Many symptoms of serotonin toxicity from medications and supplements are compounded by the fact that some physicians might be unaware of serotonin syndrome as a clinical diagnosis.
This story does not include health advice. It is for information, inspiration, and awareness purposes.
Serotonin is a critical neurotransmitter in mental health and well-being. Its significance has drawn widespread interest from various quarters, including researchers, clinicians, and the public. Well-managed serotonin therapy has helped countless people by addressing deficiency issues.
However, alongside these scientific and clinical needs, commercial interest also exists, driven by the potential profitability of serotonin-related supplements and medications—moreover, unauthorized medications and illicit drugs further compound complications for public health.
As I have previously documented the vital role, intricacies, and natural optimization methods of serotonin in my years of research, I will not repeat those details here. In this story, I aim to highlight a lesser-known aspect and a less-spoken condition called serotonin syndrome.
While extensively documented in scientific literature, this critical health condition eludes public and professional awareness. My aim is to bridge this gap by offering insights from scholarly sources and personal encounters in accessible language, facilitating a broader understanding of this intriguing phenomenon and critical public health concern.
In 1999, when the British Journal of General Practice conducted a survey to identify cases of the serotonin syndrome among patients prescribed a new antidepressant in general practice, and to determine doctors’ awareness of the syndrome, they identified that 85.4% of responding general practitioners were unaware of the serotonin syndrome.
After two decades, there are still cases where the symptoms are misdiagnosed. For example, as reported in a case study in 2023, a 79-year-old patient was diagnosed with serotonin syndrome after experiencing a rash and worsened tremors, which were initially thought to be related to Parkinson’s disease because of their family history.
Thus, the medical report advised that doctors should think about serotonin syndrome as a possible cause when older patients are taking many medications, have psychiatric conditions, are being treated by different doctors, or have a family history of neurodegenerative diseases.
My First Striking Awareness of Serotonin Syndrome
My initial encounter with what we now recognize as serotonin syndrome occurred before the term gained widespread recognition in 1984. The Knob Clinic called the dramatic case “the day medicine changed forever” and articulated the historical background of the situation.
The tragic death of Libby Zion in 1984 ignited public scrutiny over the supervision of novice physicians and created awareness of serotonin syndrome. Within eight hours of her urgent admission to New York Hospital Cornell Medical Center, Libby tragically passed away due to serotonin syndrome.
It wasn’t until later that scientists identified serotonin syndrome as the preventable cause of her death. When I started reviewing the neuroscience and psychiatry literature in the early 1990s, I came across an eye-opening review paper by neuropsychiatrist Dr. Harvey Sternbach published in the American Journal of Psychiatry.
Dr Sternbach conducted a review of the literature on the serotonin syndrome in animals and humans. Twelve reports of 38 cases in human patients were analyzed to determine the most frequently reported clinical features and drug interactions, as well as the incidence, treatment, and outcome of this syndrome.
However, the most informative scientific study was published in the New England Journal of Medicine in 2005 by Dr Edward W. Boyer (MD/PhD) and Dr. Michael Shannon (MD/MPH).
These seasoned researchers and practitioners provided a comprehensive overview of serotonin syndrome, including its epidemiology, pathophysiology, clinical manifestations, and management. This exceptional paper has been highly influential in guiding clinical practice and research related to serotonin syndrome.
They mentioned the 2002 report (later cited in the Journal of Palliative Medicine), including the Toxic Exposure Surveillance System, which received case descriptions from office-based practices, inpatient settings, and emergency departments, reported 26,733 incidences of exposure to selective serotonin reuptake inhibitors (SSRIs) that caused significant toxic effects in 7349 persons and resulted in 93 deaths.
These researchers pointed out that serotonin syndrome was not an idiopathic drug reaction. It is a predictable consequence of excess serotonergic agonism of central nervous system receptors and peripheral serotonergic receptors.
