So the linked study being used to justify these claims was about supplementing Acetaminophen (paracetamol) with CBD. But Acetaminophen also doesn't pass efficacy tests on its own, but it's still...
All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little evidence to support the efficacy of acetaminophen treatment in patients with chronic pain conditions. Assessment of continuous efficacy in the many patients using acetaminophen worldwide is recommended.
Ancedotally, CBD on its own doesn't do much for me ingested. But as a balm it does as-well or better than other balms for my muscle pains. And my wife has had good luck with balanced hybrid flower for managing menstrual pain. IMO studying CBD on its own is the wrong path...THC serves a better painkilling function because when you're high, the pain bothers you less (your mileage may vary).
My father-in-law uses high-THC as an opioid alternative for his massive post-multiple-surgery chronic pain. It's much less-bad than opioids for prolonged treatment, which is probably why the pharmaceutical industry is not enthusiastic about fully decriminalized marijuana. Even when he's high out of his mind, he's still far more coherent and pleasant to be around than my grandfather whom was on a constant morphine drip for the last 10 years of his life.
Aside from the "APAP is a lie" FUD... Acetaminophen uses the cannabinoid pathways to modulate pain tolerance. This is exactly the result that anybody with a foundational understanding of both...
Aside from the "APAP is a lie" FUD...
Acetaminophen uses the cannabinoid pathways to modulate pain tolerance. This is exactly the result that anybody with a foundational understanding of both drugs' mechanisms of action would anticipate. Beyond that, it's common knowledge in the medical cannabis field that CBD in iso is fairly ineffective, and is best utilized in combination with a stronger cannabinoid like THC to modulate the effects of, rather than as a solo treatment for...almost everything.
Beside everything else, of note is the quote from the first author:
CBD is not an alternative for pain therapy for osteoarthritis of the knee
Which is not interchangeable with pain in general. As mentioned in the article, the the first-line painkillers are diclofenac, ibuprofen, and tramadol. Both of the first two are NSAIDs. That class of drugs is almost theoretically ideal for treating arthritic bone pain. Tramadol is an opioid, but a weird one: it's an antidepressant too. If you look into further resorts for arthritis, antidepressants tend to be quite commonly prescribed. Why? Because arthritis is horrible to live with and hard to treat. So you have the nearly perfect drugs and what is an essentially mediocre (in terms of analgesic efficacy) opioid plus an antidepressant as the implicit standard to beat.
It's a shame that CBD didn't help more than APAP, or enhance its minimal effects on bone pain, but this article is not responsible reporting, and the headline on Tildes at the time of writing only exacerbates the misinformation. For heaven's sake, they say it's a placebo-controlled study, when the abstract of the article says otherwise. EDIT: To be fair and clear, I misspoke here. This is a form of placebo-controlled study, but such a distinct one from the typical that it rises to negligence for the specific methodology to be left out. Almost no laypeople are going to think about them when only one of the drugs is named.
I want to push back on this reasoning a little. This isn't the first study of its kind and as far as I'm aware there is very little evidence that CBD does help treat pain. There isn't a body of...
I want to push back on this reasoning a little.
This isn't the first study of its kind and as far as I'm aware there is very little evidence that CBD does help treat pain. There isn't a body of evidence to support the anecdotal claims.
As you said Acetaminophen may involve CB1 receptors in it's mechanism of action, but if some interference was occuring you'd expect that to show in some way. We don't see any change at all. It's odd to postulate that Acetaminophen is neutralizing any additive effect of CBD while CBD has no effect on Acetaminophen.
As an aside, I'm fairly certain there is absolutely no high quality evidence CBD is good for anything in doses less than 500mg. I'm pretty sure the studies that found anything related to anxiety or whatever gave huge 500mg+ doses.
In this study they use a 600mg dose, and it still doesn't do anything for pain.
Point being, the ubiquitous 5-20mg gummies that people are taking are most likely placebo.
I'm not arguing that it does. What I'm saying is that the pathway we know works for APAP is functionally identical to the purported pathway for CBD, should it treat pain. And we know that CBD...
I'm not arguing that it does. What I'm saying is that the pathway we know works for APAP is functionally identical to the purported pathway for CBD, should it treat pain. And we know that CBD doesn't treat pain at low doses. So administering a drug that's meant to do almost exactly what the subject of the study is supposed to be doing very well may supply all the signaling along those pathways which CBD would be hypothetically adding onto. It isn't about CBD or acetaminophen effecting one another, it's the idea that taking a morphine tablet after your oxycodone is already kicking in won't do shit.
You seem to think I'm defending CBD. I am not. I don't give a shit how well it works. What I care about is this inexplicably misinterpreted research as extending to all pain, when osteoarthritis is a multifaceted cluster of horrors. Hell, screw 20 mg being placebo, outside of legal states and rare trustworthy vendors, you're probably not even getting CBD.
