Δ9-cis-Tetrahydrocannabinol: Natural Occurrence, Chirality, and Pharmacology
A 2021 peer-reviewed study published in Journal of Natural Products compared the pharmacological activity of several D9-THC stereoisomers, including the naturally occurring (–)-trans-D9-THC and the synthetic (+)-cis-D9-THC formed during CBD conversions.
The results highlight a serious issue that continues to be ignored in cannabinoid legislation:
Natural (–)-trans-D9-THC showed strong binding to the CB1 receptor and robust psychoactive effects at low doses.
Synthetic (+)-cis-D9-THC exhibited over 100 times weaker CB1 binding and was functionally inactive at physiologically relevant concentrations.
The study also showed that the synthetic isomers lack the potency to trigger standard cannabinoid receptor responses, which could have a major impact on how medical patients experience their dose.
Despite these findings, most current legislation makes no distinction between these stereoisomers. All forms of D9-THC are treated the same, even though the pharmacological activity between them is dramatically different.
I don’t understand how this is still allowed. Converted cannabinoids are being used in consumer products under the same label as plant-derived D9-THC, but the active compounds are completely different. This creates a risk of underdosing for patients and undermines any attempt at consistency in product formulation.
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I don’t think it’s an issue with legislation, it’s more an issue with manufacturing and testing. If (+)-cis-D9-THC is showing up as (-)-trans-D9 then that’s the only place where it’s an issue.
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The issue is with legislation because it doesn’t differentiate between stereoisomers of D9-THC. That matters when medical patients rely on consistent dosing and expect a certain pharmacological effect from a product labeled as “THC.” If a product contains a stereoisomer with drastically lower CB1 binding, the effect is not just weaker, it is fundamentally different.
Even if labs can identify the difference, there is nothing in statute requiring those differences to be reported or regulated separately. So the issue is not just analytical, it is that the legal definition allows for chemically distinct, pharmacologically inactive compounds to be sold under the same label as the active form.
Wouldn’t it make more sense for the law to distinguish between naturally occurring THC and converted stereoisomers that do not act on the body in the same way?
I think you’re treating this like it’s a pharmaceutical - it’s not. That’s why it doesn’t matter as much as you’d think it would in a regulatory sense. If you’re going to treat it like a drug, then yes, you need to have a very uniform, consistent product. Though, I think even UPS drugs allow for a significant dosage leeway on their concentrations.
Also I doubt that isomerized D9 contains enough isomers for the average user to even tell the difference. If they could, it wouldn’t be selling tens of thousands of liters per month.
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That’s a fair take, and I definitely see where you’re coming from on your last point. Availability likely drives the volume too, since converted D9 can be the only option in states without a legal market. For medical patients though, do you think these products should be tested and labeled with the same precision that we expect for medicines, or is the current approach enough? More research will likely lead us to a more definite conclusion, but I’m curious what your thoughts are
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Yes. Not just for medical patients.
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I agree, but I think @primomeds makes a good point that thousands of conversion liters are still being sold, but they likely wouldn’t be if there was a substantial difference in the psychoactive properties. What are your thoughts on the study?
I disagree with this statement. I seem to remember that there have been pretty extensive discussions on the topic here in other threads, and a good number of the people I know who consume THC - I can’t anymore, it fucks with my sleep - have noted a difference.
Those converted liters are massively cheaper. “Doesn’t get me as high, but it’s way cheaper” is definitely a conscious trade-off many consumers would make.
I also wouldn’t be surprised if many consumers were so used to there being significant variability between products in the market that they write off the first experience or two being not as strong or different as just the way things go, then they get used to it.
I’m just a dumb mechanical engineer who throws pumps and filters at things, I’m not about to claim that I’m smart or educated enough to comment on the paper.
I get the feeling that @Photon_noir or @cyclopath or @moronnabis might be more qualified to comment than I am, or know who else would be.
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Is there evidence that the main conversion methods people are using generate mostly (+)-cis-D9-THC? I can’t access most of the references but it seems like the (+)-cis they used for this study was made via total synthesis and the first reference suggests that reacting CBD with HCl generates primarily (-)-trans. Better characterization of the composition of converted THC would certainly be interesting, especially with industrial samples rather than something made in an academic chemistry lab at a smaller scale with likely higher quality reagents.
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For anything medical, yeah, you need good standardized testing. The thing is though - medical programs are selling products like flower, rosin and vapes which are inherently going to be super inconsistent from each other. You have products here that combine hundreds of plant ingredients together. It’s literally impossible to standardize any kind of dosage like that - how can you possibly compare any two strains when you have a whole slew of minor cannabinoids affecting the potency and result?
This is why products like marinol and epidolex are created, it solves that problem at the expense of what users would consider attributes making cannabis a pleasurable experience.
Medical cannabis is legalized mainstream psychoactive herbal medicine, you simply cannot apply pharmaceutical standards in dosage to it.
