In the first part of this blog, i described the circumstances surrounding my decision to take more "meds".
Yea, no one wants to take more crap, but I had become frustrated by my inability to do basic human being things like sleep 7 hrs. I had been pretty much feeling better, sleep began to relapse into the unacceptable zone of <6 hrs. I have a rule; sleep at least 6 hrs. 6 is like this magic number where if you're doing that, you're probably not a mess. It's one of my personal goals / rules in addition to 'feel normally", "be a productive member of society" and "dont take seroquel", haha.
I have written previously how using a tiny dose of lithium carbonate has been a great help to me, and continues to be. It never entirely resolved my sleep problems (but to be fair to it, i'm taking a subclinical amount. Considering that, it's done huge things.) The problem with Li is it will trash your kidney. It's just not a good idea to take that unless absolutely necessary; if you're feeling otherwise okay and things are fine, its probably not the best idea to take more Li than necessary for ongoing difficulties with sleep. It's one thing to take a lot of lithium for severe mental illness, it's another reason to take it because you dont sleep as well as you would like, as a stable trait. I'd rather not have declining renal function when there are likely other safer methods to extend sleep.
I considered how totally useless all sleeping pills are. The least useless was my stint with baby seroquel (super low dose 25mg). From memory it did put me to sleep rather quickly and reliably, but failed to cure sleep duration. Furthermore, it made agitation/overstimulation worse. I loathed the thing so much for enhancing my agitation, augmenting appetite at the same time, haha. It was then i realized my enduring hatred of seroquel was because it just sucked for the purpose i was given it: it failed to help calm, and made agitation worse, and wasnt enough to resolve insomnia. Well good news, I'm not agiated, and all i need is something to reliably put me back to sleep when i wake up.
Preparing myself for angst and failure, i set out to trial low dose quel after my usual early wakeup. Lithium helps stabilize my sleep time (kratom does as well), and lithium totally cured early onset insomnia (i fall asleep rapidly when i go to bed). The problem is duration. I often sleep for 5 hrs, and begin waking when REM dreams happen . My body just quits sleeping after 5 hrs or so and thats the end of it. Nothing i do seems to resolve this last remaining symptom; the best i can accomplish is lightly sleeping an extra hour to make 6-6.5 total broken sleep.
I went to bed as i usually do, and woke early as i usually do. I took my old 'quel - expired as hell, unsure if it would even have an effect. It did. Sure enough, within an hour, i became aware of my appetite, lol. Shortly after that, I fell asleep. I woke up 1-2 hrs later to nightmares, but wake up later I DID. Total sleep time, nearly 7 hrs. Success
I assessed my condition upon waking, if it was acceptable. As a veteran of taking lithium and various sedative garbage, adding on the seroquel FUBAR was different, but not intolerable. I'm already used to being a bit shaky and slow, now we can add wobbly and physically disoriented to the mix. Meh. Appetite was not untenable, overall the effects were tolerable. Sleep of a normal duration when NOTHING else helps is extremely valuable.
I repeated this experiment the next day; and the next day, it was also successful. As I used it, I began to notice I felt better, soothed yet motivated. It felt similar to kratom when that was more effective, with a warm weather like norepinephrine motivation. For weeks i had been slumping in my chair, unable / unwilling to do things. Suddenly, using this tiny seroquel, not only was i sleeping, but upon waking i had lots of motivation and felt very well. Though more groggy waking, my wellbeing mood and motivation seemed enhanced by it. It felt very much as if it were not fall, but spring or summer - I was reminded of the early days of kratom use when it was such a help to me. This is more significant since improving sleep while improving mood/motivation is like THE EPIC DREAM , haha. Usually its one or the other.
A few times i experimented with benadryl. Low dose seroquel is primarily a H1 histamine antagonist, this is believed to mediate its sedative effects. Benadryl was worse than useless. I became slightly disoriented, hungry, with no sleep enhancement. On benadryl days I just end up eating more as i sleep poorly and have blocked histamine to maket hat worse, so i would rank benadryl as actually a poorer choice than low dose quel. The mood effects are not there with benadryl either.