Idiopathic drug reaction simply means that a person experiences a reaction to a medication, but the exact cause of the reaction is unknown or cannot be identified. It is like saying that the reaction happens for no apparent reason or without a clear explanation.
A Brief Overview of the Public Health Status of Serotonin Syndrome
Epidemiologists documented the details in various review papers, showing progress and critical implications for public health. I want to summarize the key findings from a 2019 review paper.
The paper informs that serotonin syndrome affects people of all ages, from newborns to the elderly, and its occurrence is increasing due to the more widespread use of drugs that affect serotonin levels.
The use of antidepressants in adults in the United States nearly doubled from 1999 to 2010. In 2016, over 54,000 cases of exposure to serotonin-affecting drugs were reported, with over 100 resulting in death.
Studies show that about 15% of poisonings with antidepressants lead to moderate serotonin syndrome.
However, the true number of cases and their severity are unclear because the condition is often unrecognized or underreported by doctors, surveys suggesting that many general physicians still are not familiar with serotonin syndrome.
Additionally, mild cases may go unnoticed or resolve on their own, making it difficult to estimate the full extent of the public health problem.
What is serotonin syndrome in simple terms, and what are its key symptoms?
Serotonin is a neurotransmitter that plays a crucial role in regulating mood, behavior, appetite, and several other physiological functions.
Serotonin syndrome (also known as serotonin toxicity) is a potentially life-threatening condition caused by an excess of serotonin in the body. When serotonin levels become too high, it can lead to various symptoms, from mild to severe.
Some well-documented symptoms in the literature include agitation, restlessness, confusion, rapid heart rate, high blood pressure, tremors, diarrhea, sweating, shivering, headaches, seizures, and even loss of consciousness.
As documented in this NIH book chapter, “The true incidence of serotonin syndrome is unknown, most likely because mild cases are frequently overlooked or dismissed. Even more serious cases may frequently be attributed to other causes.
The book informs that “there is no confirmatory test or specific laboratory findings, and the syndrome has a broad spectrum of severity ranging from barely perceptible to lethal.”
What are the major causes of serotonin syndrome?
This paper states that “although the exact mechanism is unknown, there are several pathways via which a significant interaction could occur. This would include the effects methadone has on N-methyl-D-aspartate in addition to the impact of methadone on the cytochrome P450 enzyme system.”
Serotonin syndrome can occur when there is an increase in serotonin levels due to various factors, such as overdosing or a combination of medication and supplements. Taking certain medications can increase serotonin levels.
Some examples are selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, pain medications known as opioids like tramadol, fentanyl, and recreational drugs like MDMA, LSD, or D-amphetamine.
For example, this 2023 case study in the Egyptian Journal of Internal Medicine informs that a 38-year-old man with a history of depression treated with fluoxetine and chronic back pain managed with tramadol presented at a Hospital in Egypt with acute confusion, hyperpyrexia, and severe agitation.
This Egyptian patient’s symptoms began a month after starting fluoxetine. Serotonin syndrome was diagnosed due to hyperpyrexia, inducible clonus, tremors, agitation, and concurrent use of two serotonergic medications.
Apart from overdosing on medications, combining multiple medications or supplements can adversely affect serotonin levels, leading to serotonin syndrome.
This paper informs that “the myriad of symptoms with which serotonin syndrome may present is compounded by the fact that more than 85% of physicians are unaware of serotonin syndrome as a clinical diagnosis.”
Can 5-HTP or Tryptophan supplementation cause It?
Both 5-HTP and tryptophan are precursors to serotonin, meaning they are converted into serotonin in the body. By increasing the availability of these precursors, serotonin levels can rise. I researched and used both and will document my experience in an upcoming story.
Studies indicate that 5-HTP (5-Hydroxytryptophan) and tryptophan supplementation might potentially contribute to serotonin syndrome, particularly if taken in high doses or in combination with other medications or substances that increase serotonin levels.