In terms of testing, sure, you can spend more time and money conducting far more granular testing on products, but what does that mean exactly to the consumer? How are they going to interpret the content of dozens of isomers of different cannabinoids?
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Point to be made here about converted liters is that they aren’t including the usual suspects in terms of minor cannabinoids that a natural distillate would. CBD → D9 isn’t generating CBG, CBC and other cannabinoids as byproducts.
A study conducted at our university showed that the major product was the (-)-trans enantiomer, though the (+)-trans enantiomer was also consistently formed, with concentration ratios reaching as high as 5:1. I initially came across another study suggesting that the cis diastereomers were the major products, but after further research, I believe that interpretation was incorrect, and my original headline was misleading based on the study I cited.
However, a 1981 study by Billy R. Martin demonstrated that the (+)-trans enantiomer is significantly less potent than its (-)-trans counterpart, with potency differences ranging from 5.6-fold to as much as 100-fold. So while the study I provided doesn’t provide the full picture, the statement in the headline remains true.
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This makes a lot of sense and I agree with your take. Thanks for sharing!
Well you’re here, so you’re obviously not that dumb! Thank you for being real though and giving your thoughts
I respect and value your perspective. I believe that you’re right, and with an herbal medicine that has so many different variations from strain to strain, it’s nearly impossible to standardize dosing. Thank you for bringing up the pharmaceutical products too, that was an important perspective that I hadn’t considered.
My main issue is with producers advertising their product as something it’s not. If I was an operator or a consumer and looking to purchase some D9-THC oil, I wouldn’t want 15-20%+ of the compound to be an enantiomer that doesn’t produce the same effect as the natural version.
In that case I’d be curious to see the same binding and functional assays performed with various ratios of the enantiomers to see if any kind of competitive inhibition arises.
I’d definitely like to help consumers better understand the products they are buying but in my experience most of them have no idea how any of this stuff is made and they are primarily driven by price, so the market will likely go for the most cost effective production methods even if the efficacy and safety profiles are not established. Regulators also seem to have very little understanding of the chemistry and pharmacology/toxicology at play so it would take a lot of work from advocates within the industry to establish higher standards for cannabis products.
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That’s a great idea for a study. I’ll bring it up with my PI and see if he has any students who might be interested in taking it on. Thank you for the suggestion!
I completely agree with your second point as well. The general population’s mindset is definitely shifting toward more health-conscious consumer choices, but it will take time, and I’m not sure how well that shift will carry over to intoxicating CPG products. I believe the best place to start raising standards for cannabis products is through discussions on forums like this one, followed by continued conversations with organizations such as ASTM or CannRA.
Do you see more consistent, or higher, standards being implemented across the industry before federal action takes place? Even with the current hemp bill discussions, it feels like legislators tend to side with whoever has the deepest pockets.
If you have resources for research I’d like to see more work on terpenoid based allosteric modulation of CB1 and CB2 receptors in response to THC and other minor cannabinoids, whether it be biased agonism or differential dimerization with other GPCRs. I would guess that at least some of the entourage effect could be explained that way and I think there is more value in developing a deeper understanding of the positive effects of more natural extracts rather than proving that side products of synthetic methods are less beneficial.
As for raising the bar on industrial standardization, I would personally prefer to see it come from a place of better consumer education and desire for higher quality over increased regulation influenced by big money or fear of a public health crisis. Given the extensive and robust distribution networks that have already been established by the illicit market over many years, and the large influx in capital equipment from the unintended effects of the farm bill, over regulating cannabis and driving the costs up for licensed producers would likely result in a surge of unregulated sales. I will say that I am obviously biased because I work in the licensed market so I’d like to go down the route that allows me to make the products I want to consume and make enough money to live the way I want.
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CB1 is a very complicated receptor. Let alone the functional assays involving down stream G proteins and arrestins. And how all that relates to top down, conscious evaluation of the “High”…is right out the latest theories on emergent causation.
Binding studies of subtle conformational changes of a partial agonist..are going to be difficult to design. Even designing the buffer to get the ligands into solution comes with caveats such as detergents . You are going to need some sort of an HPLC chiral- affinity column just to isolate the enantiomers to sufficient purity . Lots of work and lots of money.
@jollygreengiant.420 I’m not sure you’re going to find one of your PI’s students to take this on in any meaningful way. There are far more interesting questions in cannabinoid-GPCR receptor science.
@Lincoln20XX : If it gets you high and you can sell it , you are in business. A good example is West African “KUSH”…even if your legs rot off and it kills you…people will buy it and use it.
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I agree when it comes to traditional extractions.
When it comes to products of synthesis, I’m of the opinion that that’s a whole different risk profile and should be regulated/tested accordingly. Of course, even figuring out what should be tested for/regulated is a massive problem that is well beyond the capacity of the average “think of the children!” screeching we get in place of thoughtful regulation.
Sadly true. Not a game I’m willing to play, but there are always ones who will.
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