The more times i used this, the more it felt "this is a medicine that is really helping me " vs "this is a last resort i'm using with extreme penalty to sleep a little bit". I felt happier, like myself when kratom worked very well. Unlike during that time, this chemical provides a norepinephrine like motivation as I do in the summer and spring. Additionally, I was sleeping like a normal person; the sleep improvement which was my primary aim started to become one of many reasons to use this chemical. It began to feel a kin to me, potentially curative as lithium did when i discovered that.
I set out to learn more about it, how it might be helping me.
Seroquel is the brand name of the molecule quetiapine which is classified as an atypical antipsychotic. That sounds horrible, and it's also kinda wildly inaccurate in spite of reputation. This blog entry by the last psychiatrist explains the issue more accurately and humorously than i can. It's a really interesting, and misunderstood chemical. The TL;DR is that quetiapine is a calming, unique antidepressant at all doses <300mg. It has zero antipsychotic (d2 blocking) effects until about 300-400mg, depending on bodyweight of the user. The AAP class of drugs tend to bind to a ton of receptors, but they do so with different affinity, and concentration of drug in the brain determines which receptors are occupied first.
This graph borrowed from bipolarnews.org explains further:
Excusing the cheesy drug-rep like nature of this graph, what we can see here is a pretty handy guide of what 'quel does at different dose ranges for an average bodyweight patient.
At the minimum doses, you get h1 antagonism, 5ht2a antagonism, and NET inhibition. Quel is used offlabel for sedation due to the H1 antagonist and a1 antagonism (that also happens low; not all receptors are represented in this chart, obviously, just the psychiatrically major ones).
At doses higher than that you get an effect big enough to move clinical depression in combination with antidepressants.
At doses even higher than that, it is indicated as monotherapy depression for bipolar (probably with a mood stabilizer, as quel is not antimanic at this dose).
It's not until one is taking 400mg that this chemical is even slightly acting as an antipsychotic, with the unsavory side effects we associate with D2 blockade. Anything lower than that is simply mood boost, calming, more mood boost, and more sleep help .
This big "aha" moment clicked for me, and i realized the reason i HATED seroquel is I was given it in a small dose as a "calming as needed" medication, when all it can possibly do is sedate (via histamine block) while RAISING serotonin and norepinephrine. An agitated person probably has an excess of NE, one of the things Li will shut down just handily. Using low dose seroquel as a medication to calm anyone with endogenous agitation or stimulation is one of the stupidest things you can probably do, so my response of worsened agitation was kind of expected.
Here's a tip: histamine blocking isnt calming. Sedation and grogginess does not stop an agitation. Lithium does that, H1+5ht2a+NET does not, and actually makes it worse. For further evidence, in a different context using quel in the fall, in no need of "calming medication", I find it provides a helpful boost, a kick of energy and motivation from that same NET that previously worsened my agitation. In spite of the burden of grogginess from H1 blockade, my overall motivation and wellbeing has improved on just this tiny amount of medicine. It feels to me to be more like the spring or summer than the fall, a feeling i had previously enjoyed when i first discovered Kratom. Using Li to control agitation makes sense; using baby quel makes no sense at all and can only possibly worsen this.
Conversing with "normal" people i'm told many respond to any dose of quel with sedation and calming, so I guess its one of those things that only applies to people with endogenous brain chemical issues. I'm also told even tiny amounts of lithium are intolerable from mental slowing and fatigue.WHATEVS.
This was a useful insight ; a NET inhibitor may be intolerable and worsen me if agitated, although it might restore the ease of sunlight months in another context (not overstimulated, and using Li)
An insight of even greater interest is remarking the similarities between mitragynine and quetiapine in how I felt better, with greater sleep. It's been an ongoing NERD QUEST to find a drug/medicine that can do what kratom did: sleep and happy. I have hypothesized (and agonized) which effects I am responding to so I might source out alternatives. There was always a risk it might become illegal, which seems more likely than ever in light of recent events. It would also be socially convenient to take a FDA approved, evidenced and quality controlled medication vs relying on some shady plant.
