**11-Hydroxycannabinol**
**Definition**
11-Hydroxycannabinol (11-OH-THC) is a primary active metabolite of delta-9-tetrahydrocannabinol (THC), the principal psychoactive compound found in cannabis. It is produced in the liver through enzymatic oxidation and is known to contribute significantly to the psychoactive effects experienced after cannabis consumption.
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## Overview
11-Hydroxycannabinol (11-OH-THC) is a pharmacologically active metabolite formed when delta-9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, is metabolized in the body. Unlike THC itself, which is directly absorbed into the bloodstream when cannabis is smoked or vaporized, 11-OH-THC is primarily generated during the first-pass metabolism in the liver, especially after oral ingestion of cannabis products. This metabolite is considered to be more potent than THC in terms of its psychoactive effects, contributing to the intensity and duration of the cannabis high.
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## Chemical Structure and Properties
11-Hydroxycannabinol is chemically classified as a cannabinoid, sharing a similar core structure with THC but distinguished by the presence of a hydroxyl (-OH) group at the 11th carbon position. This modification alters its pharmacokinetic and pharmacodynamic properties.
– **Molecular formula:** C₂₁H₃₀O₃
– **Molecular weight:** Approximately 330.46 g/mol
– **Chemical class:** Cannabinoid metabolite
– **IUPAC name:** (6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
The addition of the hydroxyl group increases the molecule’s polarity compared to THC, influencing its solubility and interaction with cannabinoid receptors.
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## Biosynthesis and Metabolism
### Formation in the Body
When cannabis is consumed, THC enters the bloodstream and is distributed throughout the body. The metabolic transformation of THC primarily occurs in the liver via the cytochrome P450 enzyme system, particularly the CYP2C9 and CYP3A4 isoforms. These enzymes oxidize THC to form 11-hydroxy-THC.
– **Route of metabolism:** THC → 11-Hydroxy-THC → 11-nor-9-carboxy-THC (THC-COOH)
– **Primary enzymes involved:** CYP2C9, CYP3A4
The formation of 11-OH-THC is especially prominent after oral ingestion of cannabis, such as edibles, because the THC passes through the digestive system and liver before entering systemic circulation (first-pass metabolism). In contrast, inhaled THC bypasses much of this initial metabolism, resulting in lower levels of 11-OH-THC.
### Further Metabolism
After its formation, 11-hydroxy-THC is further metabolized into 11-nor-9-carboxy-THC (THC-COOH), an inactive metabolite that is eventually excreted in urine and feces. The presence of THC-COOH is commonly used as a biomarker in drug testing to indicate cannabis use.
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## Pharmacology
### Interaction with Cannabinoid Receptors
11-Hydroxycannabinol acts as a partial agonist at cannabinoid receptors, primarily CB1 and CB2 receptors, which are part of the endocannabinoid system. The CB1 receptors are predominantly located in the central nervous system, while CB2 receptors are found mainly in peripheral tissues and immune cells.
– **CB1 receptor affinity:** 11-OH-THC has a similar or slightly higher affinity compared to THC.
– **CB2 receptor affinity:** Both THC and 11-OH-THC exhibit lower affinity for CB2 receptors.
Activation of CB1 receptors by 11-OH-THC leads to the modulation of neurotransmitter release, resulting in altered mood, perception, cognition, and motor function.
### Psychoactive Effects
11-Hydroxy-THC is considered to be more potent than THC in producing psychoactive effects. This increased potency is attributed to its higher efficacy at CB1 receptors and its ability to cross the blood-brain barrier efficiently. The metabolite contributes to the delayed onset and prolonged duration of effects observed with oral cannabis consumption.
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## Pharmacokinetics
### Absorption and Distribution
– **Oral consumption:** THC is absorbed through the gastrointestinal tract and transported to the liver, where it is metabolized to 11-OH-THC before entering systemic circulation. This results in higher plasma concentrations of 11-OH-THC compared to inhalation.
– **Inhalation:** THC enters the bloodstream directly via the lungs, leading to rapid onset of effects but lower levels of 11-OH-THC.
11-Hydroxy-THC is lipophilic, allowing it to cross the blood-brain barrier and accumulate in fatty tissues.
### Metabolism and Elimination
The half-life of 11-OH-THC varies depending on the route of administration and individual metabolic factors but generally ranges from 1 to 3 hours. It is further metabolized to inactive compounds and eliminated primarily through renal and fecal excretion.
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## Clinical and Forensic Significance
### Role in Cannabis Effects
The presence of 11-hydroxy-THC is a key factor in the differing effects of cannabis depending on the method of consumption. Oral cannabis products, such as edibles, produce higher levels of 11-OH-THC, which can lead to more intense and longer-lasting psychoactive effects compared to smoking or vaping.
### Drug Testing and Detection
In forensic toxicology, the detection of 11-hydroxy-THC in biological samples (blood, plasma) can indicate recent cannabis use. However, because 11-OH-THC is rapidly metabolized, its detection window is shorter than that of THC-COOH, the inactive metabolite commonly targeted in urine drug tests.
### Therapeutic Implications
Understanding the pharmacology of 11-hydroxy-THC is important for the development of cannabinoid-based medications. The metabolite’s potency and pharmacokinetic profile influence dosing strategies and the design of oral cannabis formulations.
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## Research and Future Directions
Ongoing research aims to elucidate the precise role of 11-hydroxy-THC in the overall effects of cannabis, including its impact on cognition, pain modulation, and potential therapeutic applications. Studies also focus on individual variability in metabolism, which can affect the concentration of 11-OH-THC and thus the subjective experience of cannabis.
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## Summary
11-Hydroxycannabinol is a significant active metabolite of THC formed primarily in the liver during the metabolism of cannabis compounds. It exhibits potent psychoactive effects through its action on cannabinoid receptors and plays a crucial role in the pharmacological profile of orally consumed cannabis. Its presence and concentration influence both the intensity and duration of cannabis effects, making it an important compound in clinical, forensic, and pharmacological contexts.
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**Meta Description:**
11-Hydroxycannabinol is a potent active metabolite of THC formed during cannabis metabolism, contributing significantly to the psychoactive effects of oral cannabis consumption. This article explores its chemistry, pharmacology, and clinical relevance.