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Serotonin syndrome is a rare, but potentially life-threatening adverse drug reaction that results from intentional self-poisoning, therapeutic drug use, or inadvertent interactions between drugs. It is an iatrogenic (i.e. caused by medical treatment) toxidrome. It is most commonly referred to as serotonin syndrome, however, serotonin toxicity or serotonin toxidrome (from toxic + syndrome) are more accurate as it reflects the fact that it is a form of poisoning.   Rarely it may also be called serotonin storm.
Serotonin syndrome is not a spontaneous drug reaction, it is a consequence of excess serotonergic activity at central nervous system (CNS) and peripheral serotonin receptors. This excess serotonin activity produces a specific spectrum of clinical findings which may range from barely perceptible to fatal. 
Serotonin syndrome is caused by increased serotonin in the central nervous system. It is the result of overstimulation of 5-HT1A receptors in central grey nuclei and the medulla and, perhaps, of overstimulation of 5-HT2 receptors.   These changes are more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects.   
Drugs Which May Contribute
A large number of drugs and drug combinations have been associated with the serotonin syndrome.
|herbs||St John’s Wort, Yohimbe|
|antidepressants||Monoamine oxidase inhibitors (MAOs), TCAs, SSRIs, SNRIs, mirtazapine, venlafaxine, duloxetine|
|opioids||tramadol, pethidine, oxycodone, morphine, meperidine|
|CNS stimulants||phentermine, diethylpropion, amphetamines, sibutramine, methylphenidate|
|5-HT1 agonists||triptans (Naratriptan)|
|illicit drugs||methylenedioxymethamphetamine (MDMA or ecstasy), lysergic acid diethylamide (LSD), cocaine, PMA|
|others||tryptophan, buspirone,dolasetron mesylate, kanna, lithium, linezolid, Lorcaserin, dextromethorphan (DXM), 5-Hydroxytryptophan, chlorpheniramine, Cyclobenzaprine, bupropion, Methylene blue, Netupitant and palonosetron,  , risperidone, Sumatriptan |
|Reference: Rossi, 2005;  National Prescribing Service, 2005 |
The combination of MAOIs and other serotonin agonists or precursors poses a particularly severe risk of a life-threatening serotonin syndrome episode. Many MAOIs inhibit monoamine oxidase irreversibly, so that the enzyme cannot function until it has been replaced by the body, which can take at least two weeks. A dangerous serotonin syndrome reaction can occur unless serotonin agonists and even serotonin precursors such as foods containing tryptophan are strictly avoided until the monoamine oxidase has been replaced.
There have been no peer-reviewed case studies linking a combination of SSRIs and marijuana to serotonin syndrome, though numerous anecdotal reports exist on the internet.
A recently postulated ‘spectrum concept’ of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The dose effect relationship is the term used to describe the effects of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug (which may produce large elevations in serotonin levels). 
Risk and Severity
The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. The serotonergic toxicity of SSRIs increases with dose, but even in over-dose it is insufficient to cause fatalities from serotonin syndrome in healthy adults. The syndrome occurs in approximately 14 to 16 percent of persons who overdose on SSRIs.  It is usually only when drugs with different mechanisms of action are mixed together that elevations of central nervous system serotonin reach potentially fatal levels. The most frequent (and perhaps the only) combination of therapeutic drugs likely to elevate serotonin to that degree is the combination of monoamine oxidase inhibitors with serotonin reuptake inhibitors (various drugs, other than SSRIs, have clinically significant potency as serotonin reuptake inhibitors, e.g. tramadol, amphetamine, and mdma  .
The relative risk of serotonin toxicity provides some clues and insights about the nature and extent of drugs’ serotonergic effects. For example, it suggests mirtazapine, which has no serotonergic toxicity, has no significant serotonergic effects at all, and is not in fact a dual action drug. 
Symptom onset is usually rapid, often occurring within minutes after self-poisoning or a change in medication. Serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may only consist of tachycardia, and shivering, diaphoresis, mydriasis, intermittent tremor or myoclonus, as well as overactive or overresponsive reflexes. In addition moderate intoxication includes abnormalities such as hyperactive bowel sounds, hypertension and hyperthermia; a temperature as high as 40°C (104°F) is common in moderate intoxication. The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental status changes include hypervigilance and agitation. 
