Early AM wakeup's? Can't fall back to sleep? ~~> low serotonin is likely.

St. John's Wort can help increase serotonin; flush type niacin and tryptophan (5-HTP) are precursors for serotonin.

A post on social media site X/former Twitter was a success/odd story shared by a husband about his wife’s chronic wakefulness in the early morning hours. After trying everything they could think of for his wife’s chronically waking up at 2-3 am and not being able to fall back asleep, he gave her one aspirin and that night she slept for ten hours.

I replied ~ that while an aspirin might help if pain was keeping someone awake, chronically waking in early morning hours is a symptom of low serotonin levels. (Portas, et al. 2000) *paywall and not a clear reference for my point - serotonin modulates sleep in coordination with other neurotransmitters so it is not well understood, or not easy to say exactly how serotonin effects sleep. It has larger roles to play in wakefulness, so just gulping down serotonin wouldn’t help us stay asleep either. St. John’s Wort also modulates multiple neurotransmitters which may be why it seems to help people with sleep problems. More below.

I checked the search engine, and yes, aspirin can lead to increased serotonin levels within the brain in a couple ways - less breakdown being one of the mechanisms of action.

I have experienced this problem and recognized the classic symptom - early am waking up without being able to go back to sleep. *Classic symptom for an herbalist maybe, I am not finding the exact same phrasing that I found easily when I needed it many years ago. ~ “Waking up at 4 am, can’t fall back asleep,” had led me quickly to St. John’s Wort and serotonin when I looked more than a decade ago.

I have tried 5-HTP, tryptophan, a precursor amino acid, but I ended up preferring St. John’s Wort and have used it fairly consistently over the years. St. John’s Wort is a herbal medicinal which modulates serotonin metabolism - how I don’t know. It worked, or it helped enough for me to continue using it.

• St. John’s Wort, insomnia.net. *positive in tone - this helps people. It may be so effective that it gets a Caution: “There are some risks associated with St. Johns Wort especially when taken in combination with other medications, particular MAOI inhibitors and other drugs and supplements that increase serotonin. Large doses of serotonin could lead to serotonin syndrome or toxicity.”

  • St. John’s Wort “inhibits reuptake … of glutamate, serotonin, norepinephrine, and dopamine.” (Vance, et al., 2014)

• 5-HTP, insomnia.net. *more cautious in tone - mixed results, less clear help.

• Vitamins, insomnia.net. Very positive in tone re B vitamins, excerpt follows, and copper, iron, and magnesium deficiencies are mentioned. “These things helped me.” **Addition - Take your B complex or higher dose niacin early in the day as it is stimulating. Dimethylglycine or magnesium glycinate before bed may be calming. Lavender tea can be quite soothing and sleep inducing too. Valerian root is too but smells and tastes funny. Lavender tea is really good.

“B Vitamins and Restfulness

The B vitamins include a battery of essential nutrients, including thiamine (B1), riboflavin (B2), niacin (B3), and folic acid [pyridoxine] (B6), [and folate (B9)], and many more. The B’s are important building blocks in cellular regeneration and provide essential support for your immune system, as well as your skin and central nervous system, the latter of which monitors many of the chemical processes involved with mood and sleep.

When your body is deficient in any of the major B vitamins common early symptoms could include depression and insomnia. But serious deficiencies can be life-threatening. Some people have reported that insomnia symptoms have diminished noticeably once they begin a regular routine of taking B-complex vitamins, a supplement that packages all the B’s together.” (Vitamins/insomnia.net)

The high dose niacin protocol helped my mood and energy and probably my sleep more obviously. It helps increase serotonin and can be amazing if you have been low most of your life. More serotonin can feel like a good mood, and better energy, but you can go too high or crash in serotonin if you suddenly take a bigger dose or forget a big dose that you had been consistently using. Even my 50 mg doses can affect my serotonin balance if I forget to take it for a day. Fifty milligrams is a larger dose than the RDA but is not a megadose, roughly double or three times the standard recommendation.

St. John’s Wort can inhibit reuptake of serotonin - if you already have some serotonin, but if you are chronically low in serotonin, then the body needs enough of the precursors in order to make it.

My main niacin protocol post: (Substack)

Niacin, & early treatment in general for SARS-CoV-2 is sensible, reduces hospitalization and mortality rate.

St; John’s Wort is a common wildflower that can be invasive. It grows in prairie like expanses of a wetland area or in a sunny meadow or clearing and may be two to three tall, mixed among other grasses or reeds. Photo by Lex Melony on Unsplash

Not really related to sleep and serotonin, but these turned up while I was browsing:

Reminder not to mix pharmaceuticals, (published July 2, 2024)

Drug side effects can have a synergistically negative effect - worse together than either alone. Stress cardiomyopathy may result when selective serotonin reuptake inhibitors (SSRIs) are used in combination with serotonin and norepinephrine reuptake inhibitors.

