for depression, I vote for
There was a study that came out a couple years ago from this group, which further looked into the mechanism of PPAP and BPAP (and presumably selegiline’s) potentiation of impulse-dependent monoamine release, which I’m guessing is related to any longevity effects.
I’ve taken PPAP a handful of times. It’s pretty subtle, at least at the doses I’ve taken.
I wonder if these compounds are somehow protecting monoamine neurons, for example they showed BPAP could prevent tetrabenazine-induced dopamine depletion, suggesting that it favors vesicular sequestration of dopamine. Dopamine can autoxidize to superoxide in a pH-dependent manner in the cytosol, so you want to keep it in the vesicles as much as possible. I personally think if you use amphetamines you should avoid NO boosters for this reason, as peroxynitrite (formed from superoxide and NO) is the primary species contributing to toxicity observed in animal models of amphetamine use.
Probably the most well-known aging-related loss of dopamine neurons occurs in Parkinson’s disease, but less extreme age-related alterations in dopamine (and other monoamine) systems could alter motivation, mood, stress responses, etc in a way detrimental to longevity.
I think you all would see your depressive symptoms disappear like magic if you took a single Adderall. Everything else you guys have mentioned here has almost zero effect on mood when compared to amphetamine. It also increases athletic performance, enhances your learning speed & creativity, and is a mild pain killer. You do pretty much everything better with Adderall (except sleep). It’s really life-changing.
Crazy how differently things affect people.
Even stuff like modafinil (generally considered much milder than Adderall or methylphenidate) tends to make me scatterbrained, tunnel vision, paranoid, and moody. The first couple hours is okay and the increased sociability is nice, although the cognitive benefits tend to favor mechanical and repetitive tasks rather than learning anything novel, but after that it’s downhill.
I’ve also tried a lot of different analogues of amphetamine and methylphenidate, but coffee, or at the very least caffeine, is still the best cognitive enhancer and the only true long-term solution for me.
Thanks a lot for your detailed reply. I reviewed most of these papers when I wrote the Selegiline article for the Longevity Wiki: Selegiline - Longevity Wiki
Of course, the lack of financial incentives for deprenyl makes it less studied. Still, we have dozens of studies around other patent-free compounds (rapa, vitamins, creatine, taurine, etc.). And deprenyl is actually still studied at higher doses for Parkinson’s disease and depression (famously used by Sam Bankman-Fried, who complained about not being able to take his deprenyl patch while in jail!). So the lack of financial incentives doesn’t explain everything.
The weirdest thing to me is that the team that came up with deprenyl is no longer studying it. In their latest paper (2023), they looked at BPAP, a deprenyl derivative and found no beneficial effects on cognitive capabilities or lifespan. And after I emailed them to ask questions about deprenyl and its longevity potential: no answer. These are red flags to me. If you’re a researcher who discovered a compound with great longevity properties and you’re convinced of its potential: why do you stop publishing papers about it? why do you instead publish papers about derivative compounds? why don’t they apply to the ITP (fairly easy to do so, and I emailed them about that)? I don’t get it. I’d love to see deprenyl tested in the ITP, but I’m afraid it will most likely be a failure…
This paper is just a non-peer-reviewed editorial by one dude from a small hospital in a small village in New York State; it’s a weak source.
Unfortunately, SSRI use might be linked to higher rates of dementia: “In line with previous findings, we found elevated risks of developing dementia associated with SSRI and SNRI treatment, especially with short-term treatment.” (To Be Continued? Long-Term Treatment Effects of Antidepressant Drug Classes and Individual Antidepressants on the Risk of Developing Dementia: A German Case-Control Study 2020)
Of course, we need more data to check whether this is because depression is an early symptom of dementia or if SSRIs are actually neurotoxic. Researchers normally try to adjust for these confounders but it’s hard to do. Still, SSRIs were trialed in many neurological diseases, and they did not seem to improve things. They can actually make it even worse:
So we need more Mendelian randomization studies comparing the use of various antidepressants and the long-term outcomes to be able to conclude. It’s highly possible that among all antidepressants, some have beneficial effects while others are neurotoxic. It’s also possible that the response is highly individualized and based on some genes. But so far, we don’t know and I’m cautious.
