Sleep (Part 4) - Supplements and Medications
If sleep hygiene and CBT-I haven't solved your sleep puzzle,
Perhaps the science of supplements and medication holds the missing piece.
** This blog post will be a bit information and mechanism driven.
I’ll try to make it more digestible.
Learn what you want and can.
Then, make your choice.
Section 4: Supplements
Magnesium
Magnesium is critical for
nerve function
muscle relaxation
neurotransmitter regulation
Pharmacokinetics
Absorbed in the small intestine
Excreted by the kidneys
Side Effects
Diarrhea (especially with citrate form)
Gastrointestinal discomfort
Price
$10-$30/month
Generic Available?
Yes
Recommended Types
Magnesium Glycinate
Recommended Dosage
200-400 mg per day
Mechanism
Increases GABA, promoting relaxation (Gholizadeh-Moghaddam et al., 2022)
Counseling Points
Easier on your stomach than other forms of Magnesium
Take in divided doses with meals for absorption.
Magnesium Bisglycinate tend to have high bioavailability.
Magnesium L-Threonate (Magtein®)
Recommended Dosage
Start with 500 mg/day
Up to 2 g/day in divided doses (144 mg of elemental magnesium)
Counseling Points
Crosses the blood-brain barrier
Potential improvement in cognition (Mah & Pitre, 2021)
May cause upset stomach
Look for Magtein® patent for proven quality and efficacy (No affiliation)
Magnesium Citrate
Helps relax muscles and improve sleep quality (Mah & Pitre, 2021)
May cause significant GI issues (diarrhea)
Melatonin
Melatonin was covered in the first post of our sleep series.
Regulates the sleep-wake cycle, helping adjust to new schedules or jet lag.
Dosage
0.5-3 mg before bedtime
Studies
Effective for circadian rhythm disorders (Cajochen et al., 2005; Roehrs & Roth, 2008)
Pharmacokinetics
Rapidly absorbed
Peaks in 60 minutes
Metabolized by the liver
Excreted in urine.
Side Effects
Drowsiness
Dizziness
Headache (long-term use)
Price
$5-$15/month
Generic Available?
Yes
L-Theanine
Promotes relaxation by increasing calming neurotransmitters.
Dosage
100-200 mg before bedtime or during the day
Studies
Increases alpha brain wave activity, promoting relaxation (Murphy & Campbell, 1997)
Pharmacokinetics
Absorbed in the intestines
Crosses the blood-brain barrier
Metabolized by the liver
Side Effects
Generally well-tolerated; occasional headaches
Price
$10-$30/month
Generic Available?
Yes
Valerian Root
Used for centuries to treat insomnia and anxiety by increasing GABA levels.
Dosage
300-600 mg before bedtime
Studies
Improves sleep quality without significant side effects (Cauffield & Forbes, 1999)
Pharmacokinetics
Metabolized by the liver
excreted in urine
Side Effects
Headache
Dizziness
Upset stomach
Price
$10-$20/month
Generic Available?
Yes
Apigenin
Found in chamomile. Sedative properties
Dosage
50 mg before bedtime
Studies
Binds to benzodiazepine receptors, promoting relaxation and sleep (Cho & Shimizu, 2015)
Pharmacokinetics
Metabolized by the liver
Excreted in urine
Side Effects
Rare; allergic reactions in individuals sensitive to ragweed
Price
$10-$20/month
Generic Available?
Yes
GABA Supplements
Promote sleep by calming the nervous system
Dosage
100-500 mg before bedtime
Studies
Shown to reduce sleep latency and improve sleep quality (Byun, 2018)
Pharmacokinetics
Limited absorption through the blood-brain barrier
Side Effects
Rare; mild gastrointestinal discomfort
Price
$10-$30/month
Generic Available?
Yes
Lavender Essential Oil
Used in aromatherapy to promote relaxation and improve sleep
Dosage
A few drops in a diffuser or on a pillow
Studies
Shown to improve sleep latency (Cho & Shimizu, 2015)
Pharmacokinetics
Inhaled
Metabolized by the liver
Excreted in urine
Side Effects
Rare; skin irritation in some individuals
Price
$10-$20/bottle
Generic Available
Yes
Section 5: Medications
Orexin Antagonists (Schedule IV)
If you've been following along, you know I promised a closer look at this. Let's get started.
