Can L-Theanine Cause Serotonin Syndrome Or Seizures?
In our latest question and answer, the pharmacist discusses whether or not L-theanine can cause seizures or precipitate serotonin syndrome.
Can you let me know if there is anything in the medical literature or FDA adverse reports regarding L-Theanine precipitating serotonin syndrome or seizures? Also, can L-Theanine be used in concurrence with MAOI's?
It can be extremely difficult to give definitive answers regarding the efficacy or side effects of over the counter supplements and herbal products simply due to the lack of high-quality studies regarding them.
As it concerns L-theanine, things are no different...studies are lacking. Making things more difficult is the fact that most studies that research L-theanine often utilize it in combination with other ingredients, like caffeine, making it challenging to deduce the effects of a single agent.
Nevertheless, we do have some reliable, albeit preliminary, information that has been published about l-theanine, and can, therefore, have a discussion regarding its potential therapeutic uses, adverse effects, etc...
In the next sections, I will discuss your questions in more detail, which are:
- Can L-Theanine precipitate (i.e. cause) serotonin syndrome? (Maybe, since it can increase serotonin levels)
- Can L-Theanine cause seizures? (Maybe, but studies are conflicting)
- Can L-Theanine be used with MAOI's? (There may be an interaction, but there is a lack of drug interaction data to go off of)
First, I will start off by discussing what exactly L-Theanine is.
What Is L-Theanine?
Theanine is an amino acid that was originally discovered as a constituent in green tea in the late 1940s. While it is an amino acid, it is a non-protein one, and therefore, isn't classified as either essential or non-essential. Nevertheless, it is very similar in structure to the non-essential amino acid L-glutamine, as shown in the below image.
In green tea, in addition to its potential medicinal effects, it is thought to contribute to the umami taste of the beverage.
Since its discovery, L-theanine has been popularly used in over the counter supplements and used to treat a variety of conditions, including:
- Anxiety and stress
- Alzheimer's disease
- Attention deficit-hyperactivity disorder (ADHD)
It also is used to improve cognitive performance.
How Is L-Theanine Produced?
As mentioned, L-theanine was first discovered as a component of green tea.
More recent studies have shown that green tea, on average, contains 1% to 3% theanine (98% of which is 'L-theanine while the other 2% is 'D-theanine', which isn't thought to be as active as L-theanine).
While L-theanine can be consumed via intake of tea, it is produced commercially (for use in supplements) via extraction from tea leaves or via chemical/biosynthesis.
What Does L-Theanine Do?
L-Theanine is thought to have a wide variety of actions and effects in the body.
Most studies report the following actions:
- Increases concentrations of GABA
- Increases concentrations of serotonin
- Increases alpha activity in the brain
- Increases concentrations of dopamine
- Competes with L-glutamine for binding with glutamate receptors (i.e. acts as an antagonist)
All of the above are thought to contribute to L-theanine's effects.
Let's take the L-theanine's use in anxiety for example. While the physiology of anxiety is complex, studies have shown that L-theanine can decrease anxiety levels after supplementation. This is likely to do with L-theanine's ability to increase GABA, an inhibitory neurotransmitter, and serotonin, a neurotransmitter integral in mood regulation.
For depression, it is thought that theanine's antidepressant effects are related to its effects on the glutamatergic pathway (this mechanism may also be why L-theanine could have benefits for patients with dementia).
One study, researching L-theanine for its anti-anxiety and antidepressant effects, concluded the following:
Our study suggests that chronic (8-week) l-theanine administration is safe and has multiple beneficial effects on depressive symptoms, anxiety, sleep disturbance and cognitive impairments in patients with MDD [major depressive disorder]. However, since this is an open-label study, placebo-controlled studies are required to consolidate the effects.
Can L-Theanine Cause Serotonin Syndrome?
Serotonin syndrome is a rare but serious medical condition that occurs from elevated serotonin levels in the brain. Symptoms of serotonin syndrome include:
- Muscle tremors and rigidity
- Increased blood pressure
If left untreated serotonin syndrome can result in coma or even death.
While the overall incidence rate of serotonin syndrome in those taking serotonergic drugs (like SSRIs) alone is low, the more drugs you take that affect serotonin, the more at risk you are of it occurring.
This is why there will nearly always be a listed drug interaction between two serotonergic drugs. The 'prescribing information' for drugs that act on serotonin will always warn of the potential of serotonin syndrome. For example, the following is from the prescribing information for Zoloft (sertraline), an SSRI:
The risk [of serotonin syndrome] is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin...
