethylamine in the human body"


Well guess what, Elemicin metabolizes into 3 3,4,5 Trimethoxyphenyl propionic acid so that means you can get Mescaline aka Trimethoxyphenethylamine from Nutmeg, no?! I think if not that its one of the isomers of Mescaline unless im wrong.
.
 
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The Holy Quadruplty said:
Yo check this out...


"Yes, it's possible that 3-(3,4,5-trimethoxyphenyl)-propionic acid can be metabolized into trimethoxyphenethylamine in the human body"


Well guess what, Elemicin metabolizes into 3 3,4,5 Trimethoxyphenyl propionic acid so that means you can get Mescaline aka Trimethoxyphenethylamine from Nutmeg, no?! I think if not that its one of the isomers of Mescaline unless im wrong.
.
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why would that matter if there are only 2 molecules that get metabolized by that pathway and the rest of the 4000000000 molecules dont
 
Allylbenzene said:
There are no amphetamines in nutmeg or mace. It's unlikely that allylbenzenes are metabolised into amphetamines, as shown by Oswald in 1971 (details below).

This all relates to Shulgins so-called "essential amphetamines" and their corresponding essential oil precursors. Shulgin proposed a possible in-vivo mechanism for the conversion of allylbenzenes to their equivalent amphetamine; elemicin would make TMA. Myristicin (parsley seed oil) would make MMDA. Dillapiole (dill seed oil) would make DMMDA-2. Eugenol (clove oil) would make HMA. Safrole would make MDA, etc.

A few years after Shulgin proposed this, someone called Oswald discovered another possibility. Oswald found aminated metabolites from 5 of the essential oil precursors and wrote several papers about this. (Did Shulgin ever read them I wonder?)

Here's some quotes from Oswalds papers:




Oswald didn't investigate which enzymes are involved in the biological conversion but recent research implicates ADH, ALDH, SSAO, GST, 17bHSD2, tyrosinase and several SULT, UGT & CYP enzymes. The necessary secondary amines (piperidine, pyrrolidine, dimethylamine) occur naturally in the human body and levels can be influenced by diet.

Re the importance of 17bHSD2



Common 17bHSD2 inhibitors include quercetin and linoleic acid (vegetable oils) which are both very common components of most diets. Things with particularly high quercetin content include tomatoes, tea, onions and grapefruit / grape / orange / lemon juice. Vegetable oils include soy, corn, canola, grape seed, sunflower, cottonseed & safflower.

Torsten from the shaman-australis forum has written a lot about this topic, favouring topical application followed by rigorous physical activity like running or dancing. He told me that he still believes the in-vivo allylbenzene bio-transformation produces amphetamine metabolites - whereas Oswald discovered tertiary aminopropiophenones which look very different.

There's also a recipe from 1991 on erowid that details a mix specifically designed to encourage nutmegs allylbenzenes (myristicin, safrole, elemicin) to become active. Judging by the ingredients, whoever designed it clearly knew about some of the enzymes involved and probably how lysine & arginine are metabolized by gut bacteria into piperidine & pyrrolidine - key secondary amines involved in the bioactivation process.

Oilman from the dmt-nexus forums designed Space Booze based on this 1991 erowid recipe. There's also "Space Cake" iirc. These are all based on the same concept. Fwiw, mace is a safer alternative to nutmeg and usually has a more reliable allylbenzene content.

Based on reports it seems that for ~30% of people the allylbenzenes are active without needing enzyme inhibitors or inducers. Incomplete bioactivation usually causes sedative effects.

Whole nutmeg contains a toxic anxiogenic saturated fat called trymistrin alongside pro-endocannabinoid substances. These sedatives/intoxicants are not present in nutmeg essential oil or mace. Nutmeg oil usually contains pro-cholinergic terpenes (eg cineole) alongside varying allylbenzene content.

Safrole metabolites:
Myristicin metabolites:
Elemicin metabolites:
PS @Skorpio @fastandbulbous @Kaleida @Pfafffed @Neuroborean @G_Chem @SmilexGwG @unodelacosa @Jabberwocky @Xorkoth @negrogesic @Ericjones03 @yaesutom @atara @vecktor
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I have always found the most parsimonious explanation for nutmeg’s effects to be FAAH inhibition. Nutmeg has always felt cannabimimetic to me.

This one paper fractionated nutmeg oil and tested the fractions on microsomal FAAH and MAGL, then gave the fractions to rodents to test behavioral effects.

They identified the compound 5-Meo-licarin A as the most potent FAAH inhibitor, which produced behavioral effects.

No need to invoke complex transamination reactions and have to talk around the problem of metabolic flux.
 
