Why intoxicating cannabinoids cannot be compared

Consumers assume that newer potent cannabinoids like THCp mimic their relatives found in cannabis. A deeper look reveals clear differences between these intoxicating imposters and Delta-9-THC. This is because potency is not just a number. These artificial substances facilitate far different effects than most botanical cannabinoids found in natural abundance. Scientists are, however, still uncertain why THC is a partial agonist at the active site compared to high-affinity cannabinoids.

What is a common THC analogue?

Cannabis produces delta-9-tetrahydrocannabinolic acid (THCA) in abundance. THCA is the natural precursor to delta-9-tetrahydrocannabinol (THC). The THCA molecule contains 30 hydrogen atoms and 22 carbon atoms, arranged around a three-ring molecular framework. Five of its carbon atoms form a side chain attached to this framework. Other cannabinoid analogues share related molecular structures but differ in their atomic arrangements and chemical properties.

THCp is an uncommon analogue that cannabis produces in minute quantities. Its difference is that it contains a longer 7-carbon side chain (tail). Research spanning the past half-century has identified the tail as an influencer on cannibinoid potency. By influencing how a molecule interacts with the cannabinoid receptor, its length will invoke a level of binding affinity and receptor activation. In other words, an analogue of THC with a five-carbon tail is less potent than one with seven.

One characteristic of how THC differs in comparison might have been missed in older pharmacore research. Results from computations published in the Cell Press journal iScience showed remarkable differences between common THC and THCp. The iScience study published last year uncovered details that help explain how some molecules act as partial CB1 agonists.

Partial agonism

Canadian researchers from the University of Windsor in Ontario authored the iScience paper. They simulated the binding of different tetrahydrocannabinol analogues to adjacent cannabinoid receptors. Their computational analysis and cellular experiments support a proposed model that may help explain partial agonism.

A full CB1 receptor agonist will nestle into a deep pocket inside the CB1 receptor where it can form a tight bond with the binding site. THCp, for example, selectively locks into this pocket with its long seven-carbon tail. Whereas THCb (butyl-THC) and its four-carbon tail sit in a nearby shallow opening, according to data published in iScience. In contrast to the more stable position identified between THCp and CB1 receptors, the authors propose that THC can non-selectively occupy one of two distinct binding modes within CB1.

An important takeaway from the in silico analysis and cellular assay is that D9-THC allegedly reaches a special toggle switch through either pathway and remains indecisive. The D9- THC analogue with a pentyl tail enters through the side of the receptor. Its shape, however, allows it to switch positions between the deep pocket and a second, shallow opening. Its short tail prevents it from locking into the receptor.

Shahbazi-Raz et al. 2025. iScience.

In closing

CB1 receptors possess more than one entry point. Drawings often show agonists binding to the top of a receptor on the outside of the cell membrane. The researchers from Windsor propose that THC may also access the CB1 binding pocket laterally through the cell membrane. Because cannabinoids are lipophilic (fat-loving), lateral entry through the cell membrane is a plausible pathway proposed by the iScience study.

Their hypothesis further suggests that full agonists of the receptor possess a decisive nature that enters a deep binding pose. Whereas D9-THC can enter a pocket inaccessible to more potent CB1 agonists. We, therefore, might not be able to easily compare THCp to abundant cannabinoids. This points to the complex molecular structure and receptor activation that cannot be quantified by a simple potency ranking.

Sources

1. Papahatjis DP, Kourouli T, Abadji V, Goutopoulos A, Makriyannis A. Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1′-substituted delta 8-tetrahydrocannabinols. J Med Chem. 1998;41(7):1195-1200. doi:10.1021/jm970277i

2. Aung MM, Griffin G, Huffman JW, et al. Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding. Drug Alcohol Depend. 2000;60(2):133-140. doi:10.1016/s0376-8716(99)00152-0

3. Shahbazi-Raz F, Meister D, Mohammadzadeh A, Trant JF. How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1. iScience. 2025;28(7):112706. Published 2025 May 21. doi:10.1016/j.isci.2025.112706