Posted by: leigh | June 7, 2010

Cannabinoid agonists and JWH-018- part 2

Continuing my discussion of the purported “legal marijuana” from my previous post, today I’ll move to the topic that’s probably of greater interest: what do these drugs actually do, and what’s different about them?

I already covered that JWH-018 is a synthetic compound that is structurally unrelated to THC, the principal psychotropic component of marijuana. I also mentioned, but not in great detail, that it works via the same receptors as THC does, and that it and some other compounds from its family of structures (the aminoalkylindoles) produce cannabimimetic (cannabis-mimicking) effects.

Cannabimimetic effects encompass several different physiologic changes. In rodent models, a “tetrad” of effects (catalepsy, decreased locomotion, hypothermia, and hypoalgesia) are measured as the benchmark of cannabimimetic effects. Of course, rodents aren’t so good at telling us when they’re experiencing particular psychedelic effects, so we can’t measure that specifically. In humans, perceptual alterations, memory alterations, and euphoria are commonly discussed cannabimimetic effects.

That brings us to the big question:

If these drugs produce similar effects and work via the same mechanism, how can they be different?

Oh, there are many ways.

Let’s consider some of the most basic pharmacological properties of any given drug. The drug has to bind to its target, it has to cause an action at that target- and if it’s psychotropic, it has to get across the blood-brain barrier to do any of this. Only then are the effects of the drug actually set into motion.

Before it can cause an effect, the drug molecule needs to run into and bind to its target. This very first step carries a lot of variability across different drugs, even at the same target. Seemingly small changes in chemical structure of a drug can have a dramatic impact upon how well that drug will bind to its target. In this case, the target is the cannabinoid CB1 receptor, which is expressed widely throughout the brain and mediates the psychotropic effects of THC. Since living systems add a big pile of other variables we won’t get to just yet, pharmacologists typically measure this basic property of drug-target affinity in vitro. If a drug will bind easily to the receptor even at very low drug concentrations (very low doses), that constitutes very good affinity. Potency is a closely related measure, where the dose that causes a physiologic effect in a system is measured.

Figure 1. Drug potency as shown in typical dose-response format. A drug that produces an effect at a lower concentration is considered to be more potent. Lower potency drugs have curves that are shifted to the right, meaning that more drug is required before physiologic effects can be measured.

The few studies that have looked at the pharmacology of JWH-018 at the CB1 receptor have shown that JWH-018 is more potent than THC. It will bind the CB1 receptor at considerably lower concentrations than THC will, and lower doses of JWH-018 are required to produce physiological responses.

Next is the specifics of the drug action on its target. Most drug targets don’t function as all-on or all-off, like a light switch. Instead, consider them more like a dimmer switch. Different drugs (again due to their differences in chemical structure) can cause different levels of activation of the target. This is the efficacy of a given drug at a given target.

Figure 2. Drug efficacy, again in typical dose-response format. Drugs with high efficacy produce a greater maximal effect than low-efficacy drugs. These curves can also vary by effect for drugs that produce multiple measurable effects. There are places in medicine, for example, where full agonists are the preferred tool to use, and places where a partial agonist is better. It all depends on the conditions! More effect is not always better.

A drug that activates the receptor is generally known as an agonist. But since there are varying levels of activation that a given drug can cause at a receptor, we sort the agonists into categories. There are partial agonists, that don’t activate the full capacity of the target, and full agonists, that do. THC is a partial agonist at the CB1 receptor, only partially activating it. On the other hand, JWH-018 is a full agonist. This is a major difference in and of itself- CB1 receptor responses, and immediate and long-term cellular adaptations in response to drug, vary with different agonist efficacy. The particular psychotropic effects of THC are distinctly related to its partial agonist nature. This does not mean that JWH-018 will make users “more high” than THC or is somehow “better” than THC – just that the immediate and long-term effects are distinct and can’t be described as “the same thing but more powerful.” If you take one thing away from this post, let it be that.

Recall that living systems add a whole lot of complexity on top of the already fairly complex drug-target interactions that I’ve discussed so far. Let’s consider how the drug gets to the receptor in the first place. Drugs have varying absorption and distribution kinetics, which can also modify the drug effect. Something that gets into the brain very slowly will give a different effect than something that reaches the brain rapidly. We know essentially nothing about the absorption and distribution kinetics of JWH-018, it’s all up to speculation.

Speaking of kinetics, metabolism/elimination kinetics are also quite variable between different drugs. And on that hand, we’re in the same position as with the absorption and distribution kinetics. No solid understanding. Some clever folks are developing methods to detect metabolites of JWH-018, but that’s where we are.

So to summarize:

1. JWH-018 is more potent than THC. Lower concentrations of drug will produce notable effects with JWH-018 than with THC.

