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Health Protocols


Novel and Emerging Treatments

Targeting Melatonin Receptors

Melatonin is a hormone involved in controlling the body’s sleep-wake cycle. Supplemental melatonin supports the body’s natural melatonin cycle. Melatonin activates two receptors, MT