Severe symptoms include severe hypertension and tachycardia that may lead to shock. Severe case often have agitated delirium as well as muscular rigidity and high muscular tension. Temperature may rise to above 41.1°C (105.98°F) in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation. 
The symptoms are often described as a clinical triad of abnormalities:
There is no lab test for serotonin syndrome, so diagnosis is by symptom observation and the patient’s history. Serotonin toxicity is a toxidrome (i.e. has a characteristic picture). It is unique and hard to confuse with other medical conditions but in some situations it may go unrecognized because it may be mistaken for a viral illness, anxiety, neurological disorder, or worsening psychiatric condition.  Much confusion has been produced by muddling it with side effects from serotonergic drugs. These rarely, if ever, become dangerous or fatal. Clinicians must also differentiate between serotonin syndrome and neuroleptic malignant syndrome, which has similar symptoms. Patients taking serotonergic drugs and who have sudden onset of symptoms should immediately seek medical care.
The findings of serotonin syndrome, with use of Sternbach, Radomski and Hunter diagnostic criteria and comparison to malignant hypothermia, have been systematically reviewed. 
An important finding is clonus. 
The distinction between serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, and toxicity from cholinergic agents has been reviewed (see chart).  The most difficult distinction is between serotonin syndrome and neuroleptic malignant syndrome as patients may be on drugs that could cause either disorder. Serotonin syndrome shows hyperkinesia, hyperreflexia, and hyperactive bowel sounds, while neuroleptic malignant syndrome shows bradykinesia, bradyreflexia and normal or diminished bowel sounds. A helpful guide is that “dopamine antagonists [such as used to sedate a psychosis] produce bradykinesia, whereas serotonin agonists [such as used to reduce depression] produce hyperkinesia”.  Lastly, neuroleptic malignant syndrome may develop over several days while serotonin syndrome develops faster.
There is no antidote to the condition itself, and management involves the removal of the precipitating drugs, the initiation of supportive care, the control of agitation, the administration of serotonin antagonists (cyproheptadine or methysergide), the control of autonomic instability, and the control of hyperthermia.  
The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving benzodiazepines, and waiting for the symptoms to resolve. If the offending medication is discontinued, the condition will often resolve on its own within 24 hours.   Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists (i.e. cyproheptadine). Critically ill patients should receive the above therapies as well as sedation, neuromuscular paralysis, and intubation. 
Neuroleptic Malignant Syndrome and Serotonin Syndrome
The clinical features of neuroleptic malignant syndrome (NMS) and serotonergic syndrome are very similar. This can make differentiating them very difficult. 
Features, classically present in NMS, that are useful for differentiating the two syndromes are: 
- Muscle rigidity
- Labratory values (increased WBC and CK)
The death of Libby Zion was due to serotonin syndrome caused by a combination of meperidine and phenelzine.  This case had a profound impact on graduate medical education and residency work hour limitations. 
Serotonin syndrome WikiDoc Resources for Serotonin syndrome Evidence Based Medicine Guidelines / Policies / Govt Patient Resources / Community Healthcare Provider Resources
In 2017, the National Institutes of Mental Health reported that a staggering 17.3 million adults, or 7.1% of all American adults had at least one major depressive episode in that year. Of that number, 65% of those folks received support from a health professional, medication or both. Surprisingly, a whopping 35% had no treatment whatsoever.
Because of the difficulty in accessing mental health care, stigmas about disclosing mental illness and the high cost for treatment and medication, it’s not surprising that some people turn to cannabis to help manage their depression.
Many often take marijuana alongside antidepressant medications. But is this safe? Let’s examine the information currently available so that you can make safe, informed choices.
What Are SSRIs & How do They Work?
Selective Serotonin Reuptake Inhibitors (SSRIs) are often prescribed for depression. These medications include:
- Citalopram (Celexa)
- Escitalopram (Lexapro)
- Fluoxetine (Prozac)
- Paroxetine (Paxil, Pexeva)
- Sertraline (Zoloft)
- Vilazodone (Viibryd)
Serotonin is a neurotransmitter that carries chemical signals through the brain’s nerve cells. It has many important functions, including:
- Balancing mood
- Regulating sleep cycles
- Managing digestion
- Aiding memory
- Controlling sexual function
The brain and the intestines produce serotonin, and it’s found throughout the body. Though scientists don’t yet know what causes depression, it’s widely believed that imbalances of the body’s neurotransmitters, particularly low levels of serotonin, are significant factors. SSRIs work by blocking the body from reabsorbing serotonin, making it more available for neurotransmission.
