SEQUENCE A (based on work by Oswald)
NEW EVIDENCE IS SHOWING PROBLEMS IN THE SEQUENCE A THEORY
Sequence B (based on work from the Oilahuasca pioneers) appears to have more evidence to support it than Sequence A (based on work by Oswald) in humans. Unlike Sequence A, one of the alkaloid metabolites in Sequence B is proven to occur in humans. The 3 end alkaloid metabolites in the Sequence A theory are only proven to be created in animals in vivo. There is of yet no evidence to suggest that they occur in humans.
Metabolites from steps 1-3 are proven steps to occur. How Sequence A is supposed to go from step 3 to step 4 is currently unknown. And no supporting evidence has yet been found for this to happen in humans.
Over the past few years, an overwhelming amount of test results seem to indicate that Sequence A probably does not work in humans. Human Oilahuasca tests seem to point in the direction of Sequence B being the more likely activation sequence.
A big problem with Sequence A is step 2. Inhibiting CYP2C9 and CYP1A2 has been shown countless times to help activate allylbenzenes. The claimed1 potent inhibitors of CYP2A6, such as safrole, benzaldehyde and cinnamaldehyde also appear to be beneficial. These enzymes are known to 1'-hydroxylate allylbenzenes. If CYP2C9 and CYP1A2 are not inhibited, the chance of getting the "melatonin" effect of improperly activated elemecin is very high. It's very likely that 1'-hydroxyelemicin is the compound that causes the "melatonin" effect. Both caffeine and berberine help activate nearly all allylbenzenes. Caffeine inhibits CYP1A2. Berberine is a potent Oilahuasca admixture. It is proven to strongly inhibit CYP2C9, and also inhibit CYP2D6, and CYP3A4. The fact that inhibiting CYP2C9 and CYP1A2, and potentially inhibiting CYP2A6 is beneficial seems to indicate that 1'-hydroxylation is a route to inactivation, and not a route to activation.
SEQUENCE A - STEP 1: ORAL INGESTION (OR TOPICAL APPLICATION)
Elemicin is ingested orally (or applied topically to the skin).
SEQUENCE A - STEP 2: CONVERSION TO AN ALCOHOL
Some elemicin is 1'-hydroxylated to the alcohol 1'-hydroxyelemicin. For most allylbenzenes this is performed by CYP1A2, CYP2A6, CYP2C9 and CYP2E1 to some degree.
SEQUENCE A - STEP 3: CONVERSION TO A PHENYL VINYL KETONE
1'-hydroxy-elemicin is oxidized to the phenyl vinyl ketone 1'-Oxoelemicin by 17bHSD2.prop-2-en-1-one.png)
SEQUENCE A - STEP 4: CONVERSION TO ALKALOIDS
The alkaloids that form in this section have been detected in vivo. But how exactly they form from 1'-oxoelemicin is unknown. A transaminase enzyme may be required, or 1'-oxoelemicin might condense spontaneously to form alkaloids.
1'-Oxoelemicin may condense with available dimethylamine to form the alkaloid adduct 1'-oxoelemicin-DMA, also known as 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)propan-1-one.
1'-Oxoelemicin may condense with available piperidine to form the alkaloid 3-piperidin-1-yl-1-(3,4,5-trimethoxyphenyl)propan-1-one.
1'-Oxoelemicin may condense with available pyrrolidine pyrrolidine to form the alkaloid 3-pyrrolidin-1-yl-1-(3,4,5-trimethoxyphenyl)propan-1-one.
Of the possible alkaloid metabolites, the dimethylamine form has the lowest lipid solubility and the piperidine form has the highest lipid solubility. Therefore, the piperidine alkaloid form will more easily cross the blood brain barrier.
Of the possible alkaloid metabolites, the dimethylamine form is the most likely to be vulnerable to attack by MAO-A or MAO-B enzymes. Dimethylamines are often primary substrates of MAO. For example N,N-dimethyltryptamine and N,N-dimethyl-4-hydroxyphenylethylamine (hordenine) are primary substrates of MAO.
At this time it is not known which of the possible alkaloid metabolites might be the main active metabolite for each of the allylbenzenes. Other amines may also form.
It’s important to note that in the case of the allylbenzene myristicin, piperidine and pyrrolidine metabolites have been detected but dimethylamine metabolites have not. This indicates that the dimethylamine metabolites might possibly be more vulnerable to attack by enzymes such as MAO-A, MAO-B, etc., leading to their complete destruction prior to being excreted in urine.