The primary alkaloid in kratom is mirtagynine. Mirtragynine's main receptor targets are the mu/delta receptors, an adrenergic agonist particularly at a2r, and a 5ht2a antagonist. I had already formed a working hypothesis that the mood enhancement, sleep enhancement i had previously enjoyed was primarily an effect of 5ht2a antagonism. Supporting evidence would be my lifelong intolerance of elevated serotonin states, except during the full potency of 5ht2a antagonist mitragynine. Doing well on a ketogenic diet which limits tryptophan synthesis of 5ht further suggests an innate serotonin system defect. Taking 5htp, a precursor that readily crosses the BBB to enhance serotonin levels, even while adhering to the diet, exaggerates issues similar to breaking the diet.
Before I proceed any further, it would be useful if i describe a bit what 5ht2a is and does, seeing as it is the central topic of this blog. This blog post by selfhacked is well referenced with info, and wikipedia has a bit as well.
Basically 5ht2a is bad. You do not want to have an excess of this.
The TL;DR is 5ht2a is an inflammatory, HPA activating glutamate generating serotonin autoreceptor. Its almost like an "anti serotonin" receptor; activation lowers 5ht levels, while promoting stress and inflammation.
For greater elaboration:
Hyperexpression of 5ht2a is a trait associated with depression, schizophrenia, and suicide. Pts who complete suicide are noted post mortem to have an abundance of 5ht2a receptors. This might relate to adverse drug responses such as greater suicide upon SSRI, as well as suicide risk in the spring season. Some patients are made worse with serotonin increases, if hyperexpressing 5ht2a.
It is hallucinogenic, responsible for the psychedelic effects of 5ht drugs of abuse
5ht2a is inflammatory (and blockade is antinflammatory); immune activation may make the receptors more receptive in a cycle. This would further the link between immune activation and psychiatric problems.
Stress and cortisol sensitize to 5ht2a receptors; 5ht2a also augments the stress response in a cycle by synthesizing ACTH and cortisone (complementary with sickness-like immune system enhancement previously described).
5ht2a is rather influential in sleep physiology. Blockade induces deeper, restorative sleep, and longer sleep duration. The psychiatric meds that block 5ht2a specifically like seroquel and remeron are known for normalizing sleep in patients who have more profound insomnia. In combination with previously discussed HPA augmenting effects, it seems likely overexpression of 5ht2a is a correlate of life long insomnia.
5ht2a activation is CNS excitatory generating more glutamate, excitatory states are a general mental health liability.
Reduced BDNF, another general psychiatric liability.
I have entertained the idea 5ht2a might be the "main thing" wrong. It would explain why persistent sleep issues, being made worse by higher 5ht states (eating carbs worsens me, 5htp worsens me, why antinflammatories make me feel better and help my sleep (if reducing 5ht2a function). Kratom is very antinflammatory and a direct 5ht2a blocker. I did not have the means to test my hypothesis until accidentally using low dose seroquel and discovering it reinforced the effect kratom used to give me. That highly suggests 5ht2a blockade is the primary effect, as it could be enhanced with a small amount of a blocker.
Last summer, when kratom began to fail due to tolerance, stressful life events, I spent my days analyzing a way to resolve the problem. To my knowledge at the time there was a total lack of available simple 5ht2a antagonist mediations. At the time I believed all 5ht2a blockers had intolerable metabolic and quality of life and health side effects, such as mirtazapine (which blocks 5ht2c , making it a strongner antidepressant and metabolically harmful) or atypical antipsychotics (which block D2, which ruins quality of life, and also metabolically harmful). Now if you need a stronger antidepressant , or an antipsychotic, these meds can be justified. Otherwise, they are not justifiable, and more harmful than helpful.
