The major human enzymes to induce (+) and inhibit (-) for Oilahuasca Activation.
| SSAO | 17bHSD2 | ADH | ALDH | UGT1A9 | UGT2B7 | SULT1A1 | SULT1A3 | GST |
|---|---|---|---|---|---|---|---|---|
| - | + | + | - | - | - | - | - | - |
| Cytochrome P450 Enzyme Subfamilies | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1A1 | 1A2 | 1B1 | 2A6 | 2B6 | 2C19 | 2C8 | 2C9 | 2D6 | 2E1 | 2J2 | 3A4 |
| - | +/- | - | + | - | +/- | ? | - | - | + | - | - |
17bHSD2 Induction
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Estradiol 17beta dehydrogenase type 2 (17bHSD2) oxidative action needs to be induced. This enzyme 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).[2] This metabolite is then proven to be capable of forming adducts with glutathione (GSH) leading to inactivation, or forming adducts with endogenous amines.[2] The latter action is believed to be required for the psychedelic effects of methyl chavicol and related allylbenzenes.
For information on 17bHSD2 inducers and inhibitors see the article here: Estradiol 17beta dehydrogenase type 2
| Substrate | 17bHSD2 | End Product |
|---|---|---|
| 1'-Hydroxyelemicin | 1'-Oxoelemicin | |
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UGT1A9 And UGT2B7 Inhibition
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UGT1A9 and UGT2B7 are proven to inactivate allylbenzenes once in their 1'-hydroxy form. These add a glycosyl group to an available hydroxy position on hydroxylated allylbenzenes making them inactive. For example, it turns 1'-hydroxyelemicin into 1'-hydroxyelemicin glucuronide. Inhibitors must be used. UGT2B7 is more important to inhibit than UGT1A9. For information on inhibitors see their articles here: UGT1A9, UGT2B7.
The metabolite of methyl chavicol known as 1'-hydroxyestragole is proven to undergo glucuronidation primarily by the action of UGT2B7 followed by UGT1A9, with a very small amount carried out by UGT2B15.[3] These enzymes are assumed to be responsible for the glucuronidation of all related allylbenzenes.
| Substrate | UGT | End Product |
|---|---|---|
| 1'-Hydroxyelemicin | 1'-Hydroxyelemicin glucuronide | |
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| Cofactor | Byproduct | |
| UDPglucuronate | UDP |
SULT1A1 And SULT1A3 Inhibition
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SULT1A1 and SULT1A3 are proven to inactivate allylbenzenes once in their 1'-hydroxy form. For example, the alcohol 1'-hydroxyelemicin becomes 1'-sulfoxyelemicin by these enzymes. Inhibitors must be used. For information on inhibitors see the articles here: SULT1A1, SULT1A3.
The metabolite of methyl chavicol known as 1'-hydroxyestragole is preven to undergo sulfation by the action of SULT1A1 and SULT1A3.[4] These pathways prevent 1'-oxoestragole from forming. These enzymes are assumed to be responsible for the sulfation of all related allylbenzenes.
| Substrate | SULT | End Product |
|---|---|---|
| 1'-Hydroxyelemicin | 1'-Sulfoxyelemicin | |
|
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| Cofactor | Byproduct | |
| 3'-phosphoadenylylsulfate | adenosine 3',5'-bisphosphate |
GST Inhibition and Glutathione Depletion
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Glutathione is proven to inactivate allylbenzenes once in their phenyl vinyl ketone form. For example, the phenyl vinyl ketone 1'-oxoestragole is proven to be inactivated by forming adducts with glutathione.[2]
GST adds glutathione to the 1'-oxo position of the phenyl vinyl ketones making them unable to form alkaloids. For example, it turns 1'-oxoelemicin into 3'-(glutathion-S-yl)-1'-oxoelemicin by the addition of glutathione preventing alkaloid formation by 1'-oxoelemicin.
It's not known to what degree glutathione S-transferase (GST) is involved in this inactivation.
Glutathione is proven to condense with phenyl vinyl ketones without the need for enzyme interaction (see the article 1'-Oxoestragole for more details). This means inhibiting glutathione S-transferase (GST) is not enough. We also need to deplete glutathione to prevent it from inactivating allylbenzenes (see the article Glutathione for details on ways to safely deplete glutathione).
There are several subsets of glutathione S-transferase (GST). The exact ones responsible for this action are currently unknown, as is there level of interaction in this adduct process. Inhibitors must be used. For information on inhibitors see the article here: Glutathione S-transferase.
| Substrate | GST | End Product |
|---|---|---|
| 1'-Oxoelemicin | 3'-(Glutathion-S-yl)-1'-oxoelemicin | |
|
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Cytochrome P450 Enzymes
CYP1A2, CYP2A6, CYP2C9, and CYP2E1
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CYP1A2, CYP2A6, CYP2C9, and CYP2E1 play a pivotal role in 1'-hydroxylation of many allylbenzenes, creating alcohol. This is the first major step towards activation. All of these enzymes should be induced, with the exception of possibly CYP1A2 which can help demethylenate myristicin, and probably other methylenedioxy allylbenzenes. CYP1A2 might also have some other undesirable effects on other allylbenzenes. The only allylbenzene known to need CYP1A2 for 1'-hydroxylation is methyl eugenol.