Studies show that L-theanine administration can increase concentrations of several neurotransmitters in the brain, including:
Even though we have good evidence that L-theanine increases serotonin concentrations, I could not find a single study or case report of serotonin syndrome occurring after l-theanine administration.
This certainly good news for those wishing to use it as a supplement and may be taking another serotonergic drug, but we can't rule out the fact that it may still be a risk factor for serotonin syndrome.
We simply may not have enough data to make a determination and/or potential cases may be underreported.
Other supplements that increase serotonin have been implicated in cases of serotonin syndrome, including St. John's Wort, tryptophan, and 5-HTP. In fact, Poison Control discusses the potential risk of using serotonergic supplements (like 5-HTP) in those taking serotonergic prescription drugs:
Because antidepressants generally work by increasing serotonin in the brain, 5-HTP could combine with these medications to cause high concentrations of serotonin. Having too much serotonin can lead to serotonin syndrome, a serious condition characterized by dangerously high heart rate, blood pressure, and temperature.
The overall point is that even though the risk of serotonin syndrome in those taking L-theanine appears to be small, we can't rule out the fact that it may still increase the risk of it since it does increase serotonin concentrations,
Can L-Theanine Cause Seizures?
There is mixed evidence in regard to how L-theanine could affect those with seizures.
It would make sense that l-theanine be at least investigated on its potential benefits since it affects both glutamine and GABA, both of which are involved in the pathophysiology of epileptic conditions.
One study, completed in mice, comments on this:
Surprisingly, and in spite of the known interaction with glutamate receptors and glutamine transporters as well as the reported effects of L-theanine on intracerebral gamma-aminobutyric acid (GABA) concentrations, the effect of L-theanine on seizure susceptibility was never investigated
The study referenced above found that l-theanine increased the threshold for limbic seizures (meaning they would occur less frequently) but decreases the threshold for generalized seizures (meaning they would increase in frequency):
Taken together, our data suggest that L-theanine might be useful in the development of new drugs for reducing limbic seizures but certainly not for primarily generalized seizures. This is in line with some of the existing antiepileptic drugs, such as carbamazepine and oxcarbazepine, which can be used for partial epilepsy, though as an unwanted side effect could worsen generalized epilepsies, even leading to status epilepticus.
Unfortunately, there haven't been any studies in humans so we don't exactly know how l-theanine could affect the seizure threshold in those who are epileptic or have a history of them. The FDA has not released a safety statement regarding L-theanine and seizures.
For what it's worth, antiepileptic drugs (e.g. gabapentin, topiramate, lamotrigine, valproic acid, etc...) have not been reported to interact with l-theanine.
Can L-Theanine Be Used With MAOIs?
In general, serotonergic drugs should not be used with MAOIs (monoamine oxidase inhibitors) due to the potential for serotonin syndrome.
MAOIs are a class of antidepressant drugs which work by inhibiting the activity of monoamine oxidase (MAO), an enzyme that breaks down several neurotransmitters, including:
If MAO is inhibited (by an MAOI for example), the breakdown of neurotransmitters is decreased, thus, increasing their concentrations.
Since MAOI drugs will increase serotonin concentrations, they can interact with other serotonergic drugs. In fact, serotonergic drugs are contraindicated with MAOIs. The following is from the prescribing information for Nardil (Phenelzine Sulfate), an MAOI:
There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine) have been combined with an MAO inhibitor. Therefore, the concomitant use of NARDIL with serotoninergic agents is contraindicated.
Even though we don't have any reports of l-theanine being a responsible agent for the development of serotonin syndrome, to be safe, it shouldn't be used with MAOI drugs.
SummaryThere is conflicting evidence regarding L-theanine and whether or not it could precipitate serotonin syndrome and/or seizures. While there are no reports of serotonin syndrome, it does have serotonergic effects. Additionally, animal studies show that it may decrease the frequency of certain types of seizures but increase the risk of others.
- Theanine Monograph. ToxNET
- Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis. PubMed
- Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors. PubMed
- Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study. PubMed
- 5-HTP Safety Concerns. Poison.org
- L-Theanine intake increases threshold for limbic seizures but decreases threshold for generalized seizures. PubMed (Subscription Required)
- Nardil Prescribing Information. Pfizer
- Serotonin Syndrome. PubMed
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