5 ms·

The combination is known as AXS-05 in studies and will be marketed as Auvelity. Interesting combo. Buproprion is an antidepressant by itself, but it also inhib

The combination is known as AXS-05 in studies and will be marketed as Auvelity. Interesting combo. Buproprion is an antidepressant by itself, but it also inhibits the enzymes that break Dextromethorphan down in the body. Taking the two drugs together is not equivalent to taking the same dose of Dextromethorphan alone because Bupropion induces a very different exposure to DXM and its metabolites. Ignore anyone who tries to compare this to recreational DXM consumption because they're quite different. Dextromethorphan gets a lot of attention for being an NMDA antagonist, but fewer people know that it has quite strong affinity for the serotonin transporter (the primary affinity of SSRIs). It also has potentially significant affinity for the sigma-1 receptor, the norepinephrine transporter, and several other receptors that have been noted to be potentially useful for depression modulation. In other words, this feels a little bit like a shotgun approach to poking a wide array of receptors that may or may not be helpful in modulating depressive disorders. I'd take some of the narratives about this being an "NMDA drug like ketamine" with a huuuge grain of salt. People have been trying this combination for several years in DIY fashion (not recommended, but info is out there) since the original study came out. I've seen some reports of good results, other reports of weird side effects that interfered with daily activities. I wouldn't rush to characterize this as a miracle drug or a first-line treatment, but it does seem to help certain patients who haven't seen much benefit from previous drugs. Also worth noting that other studies haven't been as overwhelmingly positive as this one. Axsome Therapeutics (company researching the drug) stumbled a few years ago when their own trial failed to show statistical significance for Bupropion+DXM over Bupropion alone. Later studies seem to have been more positive though.

forbiddenvoid 4y ago
Thank you for explaining the interaction that makes this work. I was very confused for a bit trying to understand how mixing a cough suppressant with an anti-depressant would change the chemistry to the extent highlighted in the study.
Delk 4y ago
> Axsome Therapeutics (company researching the drug) stumbled a few years ago when their own trial failed to show statistical significance for Bupropion+DXM over Bupropion alone. Later studies seem to have been more positive though. Not being familiar with pharma research, that makes me wonder where such differences in results would come from. Different dosages in different studies? Differences in other treatment parameters or modality? Differences in some kinds of chemical details despite the basic molecule being the same? Patient selection? Chance? P-hacking or something similar? The first trial failing to show an effect that does exist due to methodology?
rincebrain 4y ago
True story, about a year ago, one of my doctors suggested I try this combination experimentally, since I was already taking bupropion and tolerating it well. I didn't notice anything change in the few months I tried it, other than that I hated the taste of cough syrup even more. (This is not intended to suggest that it proves or disproves anything other than that people are suggesting this be tried.)
- gremlinsinc 4y ago
  Haven't tried it but Bupropion changed my life. SSRI's failed me. Couldn't tolerate any of them (ED, which made me more depressed). Bupropion + Vyvanse seems to make me eat less, work harder, stay focused longer and have less food cravings. Lost 50 pounds without dieting just from not eating junk food as often.
  - rincebrain 4y ago
    Oh, bupropion can be very helpful. It's also very strange, as a drug. "Definitely not a stimulant, the list of effects and side effects just kind of looks like one, only drug in its class approved in the US, also approved for helping you quit smoking..."
Maursault 4y ago
>> once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks > Ignore anyone who tries to compare this to recreational DXM consumption because they're quite different. Other promising trials for a fast acting treatment of treatment-resistant depression are using single doses up to 600mg of DXM. My personal experience is that a single dose of 600-900mg of dextromethorphan will cure depression like aspirin cures a headache, with the depression-suppressing effect lasting from a month up to 6 months and longer. The considerable side-effects of such a large dose are mitigated by 20mg of pepsid and allowing the sedative effects of DXM to sleep through the hallucinations, delusions, susceptibility to suggestion, etc. But we'll leave it to pharmaceutical companies to develop a patentable formula that requires the patient to take pills for the rest of their lives. Imagine if headaches were treated the same way. This ubiquitous ideology of permanently medicating mental health patients is nothing less than the commercialism of mental illness. Patients are being farmed by Big Pharm. There is a widespread stigma in medicine and society at large against self-medicating and specifically against using DXM to treat depression, due to its abuse by 14-year-olds and drug cowboys. I've only quoted you to remind you of same and that dosages of DXM in comparison to other pharmaceuticals is entirely arbitrary (for example, aspirin bottles indicate 650mg for a headache). The lethal dose of DXM is an estimation because, as of yet, no one has managed to achieve a fatal overdose of DXM. So it is a safe drug, and because it has been off patent since the 1950's, we're not going to see any ordinary unadulterated formulations. Lucky thing, DXM is not a controlled substance.
- pstuart 4y ago
  > 600mg of DXM That's over a pint of Robitussun -- I couldn't imagine chugging that down. I am intrigued by your claim though.
  - Maursault 4y ago
    Robitussin is not dextromethorphan in the same way that beer is not alcohol. I'm not aware of any formula of Robitussin that doesn't include other drugs that are dangerous at high doses, including probable damage to kidneys and liver. Overdosing on Robitussin is an astoundingly bad idea.
thornjm 4y ago
I worry this comment is overly dismissive of criticisms and overly optimistic about potential positives. On medicine topics I think it is important to try remain objective. 1. On DXM being an NMDA antagonist: At high concentration DXM is an NMDA antagonist and AXS-05 does dramatically increases DXM concentration [0] (slide 6). It is not clear to me why we should "ignore anyone" who makes this comparison? 2. On AXS-05 having a wide array of receptor targets: Almost all psychoactive drugs have some affinity for many receptors (just wikipedia any anti-psychotic e.g. [1]). Are any of the targets mentioned clinically significant at therapeutic concentrations? [0] https://axsometherapeuticsinc.gcs-web.com/static-files/4a50801a-d8f7-489b-99dd-2d2c28828471 https://axsometherapeuticsinc.gcs-web.com/static-files/4a508... [1] https://en.wikipedia.org/wiki/Olanzapine https://en.wikipedia.org/wiki/Olanzapine
- PragmaticPulp 4y ago
  > It is not clear to me why we should "ignore anyone" who makes this comparison? I said that we should ignore people trying to compare this drug to recreational use. It's likely that NMDA is in play and I'm not suggesting otherwise. I wanted to highlight that DXM has significant affinities for other targets like the serotonin transporter that could also explain the efficacy, so it's a mistake to focus on one receptor as the single answer.