Skorpio said:
This one paper fractionated nutmeg oil...
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The paper said:
Whole nutmeg kernels were acquired and reduced to fine powder using a coffee grinder. Total nutmeg extract was prepared by ultrasonicating 100 g of powdered nutmeg in methanol for 1 h followed by soaking overnight at room temperature.
...
Each extract was dried under vacuum to yield four separate fractions.
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To clarify, they did a full-spectrum extract using whole nutmegs, not the essential oil. Licarin, 5-methoxylicarin & malabaricone aren't present in nutmeg essential oil since they're not volatile oils.

Most people trying nutmeg use whole nutmegs (or powder) so they get cannabinoid effects amongst everything else. Others use nutmeg (or mace) essential oil which lacks any non-volatile compounds (eg licarin A) so tend to get cleaner effects. As Torsten notes, not all nutmeg/mace oils contain the desired allylbenzene oils. Best to check the CoA beforehand.

Torsten said:
I never had a toxic effect from the pre-95 [nutmeg] oil. In fact one of the reasons we consumed it so frequently was because you could have a good time and not feel like shit the next day. It was our second choice to good MDMA pills.
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Torsten said:
I have achieved good effects from consuming small amounts of sassafras oil (80%+ safrole), dill and parsley seed oil, as well as lots of experiments on nutmeg. The effects of nutmeg and sassafras oil are almost identical to MDA, but only last for about 20 mins after strenuous muscle excercise. This has me convinced of two things.

1) that the allylbenzenes are responsible for the nice effects.
2) that the conversion is dependent on muscle activity.
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Worth noting that the nutmeg terpene oils have activity of their own eg sedative, pro-cholinergic, anti-depressant (via sabinene, pinene, limonene). Also, whole nutmeg contains a lot of trimyristin (saturated fat) which isn't found in the essential oil. Trimyristin contributes sedative and anxiogenic (anxiety inducing) effects.
 
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Oh thanks for memtioning more metabolites/molecukes in general of Nutmeg as im trying to gather literally any information i can about it.

I wounder what people think about doing it with other drugs like me as i aslways take 1st generation antihistamines, opioids, benzos, and THC and everytime doing Nutmeg i was on all of them, including right now i just dosed an hoyr ago one of each substance. I havent smoked uet, but im about to after this cig.
 
Allylbenzene said:
To clarify, they did a full-spectrum extract using whole nutmegs, not the essential oil. Licarin, 5-methoxylicarin & malabaricone aren't present in nutmeg essential oil since they're not volatile oils.

Most people trying nutmeg use whole nutmegs (or powder) so they get cannabinoid effects amongst everything else. Others use nutmeg (or mace) essential oil which lacks any non-volatile compounds (eg licarin A) so tend to get cleaner effects. As Torsten notes, not all nutmeg/mace oils contain the desired allylbenzene oils. Best to check the CoA beforehand.




Worth noting that the nutmeg terpene oils have activity of their own eg sedative, pro-cholinergic, anti-depressant (via sabinene, pinene, limonene). Also, whole nutmeg contains a lot of trimyristin (saturated fat) which isn't found in the essential oil. Trimyristin contributes sedative and anxiogenic (anxiety inducing) effects.
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So trimyristicin has bothh anxgeonic, and anxiolitic effects?
 
The Holy Quadruplty said:
Also maybe amphetamines arent detected because the drug tests dont test for the said amphetamines.... hmmmm....
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Just cos a compound has an abbreviated term such as "amphetamine" in its name doesn't mean it's going to react to a panel or reagent test the same way as Meth/Amphetamine. You also have a minimum concentration needed on most tests to get sufficient color change within the reaction time limit. It's more complex chemistry than what you think, while 3,4,5-trimethoxyphenethylamine may not react with the basic 5 panel test you can bet your ass α-methylphenethylamine will.
 
I cannot help noting that the 'Oswald Papers' are anywhere from fifty to sixty years old.

That a terminal alkene will be metabolized to a highly reactive (read, carcinogenic) epoxide is no secret.

That no human trial exists is a function of ethics. Yes, you could design a double-blind study with a large cohort. But consider what that entails. Subjects would have to be given details such as what the study was designed to do and what potential risks taking part might be to provide. Because informed consent must be given to all those taking part. I suggest a study offering cancer as a possible outcome would struggle to find participents. But it wouldn't happen because we have a lot of animal models to find each of the allylbenzenes found in some essential oils reliably caused tumours to develop in many different animal models.


I've posted a link to the description of a digital asset (a chapter in a book) rather than to the actual chapter itself, because the link also provides a list of the 180 refernces used in that chapter.

The only medicines I know of that actually contain an epoxide moiety are drugs used to treat cancer. Alkylating agents really are best avoided. Certainly there are records of multiple medicines being voluntarily withdrawn from sale because it was discovered that due to genetic divergence, there were populations whose metabolism of said medicine produced an epoxide.

