Mainstream medicine does not officially recognize the condition commonly known as CFS. Depending on which doctor one asks, the response would be that CFS is either hypochondria, malingering, mental illness, hidden substance abuse disorder, subclinical viral infection, or just sensationalism. As such, the treatment for most patients suspected as having CFS has usually been prescribed (psycho)therapy and SSRI drugs to treat their suspected underlying mental illness. Unfortunately, a new study below demonstrated that SSRI drugs are just about the worst treatment a CFS patient can get due to the fact that it is elevated extracellular 5-HT potentially causing most of the CFS symptoms, especially the debilitating physical/mental fatigue. I am actually surprised it took researchers so long to make that connection, considering the well-tested so-called “central fatigue hypothesis” (CFH), which stipulates that most of the perception of fatigue is brain-derived and often is not peripherally biochemically justified. More specifically, it is the accumulation of serotonin in the brain, which leads one to perceive severe fatigue even if the bioenergetic state of their muscles do not demonstrate signs of fatigue (e.g. lactate buildup, creatine kinase and LDH leakage, ammonia accumulation, etc). Conversely, lowering serotonin levels in the brain usually leads to abolishing the feelings of fatigue. In fact, there are multiple animal studies demonstrating that tryptophan depletion in the brain (which leads to lower 5-HT levels in the brain) is a reliable mechanism to delay or even abolish feelings of fatigue even in animals whose muscles are biochemically fatigued.
Well, the primary symptom of CFS is…fatigue. Also, multiple studies have demonstrated that aside from mitochondrial dysfunction, the cells of CFS sufferers do not exhibit the biochemical signs of fatigue. In some cases, there is a buildup of pyruvate and lactate, but this finding is not consistent. It is this lack of direct evidence of true biochemical fatigue that is the likely main driver behind medicine’s decision to not recognize CFS as an actual organic condition, and to often accuse CFS patients of malingering or hypochondria. However, when viewed through the CFH lenses the CFS condition makes perfect sense and, of course, involves elevated brain serotonin (5-HT). Another fact implicating 5-HT as a causal agent in CFS is the fact that most CFS patients seem to develop the condition as a result of viral infection. As I have posted in the past, most viral infections require activation of specific 5-HT receptors (by elevated serotonin) in order for the infection to take hold, and blocking these receptors either prevents the infection altogether or can treat an already established one. Case in point, recent studies have implicated serotonin overload in COVID-19, and several studies have demonstrated that anti-serotonin drugs such as famotidine or cinanserin can be therapeutic for COVID-19. I suppose it goes without saying that chronic stress can also cause CFS since the former is a well-known inducer of 5-HT synthesis by reliably raises tryptophan (and thus 5-HT) levels in the brain.
Long story short – just 4 weeks of fluoxetine (Prozac) administration to animals induced all the signs/symptoms of CFS. Conversely, inhibiting serotonin synthesis with the drug Fenclonine reversed the already induced CFS. This finding suggests that 5-HT antagonists such as Benadryl, famotidine, cyproheptadine, and ergot class of drugs may also be reliable treatments for CFS. Aspirin inhibits tryptophan absorption from the GI tract and lowers extracellular 5-HT, so that could be another potential remedy. Finally, ingesting BCAA amino acids, as well as tyrosine/phenylalanine may also lead to 5-HT depletion in the brain. In fact, that amino acid protocol was used suucessfully in a prior animal study to delay/block central fatigue due to exhaustive exercise. Finally, androgens such as testosterone and DHT are also 5-HT synthesis inhibitors, as is progesterone, so those steroids may also be viable tools for treating CFS.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04808-x
https://www.sciencealert.com/antidepressants-could-trigger-some-cases-of-chronic-fatigue-syndrome
“…Now a new study based on mice suggests that some drugs used to treat depression, which commonly accompanies ME/CFS, could also ignite the condition. Based on clinical clues, Jin‑Seok Lee, a ME/CFS researcher at Daejeon University in South Korea, and colleagues hypothesized that a spillover of serotonin could lead to ME/CFS. Known to play a role in governing moods, declining levels of the neurotransmitter serotonin have long been thought to cause depression. Although that theory is now disputed, treatments that target serotonin pathways – such as selective serotonin reuptake inhibitors (SSRI) – are some of the most commonly prescribed antidepressants. By blocking receptors that bind and remove serotonin from the signalling pathway, the medication artificially maintains a higher level of the mood messenger. According to several decades-old studies, some patients with ME/CFS appear to have fewer serotonin transporters than healthy volunteers, and may also have receptors that only weakly bind serotonin. Lee and colleagues thought that if such people had coincidentally been treated with serotonin-based treatments for depression before they developed ME/CFS, they may have had excessive levels of serotonin in their brain. This could have triggered ME/CFS by throwing off a feedback mechanism designed to keep a lid on the immune system and inflammation.”
“…After four weeks, animals treated with fluoxetine had higher levels of serotonin in two parts of the brain, the hypothalamus and dorsal raphe nucleus. They also developed behaviors that resembled the main symptoms of ME/CFS seen in humans, including unrefreshing sleep, PEM and orthostatic intolerance, but not cognitive impairment. These behaviors disappeared six weeks after the drug was stopped…Another experiment showed inhibiting serotonin production could alleviate their symptoms. “Our study provides the first translational [animal] evidence for the involvement of serotonergic hyperactivity in the pathophysiology of ME/CFS,” Lee and colleagues conclude, adding that high levels of serotonin could also be used to distinguish ME/CFS from other similar disorders such as fibromyalgia.”