Orexin: The Wakefulness Promoter
Orexin, also called hypocretin, is a chemical (neuropeptide) in your brain that helps you stay awake and alert.
Think of it as a natural signal that keeps you from dozing off during the day.
How Orexin Works
Orexin is made in a small area of the brain called the hypothalamus.
It sends signals to various parts of the brain to keep us awake.
When orexin levels are high,
We’re alert and active.
When they're low,
We start to feel sleepy.
Why Orexin Matters
Stabilizing Sleep
Orexin helps maintain a steady balance between being awake and asleep.
Without it, we might fall asleep suddenly and unpredictably, a condition known as narcolepsy.
Regulating Appetite
Besides sleep, orexin also influences your appetite, linking sleep and metabolism.
Mood and Emotions
Orexin impacts your mood and stress levels
What are Orexin Antagonists?
Orexin antagonists or DORAs (Dual Orexin Receptor Antagonists) are a newer class of medications for insomnia.
They work by blocking the action of orexin.
How Do They Work?
They bind to Orexin receptors in the brain without activating them—
Orexin is unable to bind to these occupied receptors to send waking signals
Many sleep medications knock you out like a sledgehammer,
DORAs work gently and naturally with your body's sleep-wake cycle.
Why I love DORAs (not sponsored)
I recently learned about DORAs from a colleague in psychiatry (IYKYK).
They spoke of patients suffering from chronic insomnia for decades—
Finally discovering relief through this medication.
Intrigued, I dove into the research and was impressed by what I found—
Key Benefits
Effective Sleep Aid
DORAs like Suvorexant (Belsomra) and Lemborexant (Dayvigo) help you fall asleep faster and stay asleep longer.
Studies show they significantly improve sleep onset and maintenance (Herring et al., 2020).
Low Risk of Dependency
Unlike benzodiazepines, DORAs do not cause physical dependency or withdrawal symptoms (Sun et al., 2013).
Preserve Sleep Architecture
They maintain the natural structure of sleep without the grogginess of older medications.
Pharmacokinetics
Absorption
DORAs are well-absorbed when taken orally and reach peak levels in the blood within a few hours.
Metabolism
These drugs are primarily broken down in the liver.
Half-life
The duration DORAs stay active in the body varies.
Lemborexant (Dayvigo) - 17 to 19 hours
Suvorexant (Belsomra) - 12 hours
Daridorexant (Quviviq) - 8 hours, reducing the risk of next-day drowsiness.
Side Effects and Safety
Common Side Effects
Mild drowsiness
Headache
Unusual dreams
What to Avoid
Alcohol and other CNS depressants (“downers”), as they can amplify sedative effects.
Pricing and Availability
Suvorexant (Belsomra)
$300-$400 per month, no generic available.
Merck Savings Programs
Eligible patients with private insurance can pay as little as $30 per prescription
Example
Monthly cost reduced from $350 to $30, saving $320 each month.
More Info
Click here to apply.
Patient Assistance Program
Eligibility
Financial hardship or income below specific thresholds (e.g., $60,240 for individuals).
Example
Potential to receive Belsomra at little to no cost.
More Info
Visit Merck Medicine Assistance Tool or call 1-800-727-5400 for assistance.
Free Trial
Offer
Up to 3 free trials of 10 tablets each (excluding 5 mg strength)
Example
30 tablets at no cost
More Info
Visit here to apply.
Discount Cards
Use discount cards from GoodRx and SingleCare
Lemborexant (Dayvigo)
Similar pricing ($300 - 400/mo), no generic available.
Eisai Assistance Program
Support
Reduced costs for eligible patients, including free medication for those who qualify
Example
Reduced monthly cost from $364.89 to as low as $10
More Info
Visit Eisai Patient Support or call 1-866-349-3026
Instant Savings Card
Offer
Pay as little as $10 per prescription, up to 12 uses annually.
Example
Monthly cost reduced from $364.89 to $10.
More Info
Visit Dayvigo Savings.
Discount Cards and Coupons
Savings
Use discount cards from GoodRx and SingleCare
Example
GoodRx coupon can reduce price from $431.36 to $292.45.
Daridorexant (Quviviq)
$300-$400 per month, no generic available.