The only intuition I have here is that when CBD is administered via inhalation alongside THC, it changes the latter's effects significantly, including an increase in analgesia and sedation. I'm really not applying that to anything except for the line that's actually in agreement with you:
CBD in iso is fairly ineffective, and is best utilized in combination with a stronger cannabinoid like THC to modulate the effects of
So I don't really understand why you felt the need to push back on that line of reasoning I hadn't made. It feels like you're trying to turn a criticism of methods and practice into an argument about how much CBD does or doesn't work. That's what the science is for, and this study is flimsy.
That's a pretty big claim and I definitely don't think the paper you linked previously supports it. The average reader on this site sees this article and reads the comments to see if they can...
What I'm saying is that the pathway we know works for APAP is functionally identical to the purported pathway for CBD, should it treat pain.
That's a pretty big claim and I definitely don't think the paper you linked previously supports it.
So I don't really understand why you felt the need to push back on that line of reasoning I hadn't made.
The average reader on this site sees this article and reads the comments to see if they can trust the results. I don't disagree with you that this isn't a perfect study design. I made my comment because regardless of this study's limitations, there is insufficient evidence that CBD offers effective pain relief, this is only one paper of many and the evidence seems stacked against CBDs favour.
I wanted to communicate this and replying to your comment seemed like a good way to do so.
I also generally agree with the researchers that:
Although the study design cannot absolutely rule out an ability of paracetamol to partially hide a minor analgesic effect of CBD in painful KOA, our trial did not point to such an analgesic activity of CBD. The clinical relevance of a potential analgesic contribution of CBD, small enough to escape our present investigational approach, should be considered more than questionable.
No, that article does not support my opinion, which was based on broader research. I may be wrong. Did I not say I really don't care about the result of the CBD-as-analgesic research? Was that...
No, that article does not support my opinion, which was based on broader research. I may be wrong.
Did I not say I really don't care about the result of the CBD-as-analgesic research? Was that ever the primary concern?
My primary concern is with this article linked here. My hunches are irrelevant to that. Its content not in accordance with the Lancet article it cites. It misrepresents the methodology and interpretation of the outcome. It conflates a particular form of pain with all others. Those are my primary concerns.
I want to point out that CBD is actually an antagonist of cannabinoid receptors, compared to acetaminophen, which appears to enhance cannabinoid signaling. So theoretically, CBD should inhibit the...
I'm not arguing that it does. What I'm saying is that the pathway we know works for APAP is functionally identical to the purported pathway for CBD, should it treat pain. And we know that CBD doesn't treat pain at low doses. So administering a drug that's meant to do almost exactly what the subject of the study is supposed to be doing very well may supply all the signaling along those pathways which CBD would be hypothetically adding onto. It isn't about CBD or acetaminophen effecting one another, it's the idea that taking a morphine tablet after your oxycodone is already kicking in won't do shit.
I want to point out that CBD is actually an antagonist of cannabinoid receptors, compared to acetaminophen, which appears to enhance cannabinoid signaling. So theoretically, CBD should inhibit the pain relieving effect of acetaminophen, which I think actually strengthens the point you're trying to make. It's possible CBD relieves pain through some other mechanism (it's also an allosteric modulator of opioid receptors, and has various anti-inflammatory and immunomodulatory properties), but reducing the cannabinergic effects of acetaminophen could account for the poor results of this study.
CBD is not an antagonist of either cannabinoid receptor. It does seem like it may be a negative allosteric modulator of CB1, which is why you aren't off-base. The distinction is very meaningful,...
CBD is not an antagonist of either cannabinoid receptor. It does seem like it may be a negative allosteric modulator of CB1, which is why you aren't off-base. The distinction is very meaningful, as it's the difference between allowing attenuated signalling through the same channels and blocking it. Compare people administering CBD under their tongues when they overdo it to the way naloxone reverses opioid effects. The former is a mild effect that doesn't seem to be doing anything but calming down the chaos, the latter is intense and can be considered to immediately throw someone into withdrawal. There are so many problems with that illustration for it to be taken seriously, but that's the extreme end of the divide for, again, illustration.
But that's not what I was referring to, actually. As the above review discusses, CBD has a major effect on FAAH, an enzyme which breaks down endogenous cannabinoids like anandamide and 2-AG. Acetaminophen is currently best-assumed to work via metabolism into AM404, which acts as a strong inhibitor of cannabinoid reuptake, causing those same endogenous cannabinoids to have a larger effect, in what could be construed as a more direct action as compared to the FAAH inhibition mechanism.
I've seen research which suggests cannabidiol is in fact CB1/CB2 antagonist and at low concentrations, an inverse agonist ("[...] CBD can behave as a CB1 receptor ‘inverse agonist' at...
