#100

In 1999 / 2000 I started to have mental health problems. I would not have labeled the once in a rare moment “crazy ideas” as hallucinations or dementia, but… by 2003 I had really bad depression. I lost my job in Silicon Valley(Dir of Bioinformatics killed a VP, after being terminated for stealing corporate data) and with it my bride to be and quite a bit of money. Talk about a tailspin! I hit rock bottom pretty hard.

In any case, I muddled on until 2006 where I had full blown psychosis. I’d like to think that the shock to my system of the events in 2002/2003 led me to where I was in life in 2006. Psychiatrists and therapists don’t pull out the diagnostic manual and go, “There you are!” There is a lot that goes into a diagnosis…and after 6 to 12 months of guessing and discussions, we arrived at schizoaffective disorder type 1, depressive.

I take 2.5mg of haldol and sertraline. If I take the full 5mg of haldol I start to have problems with the dose after 3 to 5 days. “Anxieties.” I’ve tried a number of drugs(geodon, respiradol, …) and the best for me is the combination of haldol and sertraline. The other medications are impossible, and overmedicated me to the point of not being able to function at all. I do not like sleeping all day.

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#101

Even though I’ve never been depressed, I take 10 mg of tranylcypromine and 0.5 mg of roflumilast daily.

#102

PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis | Translational Psychiatry.

#103

Finally, in order to determine whether our 2c cocktail could also impact biological aging in vivo, we tested the effect of 2c treatment on the lifespan of a commonly used aging model organism, the nematode Caenorhabditis elegans . Towards this goal, we monitored survival in C. elegans treated with either 2c, Repsox, or TCP at three different concentrations (50, 100, or 200 μM) alongside a vehicle control. Strikingly, we observed that 2c treatment at 50 μM was sufficient to extend C. elegans median lifespan from 19 to 27 days, corresponding to a 42.1% increase relative to vehicle control ([Fig. 4a, e]. To a lesser extent, Repsox or TCP alone at 50 μM also increased C. elegans median lifespan to 25 days, a 31.6% increase over vehicle control ([Fig. 4a, e]. These results indicate that Repsox and TCP are each able to extend median lifespan in C. elegans , and when combined as part of the 2c cocktail, can lead to an even greater increase in median lifespan.

#104

Another new story on Flow Neurosciences headset:

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#105

Could be just some random noise, but two of us here noticed that telmisartan 40 mg increased our motivation and decreased our apathy / low-grade depression. One small paper in PD suggests the same effect for candesartan 8 mg (equivalent in terms of dose to telmisartan 40 mg):

So if your BP is not optimal (24h average > 115/75 mmHg) then treating it with telmisartan might come with this welcome side effect.

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#106

Let’s say your SBP ranges from 105-130 (depending on the day/time/machine) and DBP is between 60-80. Are there any downsides to having a potentially too-low BP from telmisartan.

Kind of like how you don’t mix viagra and BP meds?

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#107

Telmisartan has a safety profile similar to placebo so the risk is hypotension:

image

You don’t want to faint after standing up and hit your head on the corner of the table…

According to the FDA notice: “Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg.”

With your numbers, even telmisartan 20 mg might cause hypotension, but you can try and stop if you ever feel dizzy.

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#108

Do we know the potential mechanism of action?

It’s probably not homocysteine-lowering as “The findings argue against a causal role for homocysteine in the development of depression.” (Plasma homocysteine concentrations and depression: A twin study 2021)

Wikipedia says: “The exact mechanisms involved in the development of schizophrenia and depression are not entirely clear, but the bioactive folate, methyltetrahydrofolate (5-MTHF), a direct target of methyl donors such as S-adenosyl methionine (SAMe), recycles the inactive dihydrobiopterin (BH2) into tetrahydrobiopterin (BH4), the necessary cofactor in various steps of monoamine synthesis, including that of dopamine and serotonin. BH4 serves a regulatory role in monoamine neurotransmission and is required to mediate the actions of most antidepressants.”

Also: at which dose do the antidepressant effects start? Solgar sells metafolin 400 μg. Metafolin is the active ingredient of Deplin (15 mg). It’s just a branded version of levomefolate calcium, a calcium salt of levomefolic acid (aka L-5-MTHF or L-methylfolate).

I found this: “Folate supplements especially levomefolic acid (L-5-methylfolate) demonstrated improvement in clinical outcomes in certain mental health conditions, such as in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Daily dosage range is 50 microgram to 15 mg orally daily depending on the clinical diagnosis and clinical presentation.” (The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review 2022)

And this: “Meta-regression analysis demonstrated that there is no evidence of a significant linear relationship between dose and duration of folic acid supplementation and changes in HAM. Also, based on the non-linear dose response, no evidence of a relationship between dose and duration of folic acid supplementation and changes in HAM was found. […] Folic acid supplementation could possibly have an effect on lowering depression in patients. However, the clinical trials thus far are insufficient for clinical guidelines and practice.” (The effects of folic acid supplementation on depression in adults: a systematic review and meta-analysis of randomized controlled trials 2023)

However, most clinical trials looked at high-dose L-methylfolate (> 2.5 mg/day) and only as an adjunct to antidepressants: Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis 2021: “Adjunct therapy with l-Methylfolate or folic acid improves depression scale scores, patient response, and remission rates.”