At the time I was fortunate enough to utilize lithium which was a great help. Similar to direct 5ht2a blocking, Li generates 5ht, but inhibits the HPA / glutamatergic / gsk3b inducing effects of 5ht2a activation . Though Li is not a 5ht2a blocker, it selectively targes and shuts down the downstream effects of its activation: HPA, glutamate, gsk3b induction. GSK3b is more famously known as the target of lithium as an antimanic, circadian regulating agent (Li is a potent GSK3B inhibitor). However, other research suggests gsk3b is generally a psychiatric liability, and is inhibited by 5ht and all antidepressants. Here's an article of interest describing the relationship / regulation of the 5ht system and gsk3. (TL;DR, 5ht2a induces gsk3b, 5ht1a inhibits it. All antidepressants/higher 5ht tone in the brain generally inhibits gsk3b. Directly inhibiting gsk3b also abolishes anxiety and depression behavior in rats similarly as raising 5ht / antidepressants do. Clearly the GSK3b story is more complex than "bipolar/mania" but its fairly complicated."
For sake of getting too detailed, technical, and tangential I'll return to my broader point: the "cure" i had with mitragynine, was restored by adding on a little bit of quetiapine. These chemicals have nothing in common, affect norepinephrine in *opposite* ways, but both are 5ht2a blockers. What I once ironically joked as a fate worse than death due to ignorance and bad experiences, ironically ended up being the medicine I was seeking months ago.
I've gained the following insights from my experiences:
True to my primary hypothesis, the "curative" like impact of kratom was very likely orchestrated through 5ht2a blocking of mirtragynine. Mirtagynine is useful as a mood brightening, generally calming medication as it has antiadrenergic/sympatholytic effects and the mu agonist. On the other hand , quetiapine is stimulating, uplifting, and boosts norepinephrine. These two chemicals have little in common, but both block 5ht2a, and seemed more similar than anything else to feel better, while normalizing sleep.
Quetiapine has a horrific reputation, partly due to the fact it's an "antipsychotic" associated with severe mental illness, stigma and social/occupational impairment. Pharmacology wise it's actually a really nice antidepressant for people with crappy serotonin systems. If you cant handle 5ht because your genes suck, you need the 5ht2a blocker. Its also a nice NET inhibitor for a kick of motivation. Its likely a great medication if you need it. I feel badly my ignorance may have caused people to deny considering it. This is one reason i motivated myself to make this blog entry tonight in spite of limited time. I would like to share my experience and insights, but to redress any wrongs joking as I did its "horrible".
In closing, I would like to again address the unfortunate reality some humans are broken and need to do shit like take chemicals.The higher SES, healthy living, privileged white perspective is "nature is a stable default; all of humankind is entitled to health and happiness; if you have illness, it's because you're not purifed/whole 30 paleo enough". We are made perfect in god's image, if we honor respect the sacred temple of our bodies, we will have salvation. We should purge and abstain from sins of modern chemicals, food impurities, technology, and we may live eternal, ageless and exalted and in the garden of paleo eden.
Sorry, no.
Brokenness is real. I dont know how to tell you this, but its pretty likely I inherited a cluster of genetic defects, which result in me needing to take medications to sleep and feel normally. My family on my fathers side is pretty well afflicted entirely by serious mental issues, it is what it is.
Brokenness is relative. Life is not a stable enduring garden of eden free of changing selection pressures, or any pressures at all. Broken is not defined by feeling unhappy or ill, from an evolutionary perspective all that matters is genetic success. If you really comprehend evolutionary theory you ought to know this isnt a map to entitlement to happiness - its a description for survival of genes, for better or worse. A child in africa with sickle cell trait is less broken than the child who contracted malaria and dies. Mild anemia is problematic, but it is is less problematic than death. The fact +/+ inheritance is painfully fatal is incidental to the overall evolutionary valuable genetic selection of sickle cell trait. In the modern world, america, sickle cell trait has no use at all, and all carriers are always broken relative to noncarrier. There arent malaria mosquitos in america, the cost of mild anemia has no survival benefit.
There are many examples of innate, predestined brokenness which requires medication, treatments, implicit with pain and illness. Perhaps at one time these traits were the less broken option, now all it means is you cant sleep and need to take seroquel to adjust your fucked up 5ht2a receptors, while explaining to yuppies humans actually are broken.