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Oral cannabis CYP450 metabolism

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neurohack

neurohack

Rising Star
Hi there, have you ever tried oral cannabis and noted the profound difference in effect? Generally people experience this as way more psychedelic than smoking. How does this work?

There is a mechanism in which oral consumed cannabis is metabolised by CYP450 enzymes in the liver. This produces some unique products which are not present in the plant itself. One of these substance is 11-OH-THC. It's metabolised from THC by CYP3A4 and CYP2C9.

A friend has made a visual depiction of the process, which I present here as well (including link to the source).

Thc.jpg


source

Some quotes found in papers to illustrate this:

Fresh cannabis contains Tetrahydrocannabinolic acid (THCA), which is converted into THC after heating and then metabolized by the body into 11-Hydroxy-THC. Peak THC concentrations are lower after eating/drinking cannabis than after administration by smoking or vaping, but conversely, 11-OH-THC/THC ratios are higher after eating/drinking than after smoking cannabis.[12] After administration through eating or drinking, approximately equal quantities of THC and 11-OH-THC are formed, whereas 11-OH-THC is a minor constituent after administration by intravenous or smoking routes.
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en.wikipedia entry for 11-OH-THC

After oral administration, approximately equal quantities of THC and its highly active 11-hydroxy metabolite were formed, whereasthe latter metabolite is a minor constituent after administration by intravenous or smoking routes.
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The Metabolism of Δ9-Tetrahydrocannabinol and Related Cannabinoids in Man

Cytochrome P450 enzymes contribute to the metabolism of drugs by oxidizing them, which generally means incorporating an oxygen atom into the drug’s molecular structure. Oxidation will usually make a compound more water soluble and therefore easier for the kidneys to filter out. Both steps in the metabolism of ethanol, mentioned above, and the conversion of THC into 11-OH-THC involve oxidation (though ethanol is not oxidized specifically by cytochrome P450).

Different routes of cannabinoid administration have different effects. Inhaled THC enters capillaries in the lungs, passes into general circulation through the pulmonary arteries, and quickly crosses the blood-brain barrier. When ingested orally, however, THC is absorbed in the small intestine and then carried to the liver, where it is metabolized by subclasses of cytochrome P450 (abbreviated CYP), specifically the CYP2C and CYP3A enzymes.
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CBD-Drug Interactions: Role of Cytochrome P450

These results indicate that CYP2C9 and CYP3A4 are major enzymes involved in the 11-hydroxylation and the 8-(or the 7-) hydroxylation, respectively, of the cannabinoids by human hepatic microsomes.
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Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes.
 
As a biochemical enthusiast, I gotta jump on this thread :D

i had thought THC was hepatically metabolised mainly via CYP2C9. However, I'm not surprised in the least about involvement of CYP3A genre of the CYP450 enzymatic familiea (e.g. CYP3Ax, CYP2D-x, CYP2Cx, etc. Wherein x= a specific integer/number for the individual species) joining in on the metabolic fun, too! :D

Regards to the acid catalyzed conversion of CBD to THC, I was wondering if average gastric pH levels at average body temperature in a person at sea level (average pH of stomach fluids lies around 1.5 at core body temperature; use of antacids, PPI's and selective Histamine H2 receptor antagonists decrease gastric pH to 2-5 via varying mechanisms; acidic food products such as citrus, kombucha and soft drinks, along with most food products, lower pH.) would be sufficient to convert a significant amount of CBD to THC before it leaves stomach; if so, what would be the average convertion rate (ratio of THC:CBD) given an incubation time of 30 minutes before full absorption?

Another biophysical chemistry inquiry would be the pharmacokinetics of inhaled Cannabis compounds, and how their Cmax/Tmax/metabolic rates/pathways differ (inhaling is fastest means of drug administration; IV delivers drug into vessels carrying blood to heart, which is pumped to lungs to trade CO2 for fresh air for circulation. By inhaling a drug into lungs, it's diffused rapidly into arterial blood; inhalation bypasses the liver, and reaches sites of activity several seconds faster. Every ROA has it's ups and downs.)


I'm very interested in seeing to what extent one can manipulate hepatocyte activity in order to get more mileage out of their bud. This may be reflected in the average AUC, Cmax, Tmax excretion rate and duration of effects, along with rates of decline.

One lazy-ass day, 5 days into taking a 7 day long regimen of Bactrim (sulfamethoxazole/TMP;800mg/160mg), and four or so grapefruits in my stomach, I decided to smoke a bowl of Blue Dream. I consumed it over the course of 10 minutes. Upon finishing the bowl, I felt a massive cannabinoid head rush, and was far more intense compared to what I typically experience from that much herb. 5 minutes after my last exhalation of cannabis smoke/vapor, a Psychedelic Tsunami with Kaleidoscopic eyes crested over me as I was swallowed into The Psychedelic Abyss, far far away from my self and every article of my identity.

I spent the next 5 hours engrossed in a borderline overwhelming psychedelic carnival, followed by a slow euphoric decline and a strong after glow lasting into the next day. I had expected a few hours of moderate inebriation from that amount innumerable times beforehand; this one bowl gave me a trip on par in intensity to that produced by ten-fold the amount I consumed.

I was wondering if anyone has tried different CYP450 inhibitors (e.g. GFJ, cimetidine, bactrim, etc.) before ingesting cannabis via oral and vaporization ROAs, respectively, and how (if at all) it changed the effect and duration that same amount would yield without those inhibitors (if experimenting, consume inhibitor at least 30 minutes before ingestion. Let there be a washout period of 2 weeks in between tests with different CYP450 inhibitors or control test. Record results in a journal and share with us. We'd eagerly await such a case study).

Godspeed,
--God

Rant=Over
 
CBD does not transform into THC in human metabolism according to one publication (source), even though in vitro artificial gastric juice seemed to transform a small amount of CBD to THC (source). While in the body it does not seem to occur at least in any significant amounts, it is a viable pathway for synthesis using strong acids though it generally won't be enantioselective therefore you'll end up with a bunch of delta8 THC which is less active than delta9-thc (source 1, source 2)

CBD metabolism seems to be mostly in the liver, where it is hydroxylated to 7-OH-CBD by CYP450 enzymes, predominantly by the CYP3A (2/4) and CYP2C (8/9/19) (source) Generally cannabinoids later will be transformed into their carboxylic acid and then gluconoride for easier elimination due to water solubility. (source)
 
Just a question: does anybody have any idea how taking cannabidiol would affect the effects of oral cannabis? Has anybody ever experimented with combinations of cannabidiol and oral cannabis?
 
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