For example, this 2021 paper in the International Journal of Molecular Science informs that “clinically relevant ingestion of 5-HTP in dogs was found to result in a potentially life-threatening syndrome resembling serotonin syndrome in humans, which requires prompt and aggressive care.”
These researchers also mentioned that “after 5-HTP administration, the endogenous serotonin levels increased fourfold in the rat plasma and brain, associated with profound hyperthermia, oxidative stress, and nitric oxide upregulation.”
While 5-HTP and tryptophan are dietary supplements to support mood, sleep, and appetite regulation, they can still pose risks, especially when combined with other medications or supplements that also affect serotonin levels.
Therefore, patients need to consider supplementation with 5-HTP or tryptophan by consulting with qualified healthcare professionals, especially if they are already taking medications that affect serotonin or have a history of serotonin syndrome.
Healthcare providers can provide personalized guidance on the safe use of these supplements and help assess the potential risks and benefits based on individual health factors and medication regimens. Additionally, healthcare providers can monitor for signs of serotonin syndrome and adjust treatment plans accordingly to minimize the risk of adverse effects.
5-HTP is tightly regulated in some countries like Australia and is only provided with a physician's prescription. In 2002, the FDA took action to limit the availability of dietary supplements containing the amino acid that is the biological precursor of L-5-hydroxytryptophan because of the association between dietary supplements containing L-Tryptophan and the 1989 epidemic outbreak of eosinophilia-myalgia syndrome in the US.
What are SSRIs and their known risks?
In my 20s, while living in Europe, I faced SAD and mild depression that led to what I believed were healthy lifestyle choices. Doctors prescribed SSRIs, which initially alleviated my symptoms and brought the happiness that I needed.
However, with guidance from prominent psychiatrists, I later learned about potential long-term concerns associated with SSRIs. These mentors, well-versed in neurotransmitters and the ramifications of artificial manipulation, provided invaluable insights.
They inspired me to naturally increase serotonin via healthy lifestyle choices like exercise and sunlight. I documented the Striking Adverse Effects of Night Light Exposure on Mental Health.
Selective serotonin reuptake inhibitors (SSRIs) are a class of medications prescribed to treat depression and various anxiety disorders. They work by blocking the reuptake (reabsorption) of serotonin in the brain, allowing serotonin levels to increase and remain balanced in the synaptic space between neurons.
This NIH book chapter informs that “SSRIs have FDA-approved indications for treating major depressive disorder, generalized anxiety disorder, bulimia nervosa, bipolar depression, obsessive-compulsive disorder, panic disorder, premenstrual dysphoric disorder, treatment-resistant depression, post-traumatic stress disorder, and social anxiety disorder.”
The book informs that SSRIs are approved for use in adult and pediatric patients (children). The SSRIs currently in use in the US include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, and vilazodone.
While SSRIs are generally considered safe and effective, they carry some risks. Apart from serotonin syndrome, in extreme/rare cases, they might have potential side effects like nausea, headaches, insomnia, and sexual dysfunction.
As pointed out in this 2022 paper in Nature, there is concern that selective serotonin reuptake inhibitor (SSRI) treatment may increase the risk of suicide attempts or deaths, particularly among children and adolescents. However, debate remains regarding the nature of the relationship.
However, the study used nationwide Swedish registers and identified all individuals aged 6–59 years with an incident SSRI dispensation of 538,577 from 2006 to 2013. Their results do not suggest that SSRI treatment increases the risk of suicidal behavior in either youths or adults; rather, it may reduce the risk. Further research with different study designs and in different populations is warranted.
Prolonged use of SSRIs has been associated with withdrawal symptoms upon discontinuation. Therefore, it is essential for healthcare providers like family doctors, psychiatrists, and neurologists to carefully monitor patients taking SSRIs to mitigate these risks and ensure optimal treatment outcomes.