I've seen research which suggests cannabidiol is in fact CB1/CB2 antagonist and at low concentrations, an inverse agonist ("[...] CBD can behave as a CB1 receptor ‘inverse agonist' at concentrations below those at which it undergoes significant binding to the CB1 orthosteric site."). So perhaps the science isn't fully settled. Nonetheless, we're in agreement that it has some anti-cannabinergic properties.
I will mention that allosteric modulation is not always a weaker or attenuated compared to orthosteric activity. Allosteric modulation, while mechanistically indirect, can still be very powerful. For instance, barbiturates are positive allosteric modulators at GABA-A receptors, and they are potentially very powerful, with a very low therapeutic index (this danger being why they have been largely superseded by benzodiazepines). If you want to assess how much an antagonist affects receptor function, you need to look at binding affinity (for a silent antagonist) or intrinsic activity (for an inverse agonist), though of course there are always other factors at play.
It's true that CBD has pro-cannabinergic effects through its effects on FAAH, but I think it's hard to say whether these would be outweighed through its cannabinoid receptor antagonism (or negative allosteric modulation). I agree that the study in question doesn't really do a good job of compensating for or even acknowledging this issue.
That's interesting. I'm not sure how you'd distinguish a NAM physically occluding the orthostatic site from an antagonist though, and I haven't seen any more-recent research that backs up that...
That's interesting. I'm not sure how you'd distinguish a NAM physically occluding the orthostatic site from an antagonist though, and I haven't seen any more-recent research that backs up that interpretation of the data. Thanks for the link though, I'll enjoy it.
I really tried to skate over all of that, because this isn't really a study review club. I'm very aware of the mechanisms there, and you didn't mention that barbiturates are dangerous as compared to benzodiazepines specifically due to their dual-action of GABA agonism and PAM, where benzos et al only act as allosteric modulators. I was writing far more for the passersby than you, since you had a remote grasp on the issues with this article.
I think it suffices to say right now that there's a strong body of evidence for mild to moderate anticannabinergic signalling. The way that research you linked points away from any sort of competitive binding at CB receptors makes me wary to go so far as to say CBD is likely to inhibit the effects of APAP, but yeah. Either way it's gonna be way too much interference to discern. This model is a mess, and the pop-facing article is a travesty.
Could you elaborate on this? Almost every recent study I could find essentially says 'APAP is not showing to be effective at managing chronic pain, more wide-scale research is needed to study if...
Aside from the "APAP is a lie" FUD...
Could you elaborate on this?
Almost every recent study I could find essentially says 'APAP is not showing to be effective at managing chronic pain, more wide-scale research is needed to study if it should still be prescribed as a first-line treatment.'
I'm OK with placebos being used as first-line treatment for pain, given how some chronic pain is psychological more than physiological. But there is a difference between 'we think APAP is effective' and 'APAP is a useful placebo'.
But yes, my primary concern is that the methods in the study were questionable and that the reporting on it was doubly so.
Most pain is not chronic pain. That's what it comes down to. Life-altering injury can't be papered over with a tylenol. That doesn't indicate it won't help minor or major trauma.
Most pain is not chronic pain. That's what it comes down to. Life-altering injury can't be papered over with a tylenol. That doesn't indicate it won't help minor or major trauma.
It's not even a great option for acute pain. Aside from tension headaches, it's generally not that much better than placebo. It has its place, given that it's fairly safe at lower doses where...
Look, I don't understand how you're reading that review. And they rate that difference in effect size as the distinction between the "Fair" label and "Good" referring to evidentiary strength in...
Look, I don't understand how you're reading that review.
acetaminophen in a dose of 1,000 mg had an NNT of 4.6 (95 percent confidence interval [CI], 3.8 to 5.4) for at least 50 percent pain relief versus placebo.
Direct comparative studies between acetaminophen (1,000-mg dose) and NSAIDs show that NSAIDs are more effective than acetaminophen in some situations (e.g., dental and menstrual pain), but provide equivalent analgesia in others (e.g., orthopedic surgery and tension headache).
the oldest COX-2 inhibitor, celecoxib, showed fair to good efficacy for postoperative pain with an NNT of 4.5 (95 percent CI, 3.3 to 7.2) compared with placebo.
And they rate that difference in effect size as the distinction between the "Fair" label and "Good" referring to evidentiary strength in the chart of recommended painkillers. So this paper says that, compared to opioids and NSAIDs, APAP is not great at killing pain. It also says that it's superior to aspirin, codeine, and propoxyphene for analgesia, and a better risk/benefit ratio than tramadol.
