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Data said:
There are studies demonstrating variation in the structure and expression of different enzymes involved in cannabinoid metabolism in humans, which can effect how different THC metabolites build up in the body after ingestion and inhalation.

My guess is that spirit is one of those people who has a form of CYP2C9 that poorly or slowly metabolizes delta-9-THC into 11-hydroxy-THC, but has a normal structure/expression of enzymes that convert 11-hydroxy-THC into the final metabolites excreted, which would result in negligible amounts of free 11-hydroxy in the blood to bind to cannabinoid receptors.

Since almost all of the THC in edibles goes through first-pass metabolism, 11-hydroxy is the dominant psychoactive form of THC when consuming edibles. When smoking, some of the THC gets converted to 11-hydroxy, but some of it also passes through the blood-brain barrier unchanged and binds directly to cannabinoid receptors as delta-9. If my guess is correct, this would mean that spirit only experiences delta-9-thc effects, but does not experience 11-hydroxy-thc effects, which is why he's never been able to get "too high", doesn't get high from edibles but can still get high from smoking, and probably has a pretty high base tolerance to THC in general.

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Hey Mr science man can you make me something that would make me able to get too high? Do I need to eat a specific strain of grass or something before ingestion?


Edit: that may also explain why I don't really feel different kinds of highs. I just feel high or not high.(I can feel high but just not crazy high like everyone else, as I said just relaxes me a bit, it's comfy)

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(I can feel high but just not crazy high like everyone else, as I said just relaxes me a bit, it's comfy)

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kreg said:
But aren't those enzymes used for other things in the digestive process as well? Like weren't if someone completely devoid of those enzymes wouldn't they also have some known medical issues? I'd imagine something like not being able to eat kale or some weird specific foods something. No?

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kreg said:
Like if you just told me somebody was missing some opioid receptors I would expect that person to be a little off

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spirit_shadow said:
Hey Mr science man can you make me something that would make me able to get too high? Do I need to eat a specific strain of grass or something before ingestion?

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So I've always heard that mango can intensify the effects of cannabis, but I think this is because myrcene is found in both the more volatile terpene fraction of cannabis and mangoes, so I don't know if this will help you.

Oddly enough, THC and CBD are both inhibitors of CYP2C9, but with unknown strength in vivo, and your ad-hoc in vivo testing suggests that it doesn't help .

Amentoflavone is a strong inhibitor of CYP2C9, which will almost certainly intensify the high of smoked or vaped THC, and may or may not affect the ability to get high on edibles. Herbal supplements that contain a decent amount of amentoflavone are Ginko biloba and St. John's Wort.

Grapefruit has traditionally been used to potentiate the high of opiates via inhibition of P450 enzymes (primarily CYP3A4) by the compound bergamottin in the pulp of the grapefruit. It is also found in bergamot orange peel extract, which is used in the characteristic flavor of Earl Grey tea. You may find that ingestion of grapefruit or earl grey may provide some potentiating effect on a THC high, but be aware that bergamottin's effects can last for 3-7 days, and can get you into some trouble if you are taking any other prescription medications, or taking large amounts of caffeine.

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spirit_shadow said:
that may also explain why I don't really feel different kinds of highs. I just feel high or not high.(I can feel high but just not crazy high like everyone else, as I said just relaxes me a bit, it's comfy)

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I would expect this to be the case if the P450 class of enzymes have structural or expression variations. Do you also have different high duration compared to others?

I would suggest you be very careful and mention some of your variability in response to medication if your doctor ever prescribes you anything you haven't taken before. It can get you into potentially dangerous territory if they blind-dose you, and it may be that you metabolize certain things faster than others, but certain things may metabolize slower than others as well. From our discussion on your experience with opiates, I'd say you have several variations in your metabolic system.

Biology is neato

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Data said:

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kreg said:
But aren't those enzymes used for other things in the digestive process as well? Like weren't if someone completely devoid of those enzymes wouldn't they also have some known medical issues? I'd imagine something like not being able to eat kale or some weird specific foods something. No?

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Not necessarily.

CYP2C9 is a member of the cytochrome P450 superclass of oxidative enzymes. They are used as a catch-all metabolic enzyme that acts on endogenous and xenobiotic compounds. They are also known for being polymorphic (and in the case of CYP2C9, highly polymorphic). Because of their broad range of substrates, a minor change in structure may just adversely affect activity on one substrate or one class of substrates, but not necessarily all substrates. So while spirit's CYP2C9 enzymes might be bad at working on specific cannabinoids, that doesn't necessarily mean it's not effectively doing its job on arachidonic acid.