This 2017 paper in the Canadian Medical Association Journal states that failure to recognize antidepressant discontinuation syndrome may result in medical or psychiatric misdiagnosis. The researchers introduce the mnemonic FINISH. It stands for:
Flu-like symptoms (lethargy, fatigue, headache, achiness, sweating), Insomnia (with vivid dreams or nightmares), Nausea (sometimes vomiting), Imbalance (dizziness, vertigo, light-headedness), Sensory disturbances (“burning,” “tingling,” “electric-like” or “shock-like” sensations) and Hyperarousal (anxiety, irritability, agitation, aggression, mania, jerkiness).
How can we overcome or prevent serotonin syndrome?
Serotonin syndrome is a severe condition that requires prompt recognition and treatment to prevent potentially life-threatening complications. Healthcare professionals and patients must work to prevent, identify, and manage this condition effectively.
Several practices and interventions can be employed to overcome serotonin syndrome. If doctors suspect serotonin syndrome, they need to ask the patients to stop taking medications that may be contributing to the condition.
Treatment involves supportive care to manage symptoms. This may include administering intravenous fluids to prevent dehydration, controlling agitation with sedatives, and monitoring vital signs closely.
Severe cases of serotonin syndrome may require hospitalization for close monitoring and intensive care. In severe cases, medications that directly antagonize serotonin receptors, such as those known since 1999, cyproheptadine, may be administered to reduce serotonin levels and alleviate symptoms.
For example, these clinicians, published in Clinical Case Reports in 2023, successfully used Cyproheptadine and supportive care to treat serotonin syndrome, and the patient was discharged home 14 days postoperatively. Based on the literature, there is no standardized method of weaning cyproheptadine when used for serotonin syndrome.
Healthcare professionals should carefully monitor patients who are prescribed medications that affect serotonin levels, mainly when multiple such medications are being used concurrently. Patients should be educated about the signs and symptoms of serotonin syndrome so they can seek medical attention promptly if necessary.
This 2022 paper in BMJ states, “The severity of serotonin syndrome can be assessed clinically based on the number and severity of features. Severe serotonin syndrome warrants more careful management on a high-dependency unit. If the temperature exceeds 38.5°C, urgent cooling measures and sedation should be employed, progressing to rapid sequence intubation and paralysis if cooling measures are ineffective.”
Conclusions and Takeaways
Serotonin is an essential neurotransmitter crucial to mental health and well-being. Some people also need medication to balance serotonin levels in the brain. However, serotonin syndrome is a critical condition that demands attention from patients and doctors.
Serotonin syndrome is often overlooked or misdiagnosed. Triggered by an excess of serotonin, the condition presents a spectrum of symptoms ranging from mild to severe. Elevated levels of serotonin pose significant risks, especially for patients on multiple medications or supplements that impact serotonin levels in the brain.
Libby Zion’s tragic death in 1984 emphasized the need for heightened awareness, yet some physicians still seem to remain unaware of this syndrome. Therefore, we need to be more aware of this critical condition.
My journey from encountering serotonin syndrome in its early stages to exploring its growing complexities due to complicated health conditions highlights the urgency of educating both healthcare professionals and the public.
We need to know the signs and be vigilant about symptoms like agitation, hyperthermia, and tremors, especially when we are on multiple medications affecting serotonin.
When suspecting serotonin syndrome, we must promptly obtain medical help and consider stopping medications contributing to the condition.
We must educate ourselves about serotonin syndrome and its risk factors, mainly when we are on antidepressant or pain-killing medications, including serotonin.
We must exercise caution with serotonin-boosting supplements like 5-HTP or tryptophan, especially when combined with other medications. It is essential to stay away from recreational drugs, increasing serotonin levels by an order of magnitude.
Healthcare providers should closely monitor patients on serotonin-affecting medications, adjust treatment plans to mitigate risks and educate patients.
In severe cases, patients need to pursue urgent medical care for prompt treatment and management, as serotonin syndrome can lead to life-threatening complications if left untreated.
Thank you for reading my perspectives. I wish you a healthy and happy life.
If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.