• ‘Risk of stress cardiomyopathy associated with selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors: a real-world pharmacovigilance analysis.’ (Tan, et al., 2024)

CoV illness was worse in people who already had elevated autonomic activity.

Why some people got sick and others didn’t seems to do with how inflamed their system was to begin with. Illness was more likely if the Fear/Stress response was activated as a chronic state, rather than being in a more relaxed state routinely.

• ‘Pre-pandemic autonomic function as a predictor of the COVID clinical course in young adults.’ (Sharma, et al., 2023)

• This topic had a variety of related links.

~~

How does aspirin affect serotonin levels? - Brave AI

Aspirin has been found to have a complex relationship with serotonin levels in the body. While the exact mechanisms are not fully understood, here are some key findings:

• Serotonin levels in response to aspirin: One study found that aspirin exposure increased serotonin levels in the brain, particularly in individuals with depression-like symptoms. This suggests that aspirin may have a positive effect on mood regulation by increasing serotonin levels.

• Aspirin’s impact on serotonin metabolism: Another study discovered that aspirin did not alter serotonin levels but increased serotonin turnover in the brain. This means that aspirin may affect how the body processes and breaks down serotonin, rather than directly influencing its production.

• Interaction with other compounds: Aspirin has been shown to interact with other compounds, such as acetaminophen, which can affect serotonin levels. For example, acetaminophen has been found to increase brain serotonin levels, while aspirin can counteract this effect by increasing serotonin turnover.

• Variable effects in different populations: The effects of aspirin on serotonin levels may vary depending on the population being studied. For instance, one study found that aspirin affected metabolite levels similarly in men and women, while another study discovered that serotonin levels were higher in individuals with depression-like symptoms.

In summary, aspirin’s effect on serotonin levels is complex and may depend on various factors, including the individual’s health status, the presence of other compounds, and the specific mechanism of action. Further research is needed to fully understand the relationship between aspirin and serotonin levels.

Context

Fact checking AI - the third reference is behind a paywall but to the point, aspirin increases serotonin turnover in the brain:

Abstract: We previously showed that acetaminophen administration to rats increases forebrain serotonin levels as a result of the inhibition of liver tryptophan-2,3-dioxygenase (TDO). In this study we determined whether aspirin alone and in combination with acetaminophen could further influence brain serotonin as well as norepinephrine levels and if so whether the status of the liver TDO activity would be altered. The results show that acetaminophen alone increases brain serotonin as well as norepinephrine levels with a concomitant inhibition of liver TDO activity. In contrast, aspirin did not alter the levels of these monoamines but increased serotonin turnover in the brain while acetaminophen decreased the turnover. When combined with acetaminophen, aspirin overrides the reduced serotonin turnover induced by acetaminophen. This report demonstrates the potential of these agents to alter neurotransmitter levels in the brain. Aspirin curtails the acetaminophen-induced rise in brain norepinephrine levels - PubMed

Fact Checking AI - the second reference is vice.com, but it does link to animal study of depression -

Aspirin helped the lab animals with cheerfulness and “swimming more quickly when thrown into water” and the animals were found to have higher serotonin levels. Why Aspirin Is Incredible for Your Health *Note that ‘aspirin’ is the same as ‘salicylates’ in herbs, spices, cold pressed coconut and olive oil and many other healthy foods that I have to limit for my own health needs. Salicylates are anti-cancer and herbs and spices are protective for the majority of people.

“In one recent study, [by Bhatt, et al., 2016] rodents that were genetically predisposed to depression-like symptoms became downright cheerful when given low doses of aspirin for three weeks. Scans revealed higher levels of the mood-regulating chemical serotonin in their brains, and they started swimming more quickly when thrown into water—indicating what can only be interpreted as a real zest for their shitty lab-rat lives.” Why Aspirin Is Incredible for Your Health

The link was broken but I found it on Pubmed - the rats were being treated with CMS to cause depression - and a drop in serotonin, and the aspirin helped restore the serotonin level, slightly above baseline. Hmmm, maybe my sweet tooth is a side effect of retaining too much salicylate: “The groups treated with aspirin showed significant increase in sucrose preference (p < 0.05),…” (Bhatt, et al., 2016)

Fact Checking AI - the first reference is a study coming from the other direction what happens to aspirin effects when serotonin levels varied in the test subjects?

- and is interesting but less directly helpful for answering the question of “How might taking an aspirin have helped prevent early morning insomnia?”

Lower or higher levels of serotonin in a person has been found to affect the platelet aggregation effects of taking aspirin. Collagen or Arachidonic Acid was used to stimulate platelet aggregation and then aspirin was used to inhibit platelet aggregation and whether there was a difference in amount of aggregation (clumping of platelets) was measured. Serotonin alone can mildly promote collagen aggregation of platelets, adding aspirin increased that effect.

“In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20).”

