POD 76: Patron Q&A May 2023

Bing is bangin

M

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Michael Cunningham

Thank you for mentioning amaneptine! Ritalin has done wonders for my depression/cocaine depenance n i feel like more dopaminergic stimulants should be considered for the treatment of depression

Good insights on medicalization making drug use socially acceptable! It's like a magic trick, where language is the "sleight of hand" used to alter perception. (Perhaps one's own, too.) I think this type of medicalization game enforces victim mentality + the bullshit excuses eat away self-respect. So I don't think it's a very healthy game to paly! But since the social consequences of a honest "I love Xanax" could be devastating, there is a need to construct facade that the neighbours will approve of.

Honey-el

What I've learned with communicating with relatives suffering of Alzheime'rs is that *how* you tell them their loved one has died has a great impact on their reaction. If the fact is told as if it is something that has happened a long time ago and it isn't that emotionally rattling or dramatic anymore (which is often true!) they might simply accept the fact with a little bit of sadness and move on to the next topic. Ofc this communication style might not work in all cases; but as it often feels bad to lie to a loved one, giving this approach a try is not a bad idea. People suffering of Alzheimer's can be very sensitive to social cues. They don't have much of an internal memory structure anymore, so they rely heavily on external structures for memory. That is also why when a person with dementia moves to a new (nursing) home, keeping the old furniture + arranging the pieces in a familiar way can mean the difference between said person staying calm and collected vs. detoriating into incoherence. Btw: I think calling people with dementia "delusional" is incorrect and disrespectful. They are not delusional - they just have a very bad memory!

Honey-el

Love you Hamilton

Hamilton you are the TRUE mensch for sharing your knowledge on searching for free movies using bing. Not the answer I was expecting for this question but truly the answer that we all needed.

Kelly Rienerth

Hamilton, do you listen to Tipper?

gossamer

I would say I had a rather positive experience on a deliriant and I don’t think that’s too uncommon. Of course almost any other hallucinogen is probably gonna provide a more positive and insightful experience, but I think anyone interested in psychedelics could benefit from one deliriant trip in their lifetime. 500mg of diphenhydramine was really unlike any other experience for me. The nature of the hallucinations and how corporeal yet obviously fake they appear is pretty fascinating. The atmosphere is also so distinct, it almost feels like you’re experiencing an artist’s personal style projected onto your perception rather than experiencing the effects of a drug. It’s also fascinating how consistent these visual effects seem to be across people. If you go on YouTube and look up “dph simulator” you’ll find videos edited to look almost exactly the trip (based on my experience), even down to small details like the ‘textures’ of objects flickering and the walls having a whirling, sort of smoke-like pattern on them. I think experiences with deliriants also provide a lot of insight into stuff like ghost sightings and paranormal accounts throughout history. The hallucinations provided through these drugs matches up pretty closely with many of the classic archetypes of ghost stories, which kinda implies that these stories are likely the result of other delirious hallucinations caused by factors other than drugs (like sleep deprivation or illness). I could definitely go on and on about other intriguing aspects related to deliriants, however, I should definitely state that they are definitely more dangerous than things like lsd or psilocybin. If you do try them you should 100% have a sober sitter and really be careful about dose. Also I heard if you are seizure prone you should definitely stay away. Either way there is definitely a lot of interesting stuff surrounding these substances that is nowhere near close to being fully explored yet.

Please get your friend on who went to New Guinea for the deliriant experience! Sounds fascinating

Meek

Thanks for the response!

The appetite suppression caused by amphetamine is too much of an issue for me, I already struggle to maintain a healthy weight and when I took amphetamine daily as a freshman in college I weighed twenty pounds less than I do now, my BMI was 16.5. It also caused abdominal pain and terrible discontinuation effects whenever I stoped. Methylphenidate is much milder in most regards, the appetite suppression is minor and I found I could take days off without feeling like I had lost my life force. It also has a shorter duration and didn't interfere with my sleep. In general I try to keep my stimulant intake to a bare minimum, I consume a lot of caffeine (up to 600mg a day) and 150mg of bupropion most days but I try not to go much beyond that. I still take amphetamine a few times a year at low doses of around 5-10mg.

Hamilton Morris

It would be extremely helpful to me as someone with ADHD for you to go over your personal experience with stimulants. Why you chose Ritalin over an Amphetamine (I know you used to be on those too). What the side effects were that led you to stop, etc.. I'm currently on 300 mg bupropion and 70 mg Vyvanse daily and it's been a struggle my whole life figuring out what works for me, dangers, etc.. I find myself often knowing more about these drugs than my actual doctor prescribing them. I just know going into detail of you're experience (even if there are embarrassing side effects) would be a HUGE help to myself and others. Thanks man I've followed your work for 10 years now since I was 16 you've truly been a force for good in the psychoactive substances community.