I have daylight wavelength flourescent tubes above me on the ceiling in the room where I paint and draw. The ceiling is low and the lamps are very close to my head and the easel. I have to wear a black baseball cap to reduce the light getting into my eyes so I can work, but there is still plenty of light reflected off the things around me. I find that this does help with mood. But I also take ashwaghanda, magnesium, lithium orotate, EPA/DHA and several other supplements. My set up may not be as effective as a light box for SAD but it does seem to make a difference.
I would first try Transcranial Magnetic Stimulation
How do TMS and tDCS differ in terms of efficacy? tDCS seems much easier to use, especially at home, without supervision. So could it be that tDCS is like “self-administered micro-dosed TMS”?
I can’t wait to have the results of these clinical trials:
The difference between rTMS and tDCS is the years of research, clinical trials, and positive patient outcomes backing rTMS, as compared to the limited information for tDCS.
I would not wait, I would get rTMS immediately.
The only negative is the high cost.
Thanks. For those interested, here are the latest reviews of the UK National Institute for Health and Care Excellence (NICE), both from 2015:
So more data and more efficacy for rTMS indeed. Although here it says that: “Mimicking the physical discomfort of TMS with placebo to discern its true effect is a challenging issue in research.[4][12][59][60] It is difficult to establish a convincing placebo for TMS during controlled trials in conscious individuals due to the neck pain, headache and twitching in the scalp or upper face associated with the intervention.” Transcranial magnetic stimulation - Wikipedia
Anyway, I may give rTMS a try…
Here is a good article on depression / treatments, etc.
I’ve found tremendous benefits with micro dosing psychedelics (lsd and psilocybin). Recent research shows that psychedelics are potent allosteric activators of BDNF-TRKB signaling, meaning that they truly due augment neuronal plasticity. Conventional antidepressants actually act on the same receptor, albeit with far less potency.
https://www.nature.com/articles/s41593-023-01316-5
A few tips based on this research:
Exercise also increases BDNF. Exercise intensely on micro dose days to augment the positive impacts. I feel a potent mood boost from this combination.
Capitalize on the enhanced neuroplasticity with interventions known to induce positive brain changes. Incorporate things like meditation, cognitive bias modification (there are helpful apps for this), meditation, or therapeutic journaling as you begin micro dosing. The enhanced neuroplasticity from the micro dose will help these interventions “stick.”
LSD and psilocybin are much more potent activators of TrkB versus ketamine. As such, these will do much more to enhance neuroplasticity.
Following this blue print, I’ve made tremendous mental health strides over the last year.
There are risks to this approach, such as the potential for valvulopathy from 5HT2B receptor activation. We don’t know whether these risks are theoretical or real.
Very interesting recent paper on this in one of the Nature journals:
We performed the largest to date cross-sectional analysis of light, sleep, physical activity, and mental health (n = 86,772 adults; aged 62.4 ± 7.4 years; 57% women). We examined the independent association of day and night-time light exposure with covariate-adjusted risk for psychiatric disorders and self-harm. Greater night-time light exposure was associated with increased risk for major depressive disorder, generalized anxiety disorder, PTSD, psychosis, bipolar disorder, and self-harm behavior
Independent of night-time light exposure, greater daytime light exposure was asreduced risk for major depressive disorder, PTSD, psychosis, and self-harm behavior.
These findings were robust to adjustment for sociodemographics, photoperiod, physical activity, sleep quality, and cardiometabolic health.
Avoiding light at night and seeking light during the day may be a simple and effective, non-pharmacological means of broadly improving mental health.
The study was done in the UK so in your current home grounds I think @adssx
https://www.nature.com/articles/s44220-023-00135-8
Also just discussed by Huberman and Attia including an intro on the value of optimal light protocols by Huberman:
I remember experimenting with adderall in college to study for exams every once in a while. It would always make me so happy and want to talk to everyone. Wish it wasn’t so bad for us though.
I have started to wonder about the effects of adderall in terms of longevity too. In addition to my antidepressant, I also take adderall for autistim executive functioning issues. Can you elaborate on what you mean by “bad for us”?
Clearly, adderall increases dopaminergic and noradrenergic transmission, which I’m guessing could lead to increased stress. Anecdotally, I do notice that at sufficient therapeutic doses I do “feel” a mild stress response. However, this seems to be necessary to achieve the executive control I need.
Does anyone have any information on how stimulants affect longevity or related systems?
That is just my elementary level understanding of it. I haven’t done enough of a deep dive on it.