Acetaminophen is approved in nearly every regulatory framework for killing pain, is one of the most-administered and prescribed medicines on the planet, and is considered a crucial drug for any and all medical practices by the WHO. At that rate of exposure and research, given the data we have, "placebo" is an entirely misplaced conclusion. That much use, especially in emergency applications, really makes a comparison with nearly all other medically-recognized analgesics where it comes out middle of the pack incredibly unconvincing as justification for "not much better than placebo". You'll note they aren't comparing it to kisses on the booboo, a good hug, or a nice cup of mint tea. If you want to see what placebos look like on paper, consider some of the effect sizes for the most prescribed classes of psych drugs. Even those, if you told a psychiatrist they were basically a placebo, they'd have a lot of reasons to push back.
I am running on little sleep now, so yea I'm probably being a bit overly hyperbolic. Won't disagree about the psych drugs though. My psychiatrist and I have had long conversations about how...
I am running on little sleep now, so yea I'm probably being a bit overly hyperbolic.
Won't disagree about the psych drugs though. My psychiatrist and I have had long conversations about how powerful placebo is for mental health. New mental health drugs have had trouble passing efficacy tests because the placebo effect is getting stronger, and nobody knows why. There's been a bit of a push to find other drugs with off-label uses for such reasons...bypasses much of the approval process.
And as he's put it: Because the effectiveness and side effects for any given pill (or combo thereof) for any given patient is such a broad crapshoot, having more tools in the toolbox is always a good thing. He stated he periodically uses placebos as one of those tools, because the strong effect means that for some patients, it's cheaper and more effective than the latest-and-greatest non-generic that the pill-pushers are selling.
It's really not a you problem, there are a ton of spam blogs misrepresenting the research of acetaminophen popping up lately, and if you don't spend a lot of time consulting these sorts of...
It's really not a you problem, there are a ton of spam blogs misrepresenting the research of acetaminophen popping up lately, and if you don't spend a lot of time consulting these sorts of research, it's really hard to tell where they're misleading the reader. Yes, it has been shown to be less effective than previously thought for specific forms of pain, like tension headaches and back pain, but these sites are teaching a lot of laypeople to interpret anything that isn't treating chronic back pain as a placebo. When I said FUD, I meant it diagnostically.
Yeah, the truth is that since 99% of medicine is "did you die? did us poking you that way make you more likely to die? no? hell yeah, mission accomplished", psychiatric medicine is in a horrible spot. The doctors who're honest with their patients, like yours, are incredibly deserving of respect, to deal with such a horrible structure and such poor tools just to try and help people struggle through even bigger horrible structures. However, there are a lot of medications that even the psychiatric field have come around on, which still have effectively no road to widespread application, like ketamine and MDMA therapies. How dare people who struggle with trusting themselves spend an afternoon feeling good, we'd better figure out a way to isolate the therapy from that. Silver lining though, beyond things like "did you like celexa? try the good version of celexa we've had on the shelf for thirty years!", the delving into various preapproved drugs in novel combinations and applications is at least useful for risk assessment.
Phrase of the month material. I'm gonna relay that to him. He'll probably get a Tshirt made.
Yeah, the truth is that since 99% of medicine is "did you die? did us poking you that way make you more likely to die? no? hell yeah, mission accomplished"
Phrase of the month material. I'm gonna relay that to him. He'll probably get a Tshirt made.
Thanks, I've spent a lot of time trying to figure out the right ways to communicate that idea. It's woefully underappreciated in popular understandings of medical practices.
Thanks, I've spent a lot of time trying to figure out the right ways to communicate that idea. It's woefully underappreciated in popular understandings of medical practices.
So... what? The control group was also on paracetamol. If the treatment had been found to be effective, one could argue that the effect may have been caused by an interaction between the two...
So the linked study being used to justify these claims was about supplementing Acetaminophen (paracetamol) with CBD.
So... what? The control group was also on paracetamol. If the treatment had been found to be effective, one could argue that the effect may have been caused by an interaction between the two rather than CBD alone, but no significant effect was found. Are you proposing that we need another study to rule out the possibility that paracetamol inhibits the effects of CBD?
Maybe the tylenol does inhibit the cbd. This is just one study. It squares with my experience though. I get very little physical benefit. I Do find a small dose of thc (just barely feeling...
Maybe the tylenol does inhibit the cbd. This is just one study.
It squares with my experience though. I get very little physical benefit. I Do find a small dose of thc (just barely feeling effects) plus a big dose of cbd does well for nighttime anxiety and sleeplessness.
Because the conclusions they were drawing in the article is that CBD is useless based on a study that didn't study CBD on its own. And then comparing it to something else that is widely...
Because the conclusions they were drawing in the article is that CBD is useless based on a study that didn't study CBD on its own. And then comparing it to something else that is widely prescribed, dangerous to the liver, and also doesn't pass efficacy tests. We have no data from this study if CBD is more or less effective (or dangerous) than Paracetamol on its own. Yet they are claiming CBD has no benefit and other options should be explored.
Like, they were giving people 3g/day of paracetamol. 4g/day is the threshold for severe liver damage. You add a drink of alcohol, or pretty much anything else that taxes the liver a bit, and you're in danger territory easily. They say they found increase danger when combining the two, but didn't test CBD on its own? Highly sus.