2. JWH-018 is more efficacious than THC. The maximal effect of JWH-018 is greater than that of THC in every physiological measure that’s been captured to date.

3. The points I bring up in 1 and 2 DO NOT mean that JWH-018 is like THC, but “better” or “stronger” or any other comparator. The considerably different pharmacological properties of these two drugs causes them to have (perhaps related but) distinct effect profiles.

4. We have little to no scientific information about how JWH-018 is distributed and eliminated from the body.

5. We have little to no scientific information about JWH-018 beyond what I’ve outlined here.

Alright, we can talk theoretical concepts and isolated measured properties of drugs all day, but the bottom line is that people are trying this stuff out and perhaps using it regularly. How do the limited data we have translate to people? Unfortunately, there’s not a ton of properly-controlled study of the stuff in model organisms, much less humans. So we know very little except what we can speculate from the basic pharmacology that we do know about.

Not surprisingly, there are plenty of people willing to venture out and be their own n=1 case study, but the information we can gain from those people is pretty constrained. Is this a call for more study? Perhaps…


  1. […] This post was mentioned on Twitter by Drug Monkey, dr leigh. dr leigh said: more on the pharmacology of JWH-018 #spice #k2 #cannabis (also, i like that the shortlink ends in "-ha") […]

  2. Is that deliberate that there’s a google ad for JWH at the bottom of your page? Cause that just MAKES it.

    Great series!

  3. HAHAHAHA!!!!

    i don’t see ads in my browser, so i wasn’t aware of that. hilarious!

  4. Great article, absolutely thorough and detailed.

    Perhaps a post on how the effects of JWH-018 differ to that of other related substances. JWH-133, JWH-250, JWH-081 etc.. as most, including I, are unsure of why there are so many which seem to do the same!

    Dr Reeves.

  5. Edited

  6. Have you seen these JWH-018 Tox Studies?

    Hardly concrete facts, but they appear to be legitimate. Probably leaked from a smoking mix manufacturer originally, but no way of knowing.

    Does anything look out of the ordinary?

  7. Stan, thanks for the input. i’m most definitely not a medicinal chemist, but i can discuss some basic stuff. when i have another chance to dig through the literature, i’ll put something up for ya.

    Synchronium, i haven’t seen those before, thanks for pointing them out! i will give them a more detailed look- i’m particularly interested in the in vivo stuff.

  8. […] structure of the compounds are different from the active constituents in marijuana but they bind to the same receptors in the brain. In recent months, JWH compounds have become available on the internet in their pure […]

  9. […] structure of the compounds are different from the active constituents in marijuana but they bind to the same receptors in the brain. In recent months, JWH compounds have become available on the internet in their pure […]

  10. […] part 2 discussing pharmacological properties of JWH-018 can be found here.] Possibly related posts: (automatically generated)Marijuana goes mainstreamGreat JWH-018 InfoTest […]

  11. If you have smoked cannabis without harm, you might self-experiment and try ingesting JWH-018.

    I hope you are not offended by this suggestion; there is a certain tradition of self-experimentation in medicine.

    In my experience, 018 is very much like a strong THC, and it appears to be safe (incl no toxic effects at high dosages, plateau of effects at high dosages, no noticable sequalae or craving.) much like cannabis.

  12. I wanted to support the claims made in pharmacology with a personal view that in a user’s view between thc and jwh, jwh has a different effect, that is yet similar. It’s kind of like the difference between the indica and sativa varieties, or a moderate amount of high grade to a large amount of low grade marijiuana, although jwh products have a ‘flavor’ of effect different the thc and completely distinct. I also noticed differences between two different blends I purchased at the same shop.
    -spreading knowledge a bunch of words at a time.

  13. Jwh has ruined my life… i may elaborate if im still alive by the next reply

  14. When jwh-018 binds to the receptor, does it dislodge any THC that might be already bound to that receptor? The reason I ask is that I quit smoking pot in favor of jwh-018 three weeks ago, but thc is still appearing in my urine. Why would this be?

  15. a new post on my blog for you, Ben:

  16. Good post

  17. Hey i know itd been a while since anyone has posted anyhthing bout this synthetic marijuana and synthetic cocaine. So i figured i would let u know my opinion.. I font do real drugs anymore now that these “fake drugs” are more than easy to get, plus they give u the same feeling as the drug its suppose to b simulating, however it is like 800 times more potent than THC. These chemicals like the JWH018, JWH81, JHW73, HU210, and CP47 are some of the greatest things invented in my eyes i can get higher off of the chemicals that dont show up on a drug test than i could off of something that is illegal and i could go to jail for. All i got to say is thank you FDA..

  18. …just one or two hits is all you need. For this stuff, there can be too much…at least in my bloodshot eyes. that’s my only issue with it.
    Otherwise, it is a great substitute for what our idiotic lawmakers have made illegal!

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