CYP3A4 is the name of an enzyme important to the metabolism of a broad range of substances. This includes LSD, LSA, LSH, THC and likely many other entheogenic substances. Just like we inhibit the enzyme MAO to potentiate entheogens, what about inhibiting CYP3A4?

Of course, playing around with CYP3A4-inhibitors on a daily basis is not something you should attempt, as the enzyme plays a key role in metabolism of sex hormones (among other things). They should also not be attempted while taking medications metabolized by CYP3A4. This is, however, just like MAO-inhibitors. Extra care has to be taken, but when such care is taken, it is absolutely harmless. Am I missing something here?

I know some people use grapefruit juice with great success in order to potentiate mushroom journeys. The active constituent in grapefruit is bergamottin, an inhibitor of CYP3A4 and (minor) several other P450 enzymes. This seems to imply that psilocin also is metabolized by CYP3A4, although I can't find any references for that.

Now, there are a broad range of other CYP3A4-inhibitors. Piperine from black pepper, cimiracemoside and related substances from black cohosh, the flavonol quercetin from lovage and caper (and a lot of other plants, in weak concentration). Milk thistle and starfruit is also showed to inhibit CYP3A4. Many, many pharmaceutical medications also work as inhibitors.

Is there something wrong with attempting to inhibit CYP3A4? Or is this a treasure chest of potentiation just waiting to be opened?

3A4 is just one of several Cytochrome P450 subtypes.
the serotoninergics are also metabolized by CYP2D6.
by inducing one subtype, you can inhibit another, and vice-versa.

I was under the impression that 3A4 was the most prominent one when it comes to most entheogens. Do you have any information on what substances are metabolized by 2D6, and in what ratios compared with 3A4?

Really, inducing one subtype inhibit another one? That is very interesting, I didn't know that was the route of action of these inhibitors. If we were to make a list of what substances is metabolized by what subtypes, we could very easy make a list of herbs that can be used with different entheogens in order to potentiate.

off the top of my head, I couldn't give you a list of substrates (inducers/inhibitors)

but consider: the endogenous MAOI Pinoline is specifically a CYP2D6 inhibitor. this action will potentiate endogenous tryptamines by blocking their oxidation.

No, of course, I am not asking you to give a list of substrates from the top of your head, I am merely suggesting the possibilities such a list would create. If we were to create a good list of which substances get metabolized by which enzymes in which ratios, and then create a list of herbal substrates with inducing and inhibiting qualities on the different enzymes, we would effectively have a treasure chest of easy potentiation. I believe this is something we could all contribute to, it is too much work for just one person.

Pinoline is a metabolism product of melatonin. If one were to take melatonin supplements, this would lead to more pinoline, thus more 2D6 inhibition. Then melatonin, taken at the right time, can theoretically potentiate some entheogens. Really?!

yes
assuming you have adequate turnover of melatonin, and active levels of tryptamines.



this should be a theory to ponder, when considering endogenous DMT/Bufotenine/5-MeO-DMT production, isolation tanks, and deep meditation.

http://dmd.aspetjournals...ontent/37/3/443.full.pdf

Yeah, this is extremely interesting! Not to mention that "the third eye" is believed to be the pineal gland. It physically aligns perfectly. A more active pineal gland (or third eye if you want) would lead to more melatonin synthesis, then more pinoline, and then more effects from DMT and other endogenous tryptamines.

Wow, I have to go to my doctor and demand some more melatonin supplement!

Thanks for the PDF!

no problem

xenobiotics is a very expansive field of study, not exactly cut and dry. genetics (of course) has a lot to do with it, which is why some people are resistant to effects of certain drugs.

Well, that only makes it more interesting, doesn't it? Thanks man, you have planted some really great ideas in my head!

I like this thread. pulling up a chair

Theres not much that can go wrong eating grapefruit but taking potent CYP3A4 inhibitors to potentiate other substances is very risky. These enzymes exist in your body to remove toxins and other substances found in food and drugs etc. Inhibiting them without medical supervision is dangerous and mixing them with cocktails of different drugs/plants is even more dangerous.

yeah, good point
I was gonna mention that...

tread careful in your endeavors; since the Cytochrome P450 subtypes control other enzymatic expression (like the oxidase enzymes), avoid strong inhibitors. it's analogous to watching what you eat with strong MAOIs

Black pepper, or Piper nigrum, will potentiate aya/pharma.

Harmalas are metabolized by CYP2D6. I also remember reading that DMT is metabolized first pass by MAO and second pass by Cyt p450 (don't remember which).

Piper nigrum is a broad spectrum Cyt p450 inhibitor. It inhibits both CYP3A4 and CYP2D6, don't have a source handy on that one but I don't think it's disputed.

A while back, I ate a heaping teaspoon of freshly ground black pepper a few minutes before having some mimosahuasca. CEVs came within 15 minutes (quickly), the experience was more powerful than usual. However, the purge was very spicy. Not unmanageable by any means, a glass of cold water was nearby.

This combination definitely warrants further experimentation, maybe with plain piperine to avoid the unpleasant purge. Never tried white grapefruit juice with aya, wouldn't surprise me if it potentiated the experience.

Use caution, burnt and benzyme 's warnings must be observed.

Some other threads of note:
Piperine Info' Collection- Do you think its worthwile ?
Piper nigrum - harmala potentiator?

^^I think in a lot of these cases where studies report this kind of enzymatic inhibition the strength of the substances are often much milder then that of compound which were developed/synthesized for the purpose of being Cyt p450 inhibitors (different selectivity depending on the enzyme of interest).

So basically SWIM is saying mild inhibitors are probably fine as long as its not overdone. But potent inhibitors is a totally different story so pay attention to the doses and potency of the substance being used otherwise one could seriously be risking their life.

burnt: So piperine (black pepper) and bergamottin (grapefruit) are mild enough with moderation?

It'd be great to identify the safest and most effective plant source so more can investigate the combination responsibly.

some people who do opiates drink grapefruit juice for potentiation.
piperine is also a mild enough allosteric inhibitor

I would think so. Can't garuntee with all plants and all substances but overall these are mild substances.

I have read many reports on this forum, of people (i believe fractal- enchantment was one of them) saying that the use of melatonin DID indeed potentiate DMT.
Thanks to you guys we now have an explanation for this phenomenon.