Delta-9-THC

The main cannabinoid receptor in the brain, responsible for THC’s intoxicating effects, is directly activated by Delta-9-THC as a partial agonist, meaning it activates the receptor but produces a lower maximum response than a full agonist. One human-receptor study measured a CB1 Ki of 18 nM, while pooled human data estimate approximately 25.1 nM, showing some assay-dependent variation. CB1 activation reduces cAMP signalling, alters calcium and potassium channel activity and decreases neurotransmitter release. In humans this produces confirmed intoxication, altered perception, memory impairment, changes in coordination and other central effects.

The main cannabinoid receptor in the immune system, involved in regulating immune cell activity and inflammatory responses. Delta-9-THC is also a partial CB2 agonist. A human-receptor study measured a CB2 Ki of 42 nM, while pooled human data estimate approximately 35.2 nM. CB2 activation can modify immune-cell signalling and inflammatory responses, although the overall immune effects of isolated Delta-9-THC in humans are less clearly established than its CB1 effects.

Glycine receptors are ion channels that reduce nerve signalling and play an important role in pain processing and motor control. Delta-9-THC acts as a positive allosteric modulator of glycine receptors, the α1 and α3 subtypes. Rather than activating these receptors on its own, Delta-9-THC binds to a separate site and strengthens the response produced by glycine, allowing greater inhibitory signalling. Structural research has directly visualized Delta-9-THC interacting with the glycine receptor and confirmed this mechanism.

This mechanism appears especially relevant to pain. Animal research found that the α3 glycine receptor contributes substantially to the pain-reducing effects of Delta-9-THC, with these effects strongly reduced when this receptor mechanism was disrupted. This suggests that part of Delta-9-THC’s effect can occur through glycine receptors independently of CB1 and CB2.

TRP channels are ion channels involved in pain, temperature and sensory signalling. Delta-9-THC directly activates several of these channels, including TRPA1 and TRPV2, while it inhibits TRPM8.

Delta-9-THC directly activates TRPA1, a channel involved in detecting irritating stimuli, pain and temperature changes. This activation could contribute to changes in pain perception and other sensory responses, although its contribution to the effects of Delta-9-THC in humans has not been established.

Delta-9-THC directly activates TRPV2, with an EC50 of approximately 0.65 µM reported in functional research. TRPV2 allows calcium to enter cells and is involved in sensory, pain and cellular signalling. Its activation could therefore contribute to some pain-related or sensory effects of Delta-9-THC, but this has not been confirmed as a meaningful mechanism in humans.

Delta-9-THC inhibits TRPM8, a channel involved particularly in sensing cold temperatures and regulating cold-related sensory signals. Inhibiting this channel could potentially alter cold perception and pain signalling, but the relevance of this effect at normal Delta-9-THC exposure in humans remains uncertain.

GPR18 is a receptor that helps regulate how certain cells move and how immune cells respond to signals. Delta-9-THC acted as a full GPR18 agonist, with an EC50 of approximately 20 nM in a human-cell assay, meaning it strongly activated the receptor. Through this mechanism, Delta-9-THC could potentially influence immune-cell movement, inflammatory responses and communication between immune cells.

More recent research indicates that Delta-9-THC’s activity at GPR18 can vary depending on the pathway and experimental system, with partial agonist behaviour observed in assays. GPR18 activation by Delta-9-THC is therefore supported, but exactly how strongly this receptor is activated in the human body and how much it contributes to Delta-9-THC’s overall effects remain uncertain.

The 5-HT3 serotonin receptor is an ion channel involved in nausea, vomiting, pain signalling and communication between the gut and nervous system. Delta-9-THC directly inhibits 5-HT3 receptor activity. Functional research found inhibition with an IC50 of approximately 1.2 µM reported in one human 5-HT3A receptor assay.

By reducing 5-HT3 signalling, Delta-9-THC would be expected to decrease nausea and vomiting signals and may also reduce certain pain-related signals transmitted through this receptor. This provides a potential additional mechanism for some of Delta-9-THC’s anti-nausea and pain-reducing effects.

Direct inhibition of 5-HT3 by Delta-9-THC is established, but how much this mechanism contributes to its anti-nausea or pain-reducing effects in humans has not been determined.

GPR55 is a receptor involved in calcium signalling and the activity of cells, including sensory nerve cells involved in pain processing. Delta-9-THC has been shown to activate GPR55 in human-receptor experiments. This activation increases calcium signalling inside the cell and reduces potassium flow, which can make the nerve cell more active and easier to trigger.

Through this mechanism, Delta-9-THC could potentially increase certain sensory and pain-related nerve signals, rather than simply suppressing them. GPR55 signalling may also influence other neurological and cellular processes, but its exact contribution to the overall effects of Delta-9-THC remains uncertain.

PPARγ is a receptor inside cells that helps regulate inflammation, metabolism and blood vessel function. Delta-9-THC directly activates PPARγ, with measurable activation reported from approximately 100 nM, increasing further at higher concentrations up to 10 µM.

This activation can reduce inflammatory signalling and help relax blood vessels. Laboratory research found that blocking PPARγ reduced some of these Delta-9-THC effects, showing that the receptor likely contributes directly.

Unlike CB1, PPARγ works relatively slowly because it is located inside the cell and influences gene activity rather than producing an immediate signal. Once activated, it can change which proteins the cell produces, so its effects on inflammation, metabolism and blood vessel function can develop more gradually and last longer.

Delta-9-THC is metabolised mainly through liver enzymes, particularly CYP2C9, into 11-OH-THC. This metabolite is itself psychoactive and has produced psychological and pharmacological effects directly in humans. It is subsequently oxidised mainly to THC-COOH, which is not considered psychoactive, followed by conjugation and elimination. Oral absorption produces proportionally more 11-OH-THC through first-pass liver metabolism than inhalation.