It's then often used as fuel to stoke prohibition fires.
Paracetamol == useless == Fine to keep prescribing and studying as the primary pain deterrent.
CBD == useless == Danger to society, ban it and keep researching other patentable drugs that people can't grow in their backyard.
They weren't doing that though. Again, BOTH groups got the paracetamol. It's just background noise, unless the two are interacting. Good point. That does sound like a likely interaction. But...
And then comparing it to something else that is widely prescribed, dangerous to the liver, and also doesn't pass efficacy tests.
They weren't doing that though. Again, BOTH groups got the paracetamol. It's just background noise, unless the two are interacting.
They say they found increase danger when combining the two, but didn't test CBD on its own?
Good point. That does sound like a likely interaction. But that's really not the focus of the study and they don't make a big deal out of it. The discussion is focused on the analgesic effects. The strongest statement about the liver stuff I could find was:
Close monitoring of liver parameters is therefore recommended and should be mandatory when commencing CBD therapy.
And they're definitely not claiming that paracetamol is any good. Also from the discussion:
There is general consensus on a rather low or almost negligible analgesic potency of paracetamol in low back pain and painful OA.
I agree. More work should be done focusing on the array of cannabinoids found in flower and their interactions. I used to think the terpene talk was hogwash, but now that I've been in a...
IMO going down CBD on its own is the wrong path...
I agree. More work should be done focusing on the array of cannabinoids found in flower and their interactions. I used to think the terpene talk was hogwash, but now that I've been in a recreational state with reliable sources, there does seem to be a consistency between flower of similar terp profiles. Is it the terpenes themselves? Or do they just indicate particular cannabinoid profiles?
We're starting to see more attention given to CBG, I'm interested to see what we find there. Anything that can get us further from opiate based treatments is worth checking out.
My issue with these studies is what you've hit the nail on the head for: They're testing hemp instead of marijuana. You need the THC to "activate" the actual CBD to do anything.. Hemp has no THC...
Any time I see any products claiming to be CBD but are from hemp, I just walk on by. Even if I have to pay more, and go out of my way to go to a dispensary, at least I know the CBD I take for pain will actually work if I go this route.
CBD is one of those things that triggers my snake-oil alarm big time. Mainly because there are so many health claims (almost to the point of absurdity in some cases), and comes packaged in a...
CBD is one of those things that triggers my snake-oil alarm big time. Mainly because there are so many health claims (almost to the point of absurdity in some cases), and comes packaged in a comical number of unregulated products (tinctures, pills, gummies, food, drinks, skin creams, soaps, shampoos, bath bombs, dog treats). And the people I know who use it absolutely swear by it and behave strangely in the face of questions about whether it actually works or not (sometimes getting upset or angry)... I have a hard time distinguishing it in my mind from all the other homeopathic/herbal/alt-med products out there that make similar claims and have similar followings but don't hold up under proper scientific scrutiny.
So the linked study being used to justify these claims was about supplementing Acetaminophen (paracetamol) with CBD. But Acetaminophen also doesn't pass efficacy tests on its own, but it's still the #1 prescribed painkiller on the planet.
Ancedotally, CBD on its own doesn't do much for me ingested. But as a balm it does as-well or better than other balms for my muscle pains. And my wife has had good luck with balanced hybrid flower for managing menstrual pain. IMO studying CBD on its own is the wrong path...THC serves a better painkilling function because when you're high, the pain bothers you less (your mileage may vary).
My father-in-law uses high-THC as an opioid alternative for his massive post-multiple-surgery chronic pain. It's much less-bad than opioids for prolonged treatment, which is probably why the pharmaceutical industry is not enthusiastic about fully decriminalized marijuana. Even when he's high out of his mind, he's still far more coherent and pleasant to be around than my grandfather whom was on a constant morphine drip for the last 10 years of his life.
Aside from the "APAP is a lie" FUD...
Acetaminophen uses the cannabinoid pathways to modulate pain tolerance. This is exactly the result that anybody with a foundational understanding of both drugs' mechanisms of action would anticipate. Beyond that, it's common knowledge in the medical cannabis field that CBD in iso is fairly ineffective, and is best utilized in combination with a stronger cannabinoid like THC to modulate the effects of, rather than as a solo treatment for...almost everything.
Beside everything else, of note is the quote from the first author:
Which is not interchangeable with pain in general. As mentioned in the article, the the first-line painkillers are diclofenac, ibuprofen, and tramadol. Both of the first two are NSAIDs. That class of drugs is almost theoretically ideal for treating arthritic bone pain. Tramadol is an opioid, but a weird one: it's an antidepressant too. If you look into further resorts for arthritis, antidepressants tend to be quite commonly prescribed. Why? Because arthritis is horrible to live with and hard to treat. So you have the nearly perfect drugs and what is an essentially mediocre (in terms of analgesic efficacy) opioid plus an antidepressant as the implicit standard to beat.
