4 ms·

I’m glad to hear people discussing this! I love how most of the hippies that love “natural psychedelics” have a loophole for LSD. Just because a drug has a prec

I’m glad to hear people discussing this! I love how most of the hippies that love “natural psychedelics” have a loophole for LSD. Just because a drug has a precursor found in nature doesn’t make the drug itself natural. As somebody that experimented heavily with psychedelics when I was much younger, my opinion is that the 2C-B/E/I group have definite possible therapeutic value, and the main thing causing stagnation is the ridiculous hippy mindset that it’s ~synthetic~ and therefore bad. It’s ridiculous. Over the past few years it’s been interesting watching polite society “discovering” psychedelics. I really can’t wait for these people to find the therapeutic value of smoked/IV DMT, especially considering that it’s WAY safer than ayahuasca. I would love to see a study on the possible therapeutic value of dextromethorphan, but as far as I’ve seen it’s not really on the radar. I know it seems weird, but from subjective experience I found it to be very helpful a few times as a teenager. I used to jokingly call it “therapy in a bottle.” It’s a real shame that most DXM-containing products nowadays in the US come mixed with other compounds that make it dangerous to take at a recreational/therapeutic dose.

heavyset_go 5y ago
DXM is being studied in combination with bupropion as an antidepressant.
- briHass 5y ago
  See also, Nuedexta, which is used to treat pseudobulbar affect (PBA.) I agree with GP. If ketamine works for depression, there's no reason to think similar effects wouldn't occur with DXM. I've always found the 'next day' glow to be quite nice.
  - heavyset_go 5y ago
    > I agree with GP. If ketamine works for depression, there's no reason to think similar effects wouldn't occur with DXM. I've always found the 'next day' glow to be quite nice. From what I understand, ketamine's rapid antidepressant effect was once thought to have been mediated by NMDA antagonism. However, countless NMDA antagonists have been studied for depression, and their efficacy was nowhere near the S-enantiomer of ketamine, suggesting that NDMA antagonism alone isn't responsible for the full effect. DXM acts as a dirty serotonin reputake inhibitor before it's metabolized into DXO, which is actually an NDMA antagonist like ketamine. By combining DXM with bupropion, the bupropion prevents the DXM from rapidly metabolizing into DXO through enzyme inhibition, leaving more SSRI-like DXM in the blood to affect the brain. Bupropion itself is a potent inhibitor of enzymes that metabolize many pharmaceuticals. So the idea behind combining DXM+bupropion to treat depression doesn't really come from the same mechanism of action that esketamine has. It's more about the SSRI-like properties DXM has in the body as long as it isn't metabolized into DXO. Also, combining two medications that are off-patent for a new treatment means that you can patent the new combination as if it's a new drug. I suspect that's why it's being investigated. Both DXM and bupropion have pretty good safety profiles, they're cheap to manufacture, and the combination can be patented.
    - briHass 5y ago
      I don't think the SSRI effects are the primary goal. The appeal of esketamine is its rapid effect, the same thing being sought with DXM+bupropion (AXS-05). Studies with naltrexone and ketamine reduced the antidepressive effect, so maybe the mu opioid or sigma-1 are important. (https://www.cambridge.org/core/journals/cns-spectrums/article/dextromethorphanbupropion-a-novel-oral-nmda-nmethyldaspartate-receptor-antagonist-with-multimodal-activity/F46E1BACC12CE43FDC641173EFF7C62E https://www.cambridge.org/core/journals/cns-spectrums/articl...) Interestingly, there's a small trial with just DMX (300mg - aka first/second plateau) to determine safety: https://clinicaltrials.gov/ct2/show/NCT04226352 https://clinicaltrials.gov/ct2/show/NCT04226352 The bupropion seems to be only useful for slowing the DXM->DXO to allow for lower doses. A full on 'robo-trip' may actually work as well as a full on ketamine trip.
      - waffle_maniac 5y ago
        I think there's an argument to be made that a working opioid system is central to the anti-depressant effect of any anti-depressant? I actually tried naltrexone for a condition related to depression and it made me feel much worse and unable to feel much pleasure in anything. DMX is really a crappy drug with a half-life that is too long for frequent administration.
  - the_only_law 5y ago
    > I've always found the 'next day' glow to be quite nice. I’m not sure I’ve ever experienced the afterglow in the way many people describe it. Next day I would just feel kinda drowsy, and a bit muted and dumbed down.
deleted 5y ago
[deleted]

heavyset_go 5y ago

DXM is being studied in combination with bupropion as an antidepressant.

briHass 5y ago
See also, Nuedexta, which is used to treat pseudobulbar affect (PBA.) I agree with GP. If ketamine works for depression, there's no reason to think similar effects wouldn't occur with DXM. I've always found the 'next day' glow to be quite nice.
- heavyset_go 5y ago
  > I agree with GP. If ketamine works for depression, there's no reason to think similar effects wouldn't occur with DXM. I've always found the 'next day' glow to be quite nice. From what I understand, ketamine's rapid antidepressant effect was once thought to have been mediated by NMDA antagonism. However, countless NMDA antagonists have been studied for depression, and their efficacy was nowhere near the S-enantiomer of ketamine, suggesting that NDMA antagonism alone isn't responsible for the full effect. DXM acts as a dirty serotonin reputake inhibitor before it's metabolized into DXO, which is actually an NDMA antagonist like ketamine. By combining DXM with bupropion, the bupropion prevents the DXM from rapidly metabolizing into DXO through enzyme inhibition, leaving more SSRI-like DXM in the blood to affect the brain. Bupropion itself is a potent inhibitor of enzymes that metabolize many pharmaceuticals. So the idea behind combining DXM+bupropion to treat depression doesn't really come from the same mechanism of action that esketamine has. It's more about the SSRI-like properties DXM has in the body as long as it isn't metabolized into DXO. Also, combining two medications that are off-patent for a new treatment means that you can patent the new combination as if it's a new drug. I suspect that's why it's being investigated. Both DXM and bupropion have pretty good safety profiles, they're cheap to manufacture, and the combination can be patented.
  - briHass 5y ago
    I don't think the SSRI effects are the primary goal. The appeal of esketamine is its rapid effect, the same thing being sought with DXM+bupropion (AXS-05). Studies with naltrexone and ketamine reduced the antidepressive effect, so maybe the mu opioid or sigma-1 are important. (https://www.cambridge.org/core/journals/cns-spectrums/article/dextromethorphanbupropion-a-novel-oral-nmda-nmethyldaspartate-receptor-antagonist-with-multimodal-activity/F46E1BACC12CE43FDC641173EFF7C62E https://www.cambridge.org/core/journals/cns-spectrums/articl...) Interestingly, there's a small trial with just DMX (300mg - aka first/second plateau) to determine safety: https://clinicaltrials.gov/ct2/show/NCT04226352 https://clinicaltrials.gov/ct2/show/NCT04226352 The bupropion seems to be only useful for slowing the DXM->DXO to allow for lower doses. A full on 'robo-trip' may actually work as well as a full on ketamine trip.
    - waffle_maniac 5y ago
      I think there's an argument to be made that a working opioid system is central to the anti-depressant effect of any anti-depressant? I actually tried naltrexone for a condition related to depression and it made me feel much worse and unable to feel much pleasure in anything. DMX is really a crappy drug with a half-life that is too long for frequent administration.
- the_only_law 5y ago
  > I've always found the 'next day' glow to be quite nice. I’m not sure I’ve ever experienced the afterglow in the way many people describe it. Next day I would just feel kinda drowsy, and a bit muted and dumbed down.

deleted 5y ago

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