Dr. Weeks’ Comment: Sleep is your best medicine. People who sleep like babies are usually quite healthy and accomplish longevity. Conversely, if you sleep poorly, you tend to not regenerate and restore yourself, and can be tired in the morning and disoriented in life. The old caveat is worth considering: “The rest of your days depends upon the rest of your nights.”
Since we corrective health practitioners always champion safe, effective and cost-effective agents, typically using orthomolecular or correct molecules, understanding as we do that nature offers the best initial options rather than synthetic drugs, let’s explore today a very powerful and beneficial natural sleep agent: allopregnanolone, the first pass metabolite of Prometrium (bio-identical oral progesterone). This natural agent allows people to sleep like babies.
Credit where credit is due: my daughter the young and brilliant Dr. Sara Weeks, D.O. taught me how to use this powerful sleep aid.
Here is an article of interest to those seeking deeper and more restorative sleep:
Allopregnanolone affects sleep in a benzodiazepine-like fashion
M Lancel 1, J Faulhaber, T Schiffelholz, E Romeo, F Di Michele, F Holsboer, R Rupprecht
J Pharmacol Exp Ther . 1997 Sep;282(3):1213-8.
Abstract
Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 postinjection hr. Compared with vehicle, both doses of allopregnanolone reduced the latency to non-rapid eye movement sleep (non-REMS) and 15 mg/kg allopregnanolone significantly increased the time spent in pre-REMS, an intermediate state between non-REMS and REMS. Furthermore, allopregnanolone dose-dependently influenced EEG activity during non-REMS and REMS. In non-REMS, EEG activity was decreased in the lower frequencies (< or =7 Hz) and enhanced in the frequencies of > or =13 Hz. In REMS, allopregnanolone enhanced high-frequency EEG activity (> or =17 Hz). The effects were most pronounced during the first postinjection hours and gradually diminished thereafter. Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like effects on sleep.
MORE INFO:
Allopregnanolone, a first past metabolite from oral progesterone, promotes sleep through a sedative, benzodiazepine-like effect by modulating GABA-A receptors. While progesterone transdermally has a beta-adrenergic blocking effect lowering adrenaline- oral progesterone metabolizes to allopregnanalone, which has a benzodiazepine like calming effect on the GABA receptors.
Related neurosteroids act differently and typically do not enhance sleep: Pregnenolone sulfate and DHEA(-S) are negative modulators of GABA-A receptors and positive modulators of NMDA receptors.
Regarding any sleep aid or hypnotic agent, be it prescription or otherwise, it’s important to appreciate the effect on sleep architecture. Sleep architecture is comprised of the four stages of sleep: three non-REM followed by REM (rapid eye movement). Adults normally go through 4–6 cycles a night, each lasting about 80–120 minutes in order to accomplish the benefits of restorative regeneration as well consolidation of neurological functions like learning. These people who sleep well awaken in the morning, feeling refreshed.
If you consult the package inserts of SSRI drugs and many sleep medicines themselves, you will read the warning that despite be prescribed for sleep, the drug actually “disrupts sleep architecture”. That is why Prozac and other SSRI drugs are accused of disrupting sleep, and putting people into a disoriented fugue state.
Here is a list of common drugs which, despite being typically prescribed to help sleep, in fact actually disrupt sleep architecture thereby worsening the quality and reducing the benefit of sleep. In these instances, the patient appears to be sleeping, but because the sleep architecture is disrupted, the patient is simply horizontal, unconscious and amnestic for a longer period of time. The patient does not truly asleep. Indeed, in these instances, the patients are typically drugged. Again, if the sleep architecture is disrupted, the quality of sleep is poor and the general health will suffer.
- SSRI Sertraline: ↑ REM latency, ↓ REM, more fragmented sleep, ↑ periodic limb movements
- SSRI Escitalopram: REM suppression (SSRI class effect)
- SSRI Fluoxitine: ↑ REM latency, fragmentation
- Trazadone: ↑ slow-wave sleep, ↑ continuity, REM ↔
- Bupropion: ↑ REM density, slow-wave sleep ↔
- SNRI Duloxetine: ↓ REM, ↑ REM latency, ↑ periodic limb movements
- SNRI Venlafaxine: REM suppression
- TCA Amitriptyline: REM suppressed; ↓ slow-wave sleep
- Mirtazapine: ↑ slow-wave sleep; may worsen restless legs syndrome
- Beta blocker Metoprolol: ↓ melatonin; REM changes
- Beta blocker Propranolol: Lipophilic β-blockers have more CNS effects
- Steroid Prednisone: Arousing; alters sleep
- Pain Gabapentin: ↑ slow-wave sleep (anticonvulsants)
- Pain Hydrocodone: ↓ REM and ↓ slow-wave sleep; central and obstructive sleep apnea
- Benzo Alprazolam: ↓ slow-wave sleep and ↓ REM; ↑ spindles
- Z drug Zolpidem Benzodiazepine-receptor-agonist class effect
- Stimulant Amphetamine: ↓ slow-wave sleep, ↑ sleep latency
- Antipsychotic Quetiapine: ↓ arousals
- Antipsychotic Zyprexa: ↑ slow wave sleep, ↓ sleep latency
- Erectile disfunction Sildenafil: ↑ severe obstructive sleep apnea
Allopregnanolone Effects on sleep architecture based on rat data.
Faster onset: Shorter time to fall into NREM sleep, plus more “pre-REM” sleep at higher doses. [1]
EEG changes: Less low-frequency activity (≤7 Hz) and more high-frequency activity (≥13 Hz) during NREM sleep. This is the same pattern seen with benzodiazepines and high-dose progesterone. [1][7]
Over 5 days of dosing: NREM episodes stayed longer, REM onset stayed delayed, and spindle activity stayed higher, with no tolerance. This differs from short-acting benzodiazepines, which lose their hypnotic effect with repeated use. [2]
Clinical relevance
Hormonal fluctuations: Falling allopregnanolone levels – either from sudden discontinuation of Prometrium (work closely with your prescribing doctor) or naturally before menstruation or after delivery – is linked to anxiety, mood symptoms, and lower seizure threshold. Women’s response to GABAergic hypnotics may vary across the menstrual cycle and the menopausal transition
Prescribing options:
Precursor is Prometrium (bio-identical progesterone) whose 1st pass metabolite is allopregnanolone.
Approved drugs:
Brexanolone (IV allopregnanolone) and Zuranolone (oral allopregnanolone) were approved for postpartum depression, not insomnia. They are used off-label. Brexanolone has been withdrawn from the US market for financial but not safety reasons; oral Zuranolone is still available. Sedation is expected with these drugs given how they work.
Effects attributed to “pregnenolone” supplements cannot be assumed to match allopregnanolone, because pregnenolone sulfate acts in the opposite direction at GABA-A receptors.
As is always the case, Shakespeare said it best:
“Sleep that knits up the raveled sleave of care,
The death of each day’s life, sore labor’s bath,
Balm of hurt minds, great nature’s second course,
Chief nourisher in life’s feast.”