I suggest what would be of most value is to find papers that studied the cancer rates among people who were exposed to epoxides before the dangers were understood. I suspect one would have to go back a long way, anywhere from eighty to one hundred years. But that might give an insight to how significant the risks were.

But to be clear - everyone is free to self-experiment. I do not believe their is any legal control on obtaining small quantities of the natural essential oils being considered. I, for one, would be interested in learning the long-term outcomes.
 
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4DQSAR said:
My thoughts are with you at this difficult time 😉
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I haven’t done nutmeg in a solid 14 years, don’t worry too much.
Allylbenzene said:
To clarify, they did a full-spectrum extract using whole nutmegs, not the essential oil. Licarin, 5-methoxylicarin & malabaricone aren't present in nutmeg essential oil since they're not volatile oils.

Most people trying nutmeg use whole nutmegs (or powder) so they get cannabinoid effects amongst everything else. Others use nutmeg (or mace) essential oil which lacks any non-volatile compounds (eg licarin A) so tend to get cleaner effects. As Torsten notes, not all nutmeg/mace oils contain the desired allylbenzene oils. Best to check the CoA beforehand.




Worth noting that the nutmeg terpene oils have activity of their own eg sedative, pro-cholinergic, anti-depressant (via sabinene, pinene, limonene). Also, whole nutmeg contains a lot of trimyristin (saturated fat) which isn't found in the essential oil. Trimyristin contributes sedative and anxiogenic (anxiety inducing) effects.
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Good catch on the whole nut vs essential oil aspect.

Do you have the full text for the trimyristin paper? The abstract makes it seem rather non-mechanistic, but I wonder if there are any gems hidden in there.

I’d still love to see some form of empirical evidence for amphetamine formation beyond “it felt like an amphetamine”. Somebody passing one of those antibody 7 panel drug tests for mdma prior to taking an allylbenzene containing oil, and then failing it afterwards would really make me believe that the transamination occurs.
 
Skorpio said:
I’d still love to see some form of empirical evidence for amphetamine formation beyond “it felt like an amphetamine”. Somebody passing one of those antibody 7 panel drug tests for mdma prior to taking an allylbenzene containing oil, and then failing it afterwards would really make me believe that the transamination occurs.
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Oh, amination occurs. Someone provided me with a couple of papers. But it's at the termnal carbon so it appears aminohydroxylation (ring opening) of the epoxide takes place. I presume the body goes on to oxidize that secondary hydroxyl to a ketone.

But what I noted was that the researcher (in the 1960s) isolated only the basic metabolites found in the urine of the animal models. So it actually removes any epoxides. I don't think it was intentional, I think someone just wanted to see if amines WERE being formed and to characterize those amines. If memory serves both the dimethyl amine and the piperidine homologues were formed. Why those two, I don't know.

It's fine that people research these things as long as they apply the same level of critical analysis to papers that align with their prejudices* as they do to papers that do not so align.

I did note that the various 'trip reports' may be considered as unstrucctured case reports. So evidence, but low quality evidence as these things go. If nothing else, 'survivorship bias' means exactly what it says in the case of unconsidered consumption of such essential oils. Dead people generally don't post onto social media (AFAIK).

@Skorpio I spent ages trying to work out a modern idiom for 'cannabimimetic' but after ages trying variations on CannaB1mimetric, I concluded that just as I always feared, I am just not funny. Well, not 'ha, ha' funny, anyway.


*BTW a lot of people seem to think I'm insulting them if I use the term 'prejudice' but it's something we ALL do to some extent. Show me a researcher who hasn't indulged in 'conformation bias' and I will show you a liar.
 
Docta said:
Just cos a compound has an abbreviated term such as "amphetamine" in its name doesn't mean it's going to react to a panel or reagent test the same way as Meth/Amphetamine. You also have a minimum concentration needed on most tests to get sufficient color change within the reaction time limit. It's more complex chemistry than what you think, while 3,4,5-trimethoxyphenethylamine may not react with the basic 5 panel test you can bet your ass α-methylphenethylamine will.
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Thats what im trying to say, because people say they dont beleive nutmeg metabolizes into like MMDA. and stuff since amphetamines do not come up, unless a methyphenethylamine is youre saying is a metabolite of Nutmeg. Is that methylmescaline or whatever or SOMETHING?
 
No - the papers definitely identify the products in animal models to be totally unrelated to the amphetamine series.

If someone wishes to consume an essential oil to confirm that, fine. I'm just not curious enough to risk my life doing so.
 
Btw ive read Nutmeg can increase GABA, and also heard the opposite, and im really hoping someone has some information on this.
 
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