There’s no evidence that long-term use of Adderall in therapeutic doses shortens lifespan. I also can’t find much evidence of anyone ever overdosing on it, either.
People commonly say that it’s “bad for your heart” but there doesn’t seem to be much data backing that up (unless you already have existing heart issues). I think people just assume that Adderall must have the same bad side-effects as methamphetamine and cocaine (which it doesn’t). My doctor told me that people who use Adderall therapeutically are usually in better shape, because they are more physically active, less depressed, and consume fewer calories.
It’s definitely an addicting substance, though, and it’s a classified as a schedule II drug for a good reason.
I don’t have an opinion on Adderall, but I was curious and checked it in the supplemental material (Table S5) of Association of cardiovascular disease management drugs with Lewy body dementia: a case–control study.
Here are the ORs for use of “AMPHET ASP/AMPHET/D-AMPHET” (I assume this is Adderall?):
There might be confounders, but it’s massive.
On the other hand: “This study suggests that adult ADHD is associated with an increased risk of dementia and warrants reliable assessment in adulthood.” (adjusted HR, 2.77 [95% CI, 2.11-3.63; P < .001]) “There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild.” (Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia 2023)
What about dopaminergic stimulants and Parkinson’s risk? Partly why I am avoiding them, including selegiline. But I am happy to be wrong.
I think no one knows. I would not be surprised if low-dose selegiline was protective while high-dose was neurotoxic.
Interestingly, for rasagiline: “Teva conducted clinical trials attempting to prove that rasagiline did not just treat symptoms, but was a disease-modifying drug - that it actually prevented the death of the dopaminergic neurons that characterize Parkinson’s disease and slowed disease progression. They conducted two clinical trials, called TEMPO and ADAGIO, to try to prove this. The FDA advisory committee rejected their claim in 2011, saying that the clinical trial results did not prove that rasagiline was neuroprotective. The main reason was that in one of the trials, the lower dose was effective at slowing progression, but the higher dose was not, and this made no sense in light of standard dose-response pharmacology.” (Wikipedia)
But there’s still an ongoing trial of rasagiline for PD to see whether it can be disease-modifying. I don’t know at which dose, though.
I couldn’t find a lot of evidence for NAC:
The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders 2022
Whilst there is ample preclinical evidence and theoretical justification for the use of NAC in the treatment of multiple psychiatric disorders, clinical trials in most disorders have yielded mixed results. However, most studies have been underpowered and perhaps too brief, with some evidence of benefit only after months of treatment with NAC. Currently NAC has the most evidence of having a beneficial effect as an adjuvant agent in the negative symptoms of schizophrenia, severe autism, depression, and obsessive compulsive and related disorders. Future research with well-powered studies that are of sufficient length will be critical to better understand the utility of NAC in the treatment of psychiatric disorders.
N-acetylcysteine as a new prominent approach for treating psychiatric disorders 2021
It would be interesting to study GlyNAC in depression, anxiety, sleep, etc. I’m surprised there are no trials of GlyNAC for these conditions. There are only 4 ongoing trials of GlyNAC:
The first three are led by Rajagopal V. Sekhar, M.D. from the Baylor College of Medicine. They don’t mention the dose they’re using.
Rajagopal V. Sekhar is actually the author of the paper that showed a 24% increase in lifespan of old mice after GlyNAC supplementation.
But if NAC “works” for depression, anxiety, OCD, etc. and glycine improves sleep and cognition (two big ifs), then the combo would be interesting…
L-methylfolate is a form of folic acid, aka Vitamin B9, common in various vegetables. It’s part of various important chemical processes in the body, including the synthesis of serotonin, and various studies support its use in depression. Some people will try to claim that a gene called MTHFR is very relevant here, but I disagree with this and will have a page up about it eventually – the summary is that you should consider using l-methylfolate regardless of what allele of MTHFR you have. The official prescription-only version of l-methylfolate is called Deplin, and is prescription-only and more expensive, but it’s chemically identical to regular l-methylfolate which you can buy without a prescription in stores. Be careful as many stores will sell 1 mg tablets, but the recommended dose is 7.5 – 15 mg daily. - Lorien Psychiatry
This looks interesting to me, any thoughts?
Isn’t Peter Attia taking Methyl B-9 and Methyl B-9? How is it better than “normal” B9?