But as many people with depression will attest to, SSRIs aren’t a global fix for depression. There’s currently no way to measure the serotonin levels in the brain, and scientists don’t yet know whether SSRIs added to the bloodstream actually increase serotonin levels in the brain.
Folks Are Already Experimenting With Marijuana for Depression
Because of side effects and the sometimes-limited effectiveness of SSRIs, a significant number of people are substituting cannabis for a variety of antidepressant medications.
According to a 2017 study of 2,774 individuals who had taken cannabis in the previous 90 days, 12.7% of respondents stated they were consuming cannabis as a substitute for antidepressants.
The Medical Community Is Split on How Safe It Is to Mix Marijuana & SSRIs
Some doctors feel strongly that cannabis and antidepressants aren’t a good mix, primarily because you’re combining two medications that may both have psychoactive effects. Is it your Prozac, your Purple Haze or a panic attack that’s causing your increased heart rate? At this point, there’s virtually no way to tell.
However, other physicians, including Dr. Richard Kim, have a different point of view, noting that small amounts of cannabis can be beneficial to those with depression when taken strategically and carefully.
Dr. Kim cites two studies which point to the importance of consuming low doses of cannabis when addressing depression. Because heavy cannabis consumers can become less sensitive to dopamine, the pleasure-pain neurotransmitter, too much marijuana use can sometimes lead to increased depressive symptoms.
The second study points to a research project where researchers gave high doses of tetrahydrocannabinol (THC) to animals, which resulted in reduced serotonin.
Though humans may react differently, both studies point to a simple rule of thumb: When consuming cannabis to augment SSRIs or address symptoms of depression without medication, less is definitely more.
Can Cannabis & SSRIs Increase the Risk of Serotonin Syndrome?
Dr. Kim also notes that both THC and cannabidiol (CBD) can inhibit the enzymes that are involved with metabolizing SSRIs. This could create the possibility of a rise in SSRI serum, which can lead to Serotonin Syndrome, a potentially life-threatening condition when the body has too much serotonin.
Fortunately, for those experimenting with CBD, Dr. Kim explains that it would require an extremely high amount of CBD to produce this dangerous condition.
Some patients using SSRIs also have concerns about their long-term effects on the liver. Because cannabis is considered to be neuroprotective, there’s currently no evidence pointing to any connection between cannabis consumption and liver toxicity.
Tips for Combining Cannabis & SSRIs Safely
When consuming cannabis as an adjunct treatment for any disorder, it’s imperative to work with your doctor, disclose your cannabis consumption and seek out products that have been regulated and tested, so that you can be confident you’re consuming a safe, clean product.
If you’re taking antidepressants and wish to incorporate cannabis into an overall wellness program, be sure to start very slowly and document your results. If you’re a cannabis consumer interested in trying antidepressants, talk it over with your doctor and if you have one, your therapist or mental health practitioner.
Because there has been very little research on the interaction between marijuana and SSRIs, it’s important to know what some of the risks may look like. These risks are low-to-moderate for those taking SSRIs, but increase markedly for patients using other types of antidepressants.
Here are a few tips to help you decide if you should combine SSRIs and cannabis:
- Tell your doctor/counselor about your plans to try SSRIs and marijuana.
- Don’t try to add cannabis to a new SSRI prescription until you’ve fully adjusted to your medication and are on a stable dosage.
- Conversely, if you’re already consuming cannabis and adding an SSRI to your wellness program, consider stopping cannabis consumption until you’ve adjusted to your dosage.
- Closely document your cannabis consumption. Journal the type of product you’re taking, the dosage and how often you consume it.
- Start or resume your cannabis regime slowly, even if you’re a seasoned consumer. Try microdosing to ensure a safe, smooth transition.
- Remember that low doses of cannabis are far less likely to result in negative side effects.
- Remember that cannabis isn’t a one size fits all product. What works for a friend or relative may not work for you, and that’s perfectly OK.
And always remember to reach out to friends, family or your mental health professional if you feel that your depressive symptoms are getting the best of you.
Photo credit: panitanphoto/Shutterstock.com
If you’re new to cannabis and want to learn more, take a look at our Cannabis 101 index of articles. And if you have questions about cannabis, ask them and our community will answer.
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Many folks take marijuana and SSRIs, but is this safe? Let’s look at the science behind combining cannabis and SSRIs so that you can make informed choices.