Idorsia Assistance Programs
Support
Copay assistance and patient assistance programs for eligible patients.
Contact Idorsia or Quviviq Savings.
Example
Potentially reduce monthly cost of $380 to a significantly lower amount.
Discount Cards
Savings
GoodRx and other platforms offer substantial discounts.
Example
Reduce cost from $400 to $120 with a discount card.
Additional Info
Manufacturer Copay Coupons
Typically not available for patients enrolled in Medicare, TRICARE, or other federal/state healthcare programs
When applied, it can reduce deductible.
Third-party coupons (i.e. GoodRx and SingleCare)
Only available to cash-paying patients
Does NOT reduce deductible
Alternative Options
Prior Authorization
Physicians can apply for prior authorization to help with medication coverage.
Non-Profit (340B) Pharmacies
These pharmacies may offer additional copay assistance programs.
May be cheaper than GoodRx or similar platforms
Clinical Endorsement
The American Academy of Sleep Medicine (AASM) recommends DORAs for patients who (Schotland et al., 2023)—
Haven't responded well to cognitive behavioral therapy for insomnia (CBT-I), or
As an adjunct to CBT-I
Other Prescription Medications
Benzodiazepines (Schedule IV) - Last Resort
Try to stay away from this one.
Unlike DORAs, benzodiazepines work on specific sets of GABA receptor subunits—causing dependency and cognitive issues.
In my practice, most patients with dependency issues were prescribed—
benzodiazepines
and/or
opioids.
It's a tough reality.. But it's important to be aware of the risks.
Benzodiazepine withdrawals can be fatal.
Benzodiazepines
Mechanism
Enhance GABA's effect, leading to sedation
Examples
Alprazolam (Xanax)
Diazepam (Valium)
Temazepam (Restoril)
Triazolam (Halcion)
Pharmacokinetics
Metabolized by the liver
Various half-lives
Side Effects
Dependency
Dizziness
Drowsiness
Price
$10-$20/month (generics)
Generic Available?
Yes
Non-Benzodiazepine Hypnotics (“Z-drugs”)
Schedule IV Medications
Mechanism
Act on the GABA-A receptor (different sites than benzodiazepines)
Examples
Zolpidem (Ambien)
Eszopiclone (Lunesta).
Zaleplon (Sonata)
Pharmacokinetics
Rapid absorption
Metabolized by the liver
Short half-life
Side Effects
Drowsiness
Dizziness
Potential for dependency.
Price
$10-$20/month (generics)
Generic Available?
Yes
Antidepressants
Used off-label for insomnia.
Examples
Trazodone
Mirtazapine
Pharmacokinetics
Metabolized by the liver
Various half-lives
Side Effects
Dry mouth
Dizziness
Weight gain
Price
$10-$20/month (generics)
Generic Available?
Yes
Antihistamines
Common OTC sleep aids like Benadryl (diphenhydramine)
Pharmacokinetics
Metabolized by the liver
Half-life: 4-8 hours
Side Effects
Dry mouth
Dizziness
Urinary retention
Price
$5-$10/month
Generic Available?
Yes
Gabapentin
(Schedule V in some states)
Mechanism
Various GABA-A receptor subunits
Used for neuropathic pain and improving sleep
Dosage
300-900 mg before bedtime
Studies
Improves sleep quality in neuropathic pain patients (Randall, 2013)
Pharmacokinetics
Excreted by urine
Half-life: 5-7 hours
Side Effects
Dizziness
Fatigue
Peripheral Edema
Price
$20-$30/month (generics)
Generic Available?
Yes
AASM Guidelines for Chronic Insomnia
First-line - Cognitive Behavioral Therapy for Insomnia (CBT-I)
The guidelines emphasize that medications should be considered for—
Those unable to participate in CBT-I
Those who still have symptoms after CBT-I
Those who need a temporary adjunct to CBT-I (AASM, 2017)
Prescription Medications
Zolpidem and eszopiclone are recommended for sleep onset and maintenance insomnia.
Over-the-Counter Medications
Diphenhydramine is suggested for occasional use, though long-term use is not recommended due to tolerance and side effects.
Dietary Supplements
Melatonin and valerian are recommended, with melatonin being effective for circadian rhythm sleep disorders and valerian showing some evidence for improving sleep quality.
