Sleep Supplements 101
The science of sleep supplements and 7 useful examples
What makes a good sleep supplement?
To me, it’s a good sleep supplement helps calm your mind before bed, facilitates an easy transition to sleep, and enhances the quality of your sleep. In this article I’ll explain not only the neuroscience behind why certain supplements are good for sleep, but also provide a list of supplements that are so effective that you won’t need to look for more after reading.
The Neuroscience of Sleep Supplements
The majority of effective sleep supplements work by either decreasing glutamate activity or increasing GABA activity. Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters in the brain, respectively, working to either increase or decrease the likelihood of a neuron firing. Normally, these two balance each other out, allowing our neural circuitry to function as intended. However, before bed we want to tip the scales in favor of GABA activity relative to glutamate, which can help us calm our mind and transition to sleep smoothly by decreasing brain activity.
GABA
In the brain, GABA primarily works to inhibit neuronal firing via the GABAA receptor, a chloride channel that opens when GABA binds to it. Once GABA is bound, the channel associated with the receptor opens and chloride ions (Cl-) are able to enter the neuron with a large driving force. The result is a lowering of the neuron’s membrane potential (the cell becomes more negative internally) which reduces its likelihood to fire an action potential.
Increasing GABA activity is important because this neurotransmitter plays a large part in inducing sleep by inhibiting neurons that would otherwise promote a sense of wakefulness. GABAergic neurons in the ventrolateral preoptic nucleus (VLPO) project to brain areas that release orexin, histamine, and norepinephrine - which are some of the primary neurotransmitters that promote wakefulness. The inhibition of these areas underly the VLPO’s role as a key sleep promoting brain region.
An uptick in GABAergic activity will also reduce neuronal activity across the entire brain, which can help to calm a racing or active mind. There’s a reason a large number of prescription sleeping pills (i.e. Ambien, Xanax) act by enhancing GABA signaling. As you’ll read shortly, several effective sleep supplements do as well – just not as potently.
In those ways, increasing GABA activity via supplements is a great way to help reduce latency to sleep.
For those curious, Ambien and Xanax are GABAA positive allosteric modulators, meaning they bind to the GABAA receptor at a site separate from GABA (like the benzodiazepine site shown in the image of the GABAA receptor) and enhance the effect of these receptors. The result is more chloride influx into neurons, which facilitates more inhibition and less neuronal firing overall.
Glutamate
Reducing glutamate activity is also highly effective at helping us fall asleep, although it's not the most prevalent supplement mechanism. It doesn't have the double edged upside of supporting inhibition of areas that promote wakefulness, however it will effectively decrease neuronal activity across the entire brain. Since most people are generally glutamate dominant, supplements that do so can be extremely effective at promoting sleep by reducing anxiety and calming the mind.
The mechanisms discussed above are incredibly effective for supplements taken before bed as sleep aids. However, their ability to calm the mind and slow brain activity also makes many of them useful for combating anxiety and stress as well. As a result, many of the supplements I’ll mention shortly will also work to reduce anxiety. Just look for the ones that directly increase GABA signaling or decrease glutamate signaling (almost all of them).
Sleep Supplements
Magnesium
If you've been following me for a bit on twitter/X, you know how much I love magnesium. It's an essential mineral in the body that’s involved in thousands of processes and reactions, yet most people are deficient in it. While the list of magnesium supplementation benefits is incredibly long, I want to focus on how it impacts sleep.
Magnesium not only promotes GABA activity, but blocks the NMDA glutamate receptor at rest. This NMDA antagonism is its primary pro-sleep mechanism of action as it directly decreases glutamate activity. I’ve written previously about the interaction between magnesium and the NMDA receptor in more depth, and you can find that here.
It’s best to opt for an inhibitory form of magnesium before bed, since they can provide a secondary benefit for sleep based on the molecule the magnesium ion is bound to. These forms are primarily glycinate, chloride, and acetyl-taurate (which is the most potent of the bunch and is best used intermittently). Some like the threonate form, but personally I think it's overrated as a sleep supplement and is too expensive for what it is. The glycinate and chloride forms are much better daily drivers and are far more cost effective.
L-Theanine
Theanine is an amino acid found naturally in green tea. It’s very similar in structure to glutamate and as such its mechanism of action relates to it. Theanine inhibits the uptake of glutamine (the precursor to glutamate) into neurons and antagonizes AMPA glutamate receptors, overall reducing glutamate activity. The AMPA antagonism of theanine makes it extremely synergistic with magnesium, since sufficient AMPA activation is needed to remove the magnesium block from the NMDA receptor.