The alcohol 1'-hydroxyestragole is proven to be created from the allylbenzene methyl chavicol in human liver in vitro primarily by the P450 enzymes CYP1A2, CYP2A6 and CYP2E1.[1][2]
In humans the alcohol 1′-hydroxymethyleugeol is proven to be created from the allylbenzene methyl eugenol by the P450 enzyme CYP1A2.[1] Some in vitro reports state that it is primarily catalyzed by both CYP1A2 and CYP2C9 and that CYP2C19 and CYP2D6 also play a minor role.[8] Human liver in vitro tests show that methyl eugenol is not metabolized by CYP2A6.[8]
The alcohol 1'-hydroxysafrole is proven to be created from the allylbenzene safrole by the P450 enzymes CYP2C9 and CYP2E1, and to a lesser degree CYP2A6 and CYP2D6 according to one human in vitro study.[9]
| Substrate | 1'-hydroxylation | End Product |
|---|---|---|
| Elemicin | 1'-Hydroxyelemicin | |
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CYP3A4
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CYP3A4 is proven to O-demethylenate the allylbenzene myristicin, an action that breaks the methylenedioxy group of myristicin, replacing it with 2 hydroxy groups.[6] The cytochrome P450 enzyme CYP1A2 plays a minor role in this action. Therefor CYP3A4 needs to be inhibited for myristicin and probably other allylbenzenes with methylenedioxy groups. All allylbenzenes that are O-demethylenated are not known to have psychedelic action. This enzyme may also have some undesirable effects on other allylbenzenes without methylenedioxy groups.
| Substrate | O-demethylenation | End Product |
|---|---|---|
| Myristicin | Demethylenyl myristicin | |
 |
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CYP2D6
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The allylbenzene eugenol is proven to be O-demethylated to hydroxychavicol by the action of CYP2D6 in vitro.[5] CYP2D6 performs this action on hundreds of compounds and very likely also performs this action on other allylbenzenes and should therefor be strongly inhibited. No allylbenzene that is O-demethylated is known to have psychedelic action.
| Substrate | O-demethylation | End Product |
|---|---|---|
| Elemicin | Methoxyeugenol | |
|
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CYP2B6
THIS SECTION IS PARTIALLY BACKED BY SCIENTIFIC FACTS
CYP2B6, CYP3A4, CYP1A2, and CYP2J2 but not CYP2E1 can all perform ALDH-like activity.[7] They should therefor probably be strongly inhibited. ALDH-like action directly interferes with the two main activation theories presented on this page. For more details on this type of ALDH-like action of cytochrome P450 enzymes see the article here: Aldehyde Dehydrogenase
SSAO Inhibition
THIS SECTION IS BASED ON ANECDOTAL DATA ONLY
SSAO inhibitors appear to be greatly beneficial for elemicin, methyl chavicol, methyl eugenol and possibly several other allylbenzenes.
SSAO inhibitors work at any point during the effects, giving a very noticeable boost in effects for elemicin, methyl chavicol, methyl eugenol and possibly several other allylbenzenes. SSAO inhibitors can even bring back the effects if taken shortly after the effects of the allylbenzenes appear to have subsided.
The exact reason for potentiation by SSAO inhibition is unknown.
SSAO is not capable of deaminating dimethylamine, piperidine, or pyrrolidine alkaloids. It deaminates only simple amines such as mescaline, phenethylamine, methylamine and similar compounds. It's possible that some ammonia adducts form in vivo from allylbenzenes such as 1'-oxoelemicin-amine, or 1'-oxoelemicin-PEA, which could be substrates of SSAO.
For details on SSAO inhibitors and inducers please see the article found here: SSAO.
Alcohol Dehydrogenase (ADH)
THIS SECTION IS HIGHLY THEORETICAL
Alcohol dehydrogenase (as well as alcohol oxidase) should convert the 3-hydroxyl alcohol forms of allylbenzenes into their aldehyde forms which can then possibly be aminated to form dimethylamine, piperidine, and pyrrolidine alkaloids. CYP2E1 may also have the same action as alcohol dehydrogenase. For this reason alcohol dehydrogenase and possibly CYP2E1 should not be inhibited. Note that 17bHSD2 performs this action for phenyl vinyl ketones and might also perform this action on the aldehyde forms of allylbenzenes. There is currently no evidence showing which enzyme preforms this action on the aldehyde forms of allylbenzenes, although the action is proven to take place.
For details on alcohol dehydrogenase inhibitors to avoid see the article here: Alcohol Dehydrogenase
| Substrate | ADH | End Product |
|---|---|---|
| 3'-Hydroxyisoelemicin | 3,4,5-Trimethoxycinnamaldehyde | |
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Aldehyde Dehydrogenase (ALDH)
THIS SECTION IS HIGHLY THEORETICAL
Anecdotal reports have shown that aldehyde dehydrogenase and similar enzymes (such as xanthine oxidase and aldehyde oxidase) which hydroxylate aldehydes into acids contribute to the inactivation of allylbenzenes.
CYP2B6, CYP3A4, CYP1A2, and CYP2J2 but not CYP2E1 can all perform ALDH-like activity and should therefor probably be strongly inhibited. ALDH-like action directly interferes with the two main activation theories presented on this page. CYP1A2 might be needed for the activation certain allylbenzenes such as methyl eugenol and methyl chavicol. In this case it might be best not to inhibit CYP1A2.
For details on aldehyde dehydrogenase inhibitors see the article here: Aldehyde Dehydrogenase
| Substrate | ALDH | End Product |
|---|---|---|
| 3,4,5-Trimethoxycinnamaldehyde | 3,4,5-Trimethoxycinnamic acid | |
|
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