forbiddenvoid 4y ago

Thank you for explaining the interaction that makes this work. I was very confused for a bit trying to understand how mixing a cough suppressant with an anti-depressant would change the chemistry to the extent highlighted in the study.

Delk 4y ago

> Axsome Therapeutics (company researching the drug) stumbled a few years ago when their own trial failed to show statistical significance for Bupropion+DXM over Bupropion alone. Later studies seem to have been more positive though. Not being familiar with pharma research, that makes me wonder where such differences in results would come from. Different dosages in different studies? Differences in other treatment parameters or modality? Differences in some kinds of chemical details despite the basic molecule being the same? Patient selection? Chance? P-hacking or something similar? The first trial failing to show an effect that does exist due to methodology?

rincebrain 4y ago

True story, about a year ago, one of my doctors suggested I try this combination experimentally, since I was already taking bupropion and tolerating it well. I didn't notice anything change in the few months I tried it, other than that I hated the taste of cough syrup even more. (This is not intended to suggest that it proves or disproves anything other than that people are suggesting this be tried.)

gremlinsinc 4y ago
Haven't tried it but Bupropion changed my life. SSRI's failed me. Couldn't tolerate any of them (ED, which made me more depressed). Bupropion + Vyvanse seems to make me eat less, work harder, stay focused longer and have less food cravings. Lost 50 pounds without dieting just from not eating junk food as often.
- rincebrain 4y ago
  Oh, bupropion can be very helpful. It's also very strange, as a drug. "Definitely not a stimulant, the list of effects and side effects just kind of looks like one, only drug in its class approved in the US, also approved for helping you quit smoking..."

Maursault 4y ago

>> once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks > Ignore anyone who tries to compare this to recreational DXM consumption because they're quite different. Other promising trials for a fast acting treatment of treatment-resistant depression are using single doses up to 600mg of DXM. My personal experience is that a single dose of 600-900mg of dextromethorphan will cure depression like aspirin cures a headache, with the depression-suppressing effect lasting from a month up to 6 months and longer. The considerable side-effects of such a large dose are mitigated by 20mg of pepsid and allowing the sedative effects of DXM to sleep through the hallucinations, delusions, susceptibility to suggestion, etc. But we'll leave it to pharmaceutical companies to develop a patentable formula that requires the patient to take pills for the rest of their lives. Imagine if headaches were treated the same way. This ubiquitous ideology of permanently medicating mental health patients is nothing less than the commercialism of mental illness. Patients are being farmed by Big Pharm. There is a widespread stigma in medicine and society at large against self-medicating and specifically against using DXM to treat depression, due to its abuse by 14-year-olds and drug cowboys. I've only quoted you to remind you of same and that dosages of DXM in comparison to other pharmaceuticals is entirely arbitrary (for example, aspirin bottles indicate 650mg for a headache). The lethal dose of DXM is an estimation because, as of yet, no one has managed to achieve a fatal overdose of DXM. So it is a safe drug, and because it has been off patent since the 1950's, we're not going to see any ordinary unadulterated formulations. Lucky thing, DXM is not a controlled substance.

pstuart 4y ago
> 600mg of DXM That's over a pint of Robitussun -- I couldn't imagine chugging that down. I am intrigued by your claim though.
- Maursault 4y ago
  Robitussin is not dextromethorphan in the same way that beer is not alcohol. I'm not aware of any formula of Robitussin that doesn't include other drugs that are dangerous at high doses, including probable damage to kidneys and liver. Overdosing on Robitussin is an astoundingly bad idea.

thornjm 4y ago

I worry this comment is overly dismissive of criticisms and overly optimistic about potential positives. On medicine topics I think it is important to try remain objective. 1. On DXM being an NMDA antagonist: At high concentration DXM is an NMDA antagonist and AXS-05 does dramatically increases DXM concentration [0] (slide 6). It is not clear to me why we should "ignore anyone" who makes this comparison? 2. On AXS-05 having a wide array of receptor targets: Almost all psychoactive drugs have some affinity for many receptors (just wikipedia any anti-psychotic e.g. [1]). Are any of the targets mentioned clinically significant at therapeutic concentrations? [0] https://axsometherapeuticsinc.gcs-web.com/static-files/4a50801a-d8f7-489b-99dd-2d2c28828471 https://axsometherapeuticsinc.gcs-web.com/static-files/4a508... [1] https://en.wikipedia.org/wiki/Olanzapine https://en.wikipedia.org/wiki/Olanzapine

PragmaticPulp 4y ago
> It is not clear to me why we should "ignore anyone" who makes this comparison? I said that we should ignore people trying to compare this drug to recreational use. It's likely that NMDA is in play and I'm not suggesting otherwise. I wanted to highlight that DXM has significant affinities for other targets like the serotonin transporter that could also explain the efficacy, so it's a mistake to focus on one receptor as the single answer.