Some people find that theanine can have a paradoxical effect and lead to a racing mind when taken before bed, but this is typically remedied by pairing it with magnesium. For that reason, I only ever take theanine paired with magnesium before bed, and it's my favorite sleep supplement pairing of all time.
Glycine
Glycine is the most simple amino acid possible, with a side chain of a single hydrogen. In the brainstem and spinal cord it functions as an inhibitory neurotransmitter, while also playing a role as an NMDA receptor co-agonist throughout the entire brain. As an inhibitory molecule, it works extremely similar to GABA, except it acts on glycine receptors which are mostly localized in the brainstem and spinal cord.
Glycine has been shown to decrease sleep latency, improve sleep quality, and even facilitate a drop in body temperature (something that’s very beneficial for sleep).
Side note: As a powder, it is very sweet in taste. This makes it a great 0 calorie sweetener to add to bedtime teas or other beverages.
Taurine
Taurine is an amino acid found naturally in foods like meat. It has a wide range of benefits in the body, but as a sleep aid it acts primarily as a GABA and glycine receptor agonist. Activation of these receptors gives taurine a direct inhibitory effect in the brain. As such, it is a great sleep supplement.
Magnolia Bark
The bark of the Magnolia Officinalis tree has well documented anti-anxiety and sleep promoting effects. It contains two primary active compounds, honokiol and magnolol, which are potent GABAA receptor positive allosteric modulators. These molecules bind to GABAA receptors and enhance the action of GABA without directly activating them. This mechanism is extremely similar to that of Ambien or Xanax, just much less potent.
Magnolia bark can be used in its full form (steeped in tea for example), or as an herbal extract supplement (look for a high % of honokiol and magnolol).
Apigenin
Apigenin is a flavone found in chamomile that plays a large role in what makes chamomile tea so great for sleep and anxiety. It, like the active constituents in magnolia bark, acts as a positive allosteric modulator of the GABAA receptor.
Apigenin can be bought and consumed as a dietary supplement, or obtained through chamomile tea.
Lemon Balm
Lemon balm (aka Melissa Officinalis) is another herb well known for its calming effects. It’s most prominent GABAergic mechanism of action is the inhibition of GABA transaminase, the enzyme that breaks down and inactivates GABA. Inhibiting this enzyme leaves more GABA in the brain, enhancing GABA activity generally.
Similar to magnolia bark, lemon balm can be taken as an herbal extract or the whole herb (as part of tea for example).
Other Supplements
Obviously, this isn't a comprehensive list of effective/useful sleep supplements. However, the list above offers a great variety of those that can be taken nightly (Magnesium, theanine, taurine, glycine) and those that are extremely effective for when you're exceedingly anxious and need an extra bit of help calming your mind and falling asleep (magnolia bark extract, lemon balm extract, apigenin). Between these 7 supplements listed above you really shouldn’t need to go out in search of more, unless that is you enjoy experimenting with different supplements like I do.
If there’s enough interest, I can put out another post covering more obscure sleep supplements. If interested, let me know by commenting on this post.
Dosing and Usage Frequency
When it comes to the dosing of supplements, I don't like to give out specific recommendations because everyone is different. What works for me or anyone else might not work for you, and vice versa. My recommendation is always to start with the lowest dosage of any given supplement, increasing in small steps until you find a dosage that produces a desired effect. If you want to find what works best for you, it takes a bit of experimentation.
Regarding usage frequency, every supplement listed above is safe to be used nightly (magnesium can and should be taken daily) except for the herbs in an extract form. Any use of potent GABAergic supplements (i.e. lemon balm extract and magnolia bark extract) should be limited to 1-2 times per week maximum to avoid any tolerance build up as a result of GABA downregulation.
Conclusion
Sleep supplements shouldn’t be seen as a replacement for optimizing your circadian rhythm or other otherwise good sleep hygiene. Once good sleep habits are established, you should be able to get quality sleep without sleep supplements.
Despite that, supplements can be extremely useful for fixing a broken sleep schedule by helping you fall asleep, enhancing sleep quality when good habits are present, or even act as a crutch on occasion when you’re extra anxious/stressed. They are tools, and should be used as such.
That’s all for now. Thanks for reading,
-BowTiedNeuron
Disclaimer
This article is for educational purposes only and is not medical advice. Always consult your doctor before starting any new supplements.
Nice post! Making it easy to understand how these supplements effect your brain and encourage sleep.
I'm interested in the more obscure supplements, do you they help sleep in other ways than the glutamate & gaba balance?