It's a shame that CBD didn't help more than APAP, or enhance its minimal effects on bone pain, but this article is not responsible reporting, and the headline on Tildes at the time of writing only exacerbates the misinformation. For heaven's sake, they say it's a placebo-controlled study, when the abstract of the article says otherwise. EDIT: To be fair and clear, I misspoke here. This is a form of placebo-controlled study, but such a distinct one from the typical that it rises to negligence for the specific methodology to be left out. Almost no laypeople are going to think about them when only one of the drugs is named.
I want to push back on this reasoning a little.
This isn't the first study of its kind and as far as I'm aware there is very little evidence that CBD does help treat pain. There isn't a body of evidence to support the anecdotal claims.
As you said Acetaminophen may involve CB1 receptors in it's mechanism of action, but if some interference was occuring you'd expect that to show in some way. We don't see any change at all. It's odd to postulate that Acetaminophen is neutralizing any additive effect of CBD while CBD has no effect on Acetaminophen.
As an aside, I'm fairly certain there is absolutely no high quality evidence CBD is good for anything in doses less than 500mg. I'm pretty sure the studies that found anything related to anxiety or whatever gave huge 500mg+ doses.
In this study they use a 600mg dose, and it still doesn't do anything for pain.
Point being, the ubiquitous 5-20mg gummies that people are taking are most likely placebo.
I'm not arguing that it does. What I'm saying is that the pathway we know works for APAP is functionally identical to the purported pathway for CBD, should it treat pain. And we know that CBD doesn't treat pain at low doses. So administering a drug that's meant to do almost exactly what the subject of the study is supposed to be doing very well may supply all the signaling along those pathways which CBD would be hypothetically adding onto. It isn't about CBD or acetaminophen effecting one another, it's the idea that taking a morphine tablet after your oxycodone is already kicking in won't do shit.
You seem to think I'm defending CBD. I am not. I don't give a shit how well it works. What I care about is this inexplicably misinterpreted research as extending to all pain, when osteoarthritis is a multifaceted cluster of horrors. Hell, screw 20 mg being placebo, outside of legal states and rare trustworthy vendors, you're probably not even getting CBD.
The only intuition I have here is that when CBD is administered via inhalation alongside THC, it changes the latter's effects significantly, including an increase in analgesia and sedation. I'm really not applying that to anything except for the line that's actually in agreement with you:
So I don't really understand why you felt the need to push back on that line of reasoning I hadn't made. It feels like you're trying to turn a criticism of methods and practice into an argument about how much CBD does or doesn't work. That's what the science is for, and this study is flimsy.
That's a pretty big claim and I definitely don't think the paper you linked previously supports it.
The average reader on this site sees this article and reads the comments to see if they can trust the results. I don't disagree with you that this isn't a perfect study design. I made my comment because regardless of this study's limitations, there is insufficient evidence that CBD offers effective pain relief, this is only one paper of many and the evidence seems stacked against CBDs favour.
I wanted to communicate this and replying to your comment seemed like a good way to do so.
I also generally agree with the researchers that:
No, that article does not support my opinion, which was based on broader research. I may be wrong.
Did I not say I really don't care about the result of the CBD-as-analgesic research? Was that ever the primary concern?
My primary concern is with this article linked here. My hunches are irrelevant to that. Its content not in accordance with the Lancet article it cites. It misrepresents the methodology and interpretation of the outcome. It conflates a particular form of pain with all others. Those are my primary concerns.
I want to point out that CBD is actually an antagonist of cannabinoid receptors, compared to acetaminophen, which appears to enhance cannabinoid signaling. So theoretically, CBD should inhibit the pain relieving effect of acetaminophen, which I think actually strengthens the point you're trying to make. It's possible CBD relieves pain through some other mechanism (it's also an allosteric modulator of opioid receptors, and has various anti-inflammatory and immunomodulatory properties), but reducing the cannabinergic effects of acetaminophen could account for the poor results of this study.
CBD is not an antagonist of either cannabinoid receptor. It does seem like it may be a negative allosteric modulator of CB1, which is why you aren't off-base. The distinction is very meaningful, as it's the difference between allowing attenuated signalling through the same channels and blocking it. Compare people administering CBD under their tongues when they overdo it to the way naloxone reverses opioid effects. The former is a mild effect that doesn't seem to be doing anything but calming down the chaos, the latter is intense and can be considered to immediately throw someone into withdrawal. There are so many problems with that illustration for it to be taken seriously, but that's the extreme end of the divide for, again, illustration.