“Before aspirin, no difference was observed between the subjects with the highest and the lowest serotonin levels preaspirin in [Arachidonic Acid] AA- or collagen-induced platelet aggregation (Figure 3c,​dd). Postaspirin, AA-induced platelet aggregation was completely inhibited and no difference was found between the two groups (Figure 3c), whereas collagen-stimulated platelet aggregation was inhibited to a lesser extent in individuals with higher serotonin levels preaspirin (61 ± 11 vs. 72 ± 8% respectively, P = 0.02) (Figure 3d).”

“Finally, although serotonin is a well-described weak platelet activator,^23,24 little is known regarding its action in the context of aspirin therapy. Therefore, we evaluated how ex vivo addition of serotonin to platelets could modify collagen-induced platelet aggregation pre- and postaspirin incubation in a fourth independent group of 12 healthy subjects (functional cohort 2). As expected, in the absence of aspirin, addition of serotonin resulted in a slight increase in collagen-induced platelet aggregation (+2%, P = 0.01) (Figure 3e). After aspirin incubation (16.7 µmol/l or 30 min), the effect of serotonin on platelet aggregation was significantly and substantially larger (+20%, P = 4.9 × 10⁻⁴) (Figure 3e). These results demonstrate that serotonin potentiated the agonist effects of collagen on platelet aggregation more strongly upon aspirin exposure.” Pharmacometabolomics Reveals That Serotonin Is Implicated in Aspirin Response Variability - PMC

1. www.ncbi.nlm.nih.gov, Pharmacometabolomics Reveals That Serotonin Is Implicated in Aspirin Response Variability - PMC

2. www.vice.com, Why Aspirin Is Incredible for Your Health

3. pubmed.ncbi.nlm.nih.gov, Aspirin curtails the acetaminophen-induced rise in brain norepinephrine levels - PubMed

AI-generated answer. Please verify critical facts. Learn more

Follow up [Brave AI generated prompts]

How might the combination of aspirin and other compounds that affect serotonin levels, such as antidepressants, impact serotonin metabolism and mood regulation?

How does aspirin's impact on serotonin metabolism vary across different age groups, and what implications might this have for treating depression in older adults?

What are the potential side effects of increased serotonin levels in the brain, and how might aspirin's influence on serotonin levels contribute to these side effects?

~~~

Fact checking AI take home points - I still like the Brave AI, it has mostly given me accurate links and summaries (compared to Bing), and if all you need is a quick overview, that is a time saver. To understand the topic more though, the summary has been too brief. A human summary might include different key points than the AI provides, or I just don’t summaries as much as an in depth explanation.

Disclaimer: This information is being shared for educational purposes within the guidelines of Fair Use and is not intended for individual health care purposes.

Reference List

(Bhatt, et al., 2016) Bhatt S, Shukla P, Raval J, Goswami S. Role of Aspirin and Dexamethasone against Experimentally Induced Depression in Rats. Basic Clin Pharmacol Toxicol. 2016 Jul;119(1):10-8. doi: 10.1111/bcpt.12539. Epub 2016 Jan 14. PMID: 26645736. https://onlinelibrary.wiley.com/doi/10.1111/bcpt.12539

(Portas, et al. 2000) Portas CM, Bjorvatn B, Ursin R. Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies. Prog Neurobiol. 2000 Jan;60(1):13-35. doi: 10.1016/s0301-0082(98)00097-5. PMID: 10622375. https://www.sciencedirect.com/science/article/abs/pii/S0301008298000975?via%3Dihub

(Saffari, et al., 2024) Saffari PM, Asili P, Eshraghi S, Muhammadnejad A, Dehpour AR, Goudarzi R, Partoazar A. Phosphatidylserine accelerates wound healing and reduces necrosis in the rats: Growth factor activation. Clin Exp Pharmacol Physiol. 2024 Apr;51(4):e13849. doi: 10.1111/1440-1681.13849. PMID: 38408759. https://pubmed.ncbi.nlm.nih.gov/38408759/

(Sharma, et al., 2023) Sharma V, Pattnaik S, Ahluwalia H, Kaur M. Pre-pandemic autonomic function as a predictor of the COVID clinical course in young adults. Clin Exp Pharmacol Physiol. 2023; 50(7): 594-603. doi:10.1111/1440-1681.13776 https://onlinelibrary.wiley.com/doi/10.1111/1440-1681.13776

(Tan, et al., 2024) Tan, B., Chen, L., Yan, S. et al. Risk of stress cardiomyopathy associated with selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors: a real-world pharmacovigilance analysis. Sci Rep 14, 15167 (2024). https://doi.org/10.1038/s41598-024-66155-1 https://www.nature.com/articles/s41598-024-66155-1

(Vance, et al., 2014) Vance KM, Ribnicky DM, Hermann GE, Rogers RC. St. John's Wort enhances the synaptic activity of the nucleus of the solitary tract. Nutrition. 2014 Jul-Aug;30(7-8 Suppl):S37-42. doi: 10.1016/j.nut.2014.02.008. Epub 2014 Feb 28. PMID: 24985104; PMCID: PMC4128486. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128486/