Antidepressants
Medications such as trazodone and mirtazapine may be used off-label for insomnia, especially in patients with depression.
Pharmer’s perspective
As much as I love medicine,
Sleep hygiene and CBT-I are the most effective, first-line treatments for insomnia.
Consider supplements if needed, but reserve medications (even DORAs) as a last resort.
Recommendations
Magnesium Bisglycinate
200 mg before bed. Monitor for side effects.
L-Theanine
100-200 mg before bed or during the day.
GABA Supplements
100-200 mg before bed.
Melatonin
Start with 0.5-1 mg, increase up to 3 mg if needed (i.e. jet lag).
References
Byun, J. I., Shin, Y. Y., Chung, S. E., & Shin, W. C. (2018). Safety and Efficacy of Gamma-Aminobutyric Acid from Fermented Rice Germ in Patients with Insomnia Symptoms: A Randomized, Double-Blind Trial. Journal of clinical neurology (Seoul, Korea), 14(3), 291–295. https://doi.org/10.3988/jcn.2018.14.3.291
Cajochen, C., Münch, M., Kobialka, S., Kräuchi, K., Steiner, R., Oelhafen, P., Orgül, S., & Wirz-Justice, A. (2005). High sensitivity of human melatonin, alertness, thermoregulation, and heart rate to short wavelength light. The Journal of clinical endocrinology and metabolism, 90(3), 1311–1316. https://doi.org/10.1210/jc.2004-0957
Edinger, J. D., Arnedt, J. T., Bertisch, S. M., Carney, C. E., Harrington, J. J., Lichstein, K. L., Sateia, M. J., Troxel, W. M., Zhou, E. S., Kazmi, U., Heald, J. L., & Martin, J. L. (2021). Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 17(2), 255–262. https://doi.org/10.5664/jcsm.8986
Cauffield, J. S., & Forbes, H. J. (1999). Dietary supplements used in the treatment of depression, anxiety, and sleep disorders. Lippincott's primary care practice, 3(3), 290–304. https://pubmed.ncbi.nlm.nih.gov/10711131/
Cho, S., & Shimizu, M. (2015). Natural sleep aids and polyphenols as treatments for insomnia. In M. Shimizu (Ed.), Polyphenols in human health and disease (pp. 215-229). Academic Press. https://doi.org/10.1016/B978-0-12-411462-3.00015-1
Gholizadeh-Moghaddam, M., Ghasemi-Tehrani, H., Askari, G., Jaripur, M., Clark, C. C. T., & Rouhani, M. H. (2022). Effect of magnesium supplementation in improving hyperandrogenism, hirsutism, and sleep quality in women with polycystic ovary syndrome: A randomized, placebo-controlled clinical trial. Health science reports, 6(1), e1013. https://doi.org/10.1002/hsr2.1013
Herring, W. J., Connor, K. M., Ivgy-May, N., Snyder, E., Liu, K., Snavely, D. B., Krystal, A. D., Walsh, J. K., Benca, R. M., Rosenberg, R., Sangal, R. B., Budd, K., Hutzelmann, J., Leibensperger, H., Froman, S., Lines, C., Roth, T., & Michelson, D. (2016). Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials. Biological psychiatry, 79(2), 136–148. https://doi.org/10.1016/j.biopsych.2014.10.003
Mah, J., & Pitre, T. (2021). Oral magnesium supplementation for insomnia in older adults: a Systematic Review & Meta-Analysis. BMC complementary medicine and therapies, 21(1), 125. https://doi.org/10.1186/s12906-021-03297-z
Murphy, P. J., & Campbell, S. S. (1997). Nighttime drop in body temperature: a physiological trigger for sleep onset?. Sleep, 20(7), 505–511. https://doi.org/10.1093/sleep/20.7.505
Roehrs, T., & Roth, T. (2008). Caffeine: sleep and daytime sleepiness. Sleep medicine reviews, 12(2), 153–162. https://doi.org/10.1016/j.smrv.2007.07.004
Sun, H., Kennedy, W. P., Wilbraham, D., Lewis, N., Calder, N., Li, X., Ma, J., Yee, K. L., Ermlich, S., Mangin, E., Lines, C., Rosen, L., Chodakewitz, J., & Murphy, G. M. (2013). Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep, 36(2), 259–267. https://doi.org/10.5665/sleep.2386
