Oilahuasca Activation Sequence B

SEQUENCE B (based on work from the Oilahuasca pioneers)

Sequence B appears to have more evidence to support it than Sequence A in humans. Unlike Sequence A, one of the alkaloid metabolites in Sequence B is proven to occur in humans. Some of the alkaloid metabolites theoretically created by Sequence A have only been found in some animals so far.

Please note that steps 1-3 are proven to occur for some allylbenzenes such as methyl eugenol. Step 4 is a proven alkaloid metabolite for methyl chavicol (see the article 4-Methoxycinnamoylglycine for more details). These sequences will lead to similar alkaloids as produced in Sequence A. In Sequence A the step before alkaloid creation is a ketone. Ketones tend not to form adducts as easily as aldehydes. Because step 3 is an aldehyde in Sequence B, this greatly increases the likelihood of alkaloids forming in vivo. Many aldehydes such as cinnamaldehyde are proven to form adducts with amino acids and other amines very easily without the need for a catalyst. See the article Cinnamaldehyde for more details on aldehyde adducts.

For activation Sequence B, it's important to inhibit the 1'-hydroxylation pathway. This is theorized to be a route to inactivation. Enzymes known to cause 1'-hydroxylation include CYP1A2, CYP2A6, and CYP2C9.

SEQUENCE B - STEP 1: ORAL INGESTION (OR TOPICAL APPLICATION)

Elemicin is ingested orally (or applied topically to the skin).

SEQUENCE B - STEP 2: CONVERSION TO AN ALCOHOL

Elemicin is 3'-hydroxylated to the alcohol 3'-hydroxyisoelemicin. The enzymes responsible for this action are currently unknown but theorized to be CYP2E1 and possibly other enzymes.

SEQUENCE B - STEP 3: CONVERSION TO AN ALDEHYDE

3'-Hydroxyisoelemicin is oxidized to the aldehyde 3,4,5-Trimethoxycinnamaldehyde (also known as 3'-oxoelemicin) possibly by 17bHSD2, CYP2E1, or alcohol dehydrogenase.

SEQUENCE B - STEP 4: CONVERSION TO ALKALOIDS

The alkaloids in this section are purely theoretical for elemicin, but a glycine adduct alkaloid metabolite has been proven for methyl chavicol. The glycine metabolite 4-Methoxycinnamoylglycine is found in human urine after ingestion of methyl chavicol (see the article 4-Methoxycinnamoylglycine for more details). This is very strong evidence for the theoretical glycine alkaloid metabolite also being created in humans after the ingestion of elemicin.

Proven glycine adduct alkaloid metabolite of methyl chavicol		Theoretical glycine adduct alkaloid metabolite of elemicin
4-Methoxycinnamoylglycine		3,4,5-Trimethoxycinnamoylglycine

A proposed alternate glycine adduct is {(Z)-[(2E)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-ylidene]amino}acetic acid. Cinnamaldehyde is known to create a similar adduct with potassium glycine. See the Cinnamaldehyde article for more details.

Theoretical alternate glycine adduct alkaloid metabolite of elemicin		alkaloid adduct made from mixing potassium glycine and cinnamaldehyde
{(Z)-[(2E)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-ylidene]amino}acetic acid		CHEMBL3752982

3-(3,4,5-Trimethoxyphenyl)propionic acid is a metabolite of elemicin found in rat urine. 3-(3,4,5-Trimethoxyphenyl)propionic acid is a product that would form from the action of monamine oxidase enzymes on 1-(3,4,5-trimethoxycinnamoyl)dimethylamine, indicating that 1-(3,4,5-trimethoxycinnamoyl)dimethylamine formed in the rats but was enzymatically converted to 3-(3,4,5-trimethoxyphenyl)propionic acid by monamine oxidase enzymes before being excreted into the urine.

The following alkaloids are theorized to be possible active metabolites of elemicin made from it's aldehyde metabolite 3,4,5-trimethoxycinnamaldehyde forming adducts with the endogenous amines dimethylamine, piperidine, and pyrrolidine, all of which are abundant amines in humans.

Theoretical dimethylamine adduct alkaloid metabolite A	Theoretical dimethylamine adduct alkaloid metabolite B
1-(3,4,5-Trimethoxycinnamoyl)dimethylamine	(2E)-N,N-dimethyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-iminium
Theoretical piperidine adduct alkaloid metabolite A	Theoretical piperidine adduct alkaloid metabolite B
1-(3,4,5-Trimethoxycinnamoyl)piperidine	1-[(2E)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-ylidene]piperidin-1-ium
Theoretical pyrrolidine adduct alkaloid metabolite A	Theoretical pyrrolidine adduct alkaloid metabolite B
1-(3,4,5-Trimethoxycinnamoyl)pyrrolidine	1-[(2E)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-ylidene]pyrrolidin-1-ium