And I also mentioned it could be another step in the metabolism that is affecting the buildup of different psychoactive compounds. For instance, if CYP2C9 is over-expressed or overactive, then the psychoactive delta-9 could be oxidized to the psychoactive 11-hydroxy and then immediately to the non-psychoactive THC-COOH. This could also occur if the enzyme has low or average efficacy with the first step, and high efficacy with the 2nd step. Either way, the end result is that only a burst of THC straight to the brain will result in a significant high, while slower, more metabolized ingestion will be completely removed before it has time to reach the brain and bind to the CB receptors. There are also multiple enzymes in the P450 class of enzymes that can do these steps, so it may be a more complex interaction with similar results.

That being said, some enzymatic genotypes do change how certain endogenous and xenobiotic compounds are metabolized, and those changes may result in differing responses to body conditions and external compounds. This can range from detectable differences in ratios between compounds and compound metabolites in the body, all the way up to certain people needing a fraction or multiples of the average effective dose of a medication in order to get the desired effects without risk of OD or undesirable side effects. This is most obvious in different responses to various drugs between races[link] or between adults and children, and is one of the motivations for pharmacogenomics and tailoring a specific person's medication and treatments based on their genetics.

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kreg said:
Like if you just told me somebody was missing some opioid receptors I would expect that person to be a little off

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You would be correct, behavioral changes due to various opioid receptor gene knockout has been observed and documented in mice [link]. But most people do not have a random gene knockout mutation, most living humans have gene mutations that affect (but not block) enzyme expression and/or activity. This results in more nuanced physiological or behavioral changes [link].

And I think we've had this discussion too, where spirit was discussing his abnormal reaction to opiates, suggesting that he may also have some variation in the expression or function of one or more opioid receptor genes.

Enzyme and receptor gene variations are pretty common, because neurotransmitter regulation is a very dynamic and reactionary response in the body, as is the chances of ingesting (either knowingly via substance abuse or accidentally with changing external environment) different compounds that could wipe out a whole human population, necessitating high variability in xenobiotic metabolic enzyme expression and structure to increase the adaptability of a human population to a changing external environment.

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spirit_shadow said:
Hey Mr science man can you make me something that would make me able to get too high? Do I need to eat a specific strain of grass or something before ingestion?

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So I've always heard that mango can intensify the effects of cannabis, but I think this is because myrcene is found in both the more volatile terpene fraction of cannabis and mangoes, so I don't know if this will help you.

Oddly enough, THC and CBD are both inhibitors of CYP2C9, but with unknown strength in vivo, and your ad-hoc in vivo testing suggests that it doesn't help .

Amentoflavone is a strong inhibitor of CYP2C9, which will almost certainly intensify the high of smoked or vaped THC, and may or may not affect the ability to get high on edibles. Herbal supplements that contain a decent amount of amentoflavone are Ginko biloba and St. John's Wort.

Grapefruit has traditionally been used to potentiate the high of opiates via inhibition of P450 enzymes (primarily CYP3A4) by the compound bergamottin in the pulp of the grapefruit. It is also found in bergamot orange peel extract, which is used in the characteristic flavor of Earl Grey tea. You may find that ingestion of grapefruit or earl grey may provide some potentiating effect on a THC high, but be aware that bergamottin's effects can last for 3-7 days, and can get you into some trouble if you are taking any other prescription medications, or taking large amounts of caffeine.

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spirit_shadow said:
that may also explain why I don't really feel different kinds of highs. I just feel high or not high.(I can feel high but just not crazy high like everyone else, as I said just relaxes me a bit, it's comfy)

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I would expect this to be the case if the P450 class of enzymes have structural or expression variations. Do you also have different high duration compared to others?

I would suggest you be very careful and mention some of your variability in response to medication if your doctor ever prescribes you anything you haven't taken before. It can get you into potentially dangerous territory if they blind-dose you, and it may be that you metabolize certain things faster than others, but certain things may metabolize slower than others as well. From our discussion on your experience with opiates, I'd say you have several variations in your metabolic system.

Biology is neato

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You are cute assuming I have a doctor I don't remember the last time I was sick and I have never broken a bone so

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Fleabag Friend said:
Goddamn, data is one smart motherfucker. All of that went entirely over my head.

Can I pay you for lessons?

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I was on a grapefruit supplement when writing all of that up, just start dosing grapefruit and everything will start coming together.

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Fleabag Friend said:
dosing grapefruit huh? whats that supposed to do, give me big cajones?

And why would it be a bad idea to do dissociatives with it?

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