And also iron deficiency.

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#109

Company Website:

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#110

Some of the 17 million US Americans who suffer from major depressive disorder each year may soon receive a surprising new prescription from their doctor:
Have fun with a virtual reality device!

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#111

It sounds like the Flow neuroscience NHS trial was successful - but I haven’t seen an official report from the NHS:

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#112

Any updates, did you keep taking selegiline since January?

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#113

I stopped a few weeks ago to try methylene blue instead. No perceived mood change in either direction, but I might try it again soon.

Lithium is more noticable for me.

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#114

Were you taking it sublingual or oral? Most of the reports I’ve seen are quite positive for the first couple weeks, and then it seems to become much more subtle. It seems like that’s your experience as well?

#115

Just oral at about 2.5mg EOD. And yes, pretty much adapted after a few days. If I restart it will just be because of the potential neuroprotective upside and low risk.

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#116

The article says “The research found over 58% of people saw improvements within six weeks, and one in three went into remission with no depression symptoms.” so I assume it refers to this May 2024 paper: “Flow” Transcranial Direct Current Stimulation (tDCS) for Depression Treatment in a Primary Healthcare General Practice—Depression, Functioning, and Health-Related Quality of Life Outcomes as it says “PHQ-9 reliable improvement and remission rates were 58.1% and 32.3%.”

However, it’s an extremely weak paper:

  • “Open-label patient cohort design with no control group”
  • “Thirty-one adult patients”
  • “This study collected outcome measures after six weeks of treatment, with no later follow-up data collection; it is recommended that future studies employ additional follow-up data collection points: 12, 24 and 36 weeks.”
  • “treatment with Flow tDCS was open-label and adjunct to any existing depression or other treatments or therapies”
  • “24 (77.4%) females and six males (23.6%) […] The sample was over-represented by females, so the results are less generalisable to males”
  • “Pre- and post-intervention assessment with participant self-report measures”: good clinical trials for depression also include clinician-reported outcome measures (and sometimes biomarkers and neuroimaging)
  • “Funding was provided by Flow Neuroscience AB”
  • Nothing about safety and adverse events
  • No adjustment for antidepressant use (what if some people increased the use of antidepressant during the study?)
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#117

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Related to well-being but not depression per se.

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#118

Hire someone to do most of the red jobs.

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#119

https://www.eugenics.org/

Transhumanists are ambitious. We want unlimited lifespan, unlimited intelligence, unlimited computer power. But this doesn’t mean that we’re ambitious about everything, for example height. Perhaps we want to be a bit taller, and we want to ensure that e.g. midgets have the opportunity to reach “normal” stature. Yet even in Second Life, or in tomorrow’s immersive virtual realities, we don’t for the most part want to be a thousand metres tall - despite freedom from the constraints of gravity. Of course, there are some very exotic creatures in Second Life: they might say the rest of us have stunted imaginations. But intuitively, there is quite a narrow optimum for body height. Moreover, height may be regarded as what economists call a “positional good”. It’s socially advantageous to be slightly taller than average; but if everyone were to become taller, then no one would be better off.

What about happiness - which I’m here going to use as a lame piece of shorthand for emotional well-being in the very richest sense. Is happiness best regarded as an absolute good, or as a positional good, like height? Is there an optimal range of hedonic tone that we should all aspire to - both for ourselves and for other sentient beings - just as there is for human body-stature under Earth’s gravitational regime? Perhaps the heritable “set-point” of our hedonic treadmill might be genetically raised a little, just as some of us may wish to be slightly taller. By the same token, perhaps victims of chronic low mood or anxiety disorders may benefit from gene-therapies or designer drugs so they can reach an idealised version of today’s “normal” mental health - just as growth hormone can help the “abnormally” short.

There is a much more radical conception of well-being. Is happiness more akin to intelligence or lifespan, something that transhumanists should strive to enhance without limit - with the almost unimaginable implications that such an indefinite increase entails? The Transhumanist Declaration calls for the “well-being of all sentience”. But well-being extends all the way from the barest contentment to peak experiences orders of magnitude more marvellous than unenriched humans can comprehend. Just how ambitious should rational agents aim to be in the scope of our reward pathway enhancements - both for ourselves and for other life-forms? What is technically feasible? What are the potential pitfalls? Could anything go catastrophically wrong if we succeed? Should some state-spaces of sentience be placed perpetually off-limits as too wonderful even to explore?

This question won’t be answered here. As it happens, I tentatively predict that superintelligent posthumans will be animated by gradients of bliss that are literally billions of times richer than anything biologically accessible today; but whether or not such blissful civilisations exist beyond extremely low density branches of the universal wave-function is pure conjecture. Instead, I want to raise ten objections to the indefinite amplification of well-being - and sketch out ten possible replies.

Umm.

(I should probably try 15 mg methylfolate).

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