Bupropione being the only one to have „helped“ (what a naive idea..), less the anger management challenges it can lead to in some. Especially when combined with Quetiapine you have your perfect „worker drone“ combo. Don’t.

mk

To be clear, my understanding is that solfriamfetol was considered a strong lead compound for depression but was repurposed for narcolepsy due to poor preclinical outcomes. There are a lot interesting narcolepsy drugs that have arisen recently, pitolisant being another (although probably more well-known as a truly first-in-class drug). You're probably aware given the oxybate anecdotes but medical use of GHB is expanding in that context with new salt formulas being approved and such. As far as failed antidepressants I'm not aware of any explicit/reported failed trials of fairly pure DRIs or similar. There are probably some but I particularly don't think there have been any large pivotal trials of any classical stimulant/DRI drugs for MDD that have been published or publicized. A larger number of fairly selective DRI type drugs for depression were trialed back in the day for depression, including a few pemoline derivatives (e.g. thozalinone*, https://pubmed.ncbi.nlm.nih.gov/4962734/). Trials back then were poorly designed but also they never entered clinical use even with the expected high placebo/spontaneous response rate so I don't take that well. On the other hand, there have been plenty of studies over the decades that have looked at monotherapy or augmentation approaches in various study designs, including a fair number of RCTs. The best review on this topic in my opinion is this one (https://journals.lww.com/psychopharmacology/fulltext/2017/08000/The_Efficacy_of_Psychostimulants_in_Major.6.aspx), but this one includes some older trials with methamphetamine and pemoline (https://www.sciencedirect.com/science/article/pii/S0165032721005656). Note, I would strongly suggest looking at the methods, forest plots, discussion in the first one before making a judgement on the abstract. * Interestingly this was sold recently from a vendor various pemoline derivatives. Not amazing reviews afaik. Also, I can't find the manuscript of this paper anywhere (can't even find indexed in my institutions online library search tools), but if you happen to ever get a copy I'd really appreciate one too.

I'd never heard of solriamfetol, very interesting. I couldn't see any evidence for it being tested for depression on clinicaltrials.gov, do you have links to more info on that? Are you aware of other failed dopaminergic antidepressants? I also saw that concerta was tested for MDD and phase III trails were completed but I couldn't find the results.

Hamilton Morris

Personally, I would 100% believe DRIs/amphetamines are effective antidepressants if there was enough evidence for it, but they seem to be minimally effective for core mood symptoms. Below the low bar already set for antidepressants. In contrast, they have huge effect sizes re: executive dysfunction in ADHD, among the highest in psychiatric treatment in general. There's good evidence they're somewhat effective for fatigue and executive dysfunction in depression but the evidence is very inconsistent even for the better-studied stimulant candidates like methylphenidate. The effect sizes are generally smaller than "current" antidepressants w/r/t depression symptoms. Similarly, it's not like stimulant antidepressants haven't been aren't of interest, solriamfetol is FDA-approved and was initially an antidepressant candidate. Additionally, as it stands we already have powerful stimulants that are approved for psychiatric use like amphetamine & friends and methylphenidate, which are likely weaker antidepressants than bupropion despite greater DAT occupancy and likely greater DA/NE elevation (especially with amphetamines). I assure you they are used relatively often in psychiatry, including in patients with depression, particularly when multiple antidepressant trials are unsuccessful and residual symptoms include fatigue and executive dysfunction. Bupropion is a also much stronger NRI than DRI at clinical doses (~10-25% occupancy at DAT vs ~50-95% with MPH iirc), which is a traditional antidepressant target. Similarly, aside from amineptine and selegiline (the former poorly studied and kind of grandfathered in before we did good RCTs, and the latter not very effective afaik), all of the "dopaminergic antidepressants" you mentioned have greater effects (again afaik) on serotonin and norephinephrine (and greater clinical efficacy than purely dopaminergic drugs). This makes for a very uncertain clinical pipeline and competitive market before you even consider the unique regulatory hurdles of DRIs/amphetamines. Setting all that aside, we don't know for certain that SERT or NET inhibition are the actual core necessary pharmacological targets for antidepressant action in most existing drugs. They could just augment other effects we aren't aware of, could correlate with those effects in the same scaffold, or could be artifacts of using a given set of scaffolds. For example, we've seen a lot of evidence for interactions with cholesterol-binding proteins and cholesterol-rich domains, including cholesterol-binding sites with affinity for structurally diverse antidepressants within the TrkB dimer interface that promote its dimerization/phosphorylation (arguably the most well-described/understood antidepressant mechanism), as well as functional effects on signal transduction in lipid rafts. Most of modern pharmacology still relies (with good reason) on techniques only allow us to detect that which we're explicitly looking for. This is the issue with examples like amineptine as well, there are so many TCAs that are antidepressants. Tianeptine is another good example without affinity for any classical antidepressant targets (just a mu-opioid, as far as we know). My opinion re: mu-opioids in depression is pretty similar to stimulants, maybe it can do something but the target doesn't intrinsically benefit core symptoms, even if tianeptine ends having really wacky molecular pharmacology. Also, on a pedantic note, (des)venlafaxine is a bicyclic phenethylamine derivative as well.

Plans for a QnA every month? Amazing!

Wish someone asked about Nitrazines along side the xylazine.

Mitchell