But that's not what I was referring to, actually. As the above review discusses, CBD has a major effect on FAAH, an enzyme which breaks down endogenous cannabinoids like anandamide and 2-AG. Acetaminophen is currently best-assumed to work via metabolism into AM404, which acts as a strong inhibitor of cannabinoid reuptake, causing those same endogenous cannabinoids to have a larger effect, in what could be construed as a more direct action as compared to the FAAH inhibition mechanism.
I've seen research which suggests cannabidiol is in fact CB1/CB2 antagonist and at low concentrations, an inverse agonist ("[...] CBD can behave as a CB1 receptor ‘inverse agonist' at concentrations below those at which it undergoes significant binding to the CB1 orthosteric site."). So perhaps the science isn't fully settled. Nonetheless, we're in agreement that it has some anti-cannabinergic properties.
I will mention that allosteric modulation is not always a weaker or attenuated compared to orthosteric activity. Allosteric modulation, while mechanistically indirect, can still be very powerful. For instance, barbiturates are positive allosteric modulators at GABA-A receptors, and they are potentially very powerful, with a very low therapeutic index (this danger being why they have been largely superseded by benzodiazepines). If you want to assess how much an antagonist affects receptor function, you need to look at binding affinity (for a silent antagonist) or intrinsic activity (for an inverse agonist), though of course there are always other factors at play.
It's true that CBD has pro-cannabinergic effects through its effects on FAAH, but I think it's hard to say whether these would be outweighed through its cannabinoid receptor antagonism (or negative allosteric modulation). I agree that the study in question doesn't really do a good job of compensating for or even acknowledging this issue.
That's interesting. I'm not sure how you'd distinguish a NAM physically occluding the orthostatic site from an antagonist though, and I haven't seen any more-recent research that backs up that interpretation of the data. Thanks for the link though, I'll enjoy it.
I really tried to skate over all of that, because this isn't really a study review club. I'm very aware of the mechanisms there, and you didn't mention that barbiturates are dangerous as compared to benzodiazepines specifically due to their dual-action of GABA agonism and PAM, where benzos et al only act as allosteric modulators. I was writing far more for the passersby than you, since you had a remote grasp on the issues with this article.
I think it suffices to say right now that there's a strong body of evidence for mild to moderate anticannabinergic signalling. The way that research you linked points away from any sort of competitive binding at CB receptors makes me wary to go so far as to say CBD is likely to inhibit the effects of APAP, but yeah. Either way it's gonna be way too much interference to discern. This model is a mess, and the pop-facing article is a travesty.
Could you elaborate on this?
Almost every recent study I could find essentially says 'APAP is not showing to be effective at managing chronic pain, more wide-scale research is needed to study if it should still be prescribed as a first-line treatment.'
I'm OK with placebos being used as first-line treatment for pain, given how some chronic pain is psychological more than physiological. But there is a difference between 'we think APAP is effective' and 'APAP is a useful placebo'.
But yes, my primary concern is that the methods in the study were questionable and that the reporting on it was doubly so.
Most pain is not chronic pain. That's what it comes down to. Life-altering injury can't be papered over with a tylenol. That doesn't indicate it won't help minor or major trauma.
It's not even a great option for acute pain. Aside from tension headaches, it's generally not that much better than placebo.
It has its place, given that it's fairly safe at lower doses where others might not be. And its a great fever reducer.
Look, I don't understand how you're reading that review.
And they rate that difference in effect size as the distinction between the "Fair" label and "Good" referring to evidentiary strength in the chart of recommended painkillers. So this paper says that, compared to opioids and NSAIDs, APAP is not great at killing pain. It also says that it's superior to aspirin, codeine, and propoxyphene for analgesia, and a better risk/benefit ratio than tramadol.
Acetaminophen is approved in nearly every regulatory framework for killing pain, is one of the most-administered and prescribed medicines on the planet, and is considered a crucial drug for any and all medical practices by the WHO. At that rate of exposure and research, given the data we have, "placebo" is an entirely misplaced conclusion. That much use, especially in emergency applications, really makes a comparison with nearly all other medically-recognized analgesics where it comes out middle of the pack incredibly unconvincing as justification for "not much better than placebo". You'll note they aren't comparing it to kisses on the booboo, a good hug, or a nice cup of mint tea. If you want to see what placebos look like on paper, consider some of the effect sizes for the most prescribed classes of psych drugs. Even those, if you told a psychiatrist they were basically a placebo, they'd have a lot of reasons to push back.
I am running on little sleep now, so yea I'm probably being a bit overly hyperbolic.
Won't disagree about the psych drugs though. My psychiatrist and I have had long conversations about how powerful placebo is for mental health. New mental health drugs have had trouble passing efficacy tests because the placebo effect is getting stronger, and nobody knows why. There's been a bit of a push to find other drugs with off-label uses for such reasons...bypasses much of the approval process.
And as he's put it: Because the effectiveness and side effects for any given pill (or combo thereof) for any given patient is such a broad crapshoot, having more tools in the toolbox is always a good thing. He stated he periodically uses placebos as one of those tools, because the strong effect means that for some patients, it's cheaper and more effective than the latest-and-greatest non-generic that the pill-pushers are selling.
It's really not a you problem, there are a ton of spam blogs misrepresenting the research of acetaminophen popping up lately, and if you don't spend a lot of time consulting these sorts of research, it's really hard to tell where they're misleading the reader. Yes, it has been shown to be less effective than previously thought for specific forms of pain, like tension headaches and back pain, but these sites are teaching a lot of laypeople to interpret anything that isn't treating chronic back pain as a placebo. When I said FUD, I meant it diagnostically.
Yeah, the truth is that since 99% of medicine is "did you die? did us poking you that way make you more likely to die? no? hell yeah, mission accomplished", psychiatric medicine is in a horrible spot. The doctors who're honest with their patients, like yours, are incredibly deserving of respect, to deal with such a horrible structure and such poor tools just to try and help people struggle through even bigger horrible structures. However, there are a lot of medications that even the psychiatric field have come around on, which still have effectively no road to widespread application, like ketamine and MDMA therapies. How dare people who struggle with trusting themselves spend an afternoon feeling good, we'd better figure out a way to isolate the therapy from that. Silver lining though, beyond things like "did you like celexa? try the good version of celexa we've had on the shelf for thirty years!", the delving into various preapproved drugs in novel combinations and applications is at least useful for risk assessment.
Phrase of the month material. I'm gonna relay that to him. He'll probably get a Tshirt made.
Thanks, I've spent a lot of time trying to figure out the right ways to communicate that idea. It's woefully underappreciated in popular understandings of medical practices.
So... what? The control group was also on paracetamol. If the treatment had been found to be effective, one could argue that the effect may have been caused by an interaction between the two rather than CBD alone, but no significant effect was found. Are you proposing that we need another study to rule out the possibility that paracetamol inhibits the effects of CBD?
Maybe the tylenol does inhibit the cbd. This is just one study.
It squares with my experience though. I get very little physical benefit. I Do find a small dose of thc (just barely feeling effects) plus a big dose of cbd does well for nighttime anxiety and sleeplessness.
Because the conclusions they were drawing in the article is that CBD is useless based on a study that didn't study CBD on its own. And then comparing it to something else that is widely prescribed, dangerous to the liver, and also doesn't pass efficacy tests. We have no data from this study if CBD is more or less effective (or dangerous) than Paracetamol on its own. Yet they are claiming CBD has no benefit and other options should be explored.
Like, they were giving people 3g/day of paracetamol. 4g/day is the threshold for severe liver damage. You add a drink of alcohol, or pretty much anything else that taxes the liver a bit, and you're in danger territory easily. They say they found increase danger when combining the two, but didn't test CBD on its own? Highly sus.
It's then often used as fuel to stoke prohibition fires.
Paracetamol == useless == Fine to keep prescribing and studying as the primary pain deterrent.
CBD == useless == Danger to society, ban it and keep researching other patentable drugs that people can't grow in their backyard.
They weren't doing that though. Again, BOTH groups got the paracetamol. It's just background noise, unless the two are interacting.
Good point. That does sound like a likely interaction. But that's really not the focus of the study and they don't make a big deal out of it. The discussion is focused on the analgesic effects. The strongest statement about the liver stuff I could find was:
And they're definitely not claiming that paracetamol is any good. Also from the discussion:
I agree. More work should be done focusing on the array of cannabinoids found in flower and their interactions. I used to think the terpene talk was hogwash, but now that I've been in a recreational state with reliable sources, there does seem to be a consistency between flower of similar terp profiles. Is it the terpenes themselves? Or do they just indicate particular cannabinoid profiles?
We're starting to see more attention given to CBG, I'm interested to see what we find there. Anything that can get us further from opiate based treatments is worth checking out.
My issue with these studies is what you've hit the nail on the head for: They're testing hemp instead of marijuana. You need the THC to "activate" the actual CBD to do anything.. Hemp has no THC in it so it can't activate the CBD.
Any time I see any products claiming to be CBD but are from hemp, I just walk on by. Even if I have to pay more, and go out of my way to go to a dispensary, at least I know the CBD I take for pain will actually work if I go this route.
CBD is one of those things that triggers my snake-oil alarm big time. Mainly because there are so many health claims (almost to the point of absurdity in some cases), and comes packaged in a comical number of unregulated products (tinctures, pills, gummies, food, drinks, skin creams, soaps, shampoos, bath bombs, dog treats). And the people I know who use it absolutely swear by it and behave strangely in the face of questions about whether it actually works or not (sometimes getting upset or angry)... I have a hard time distinguishing it in my mind from all the other homeopathic/herbal/alt-med products out there that make similar claims and have similar followings but don't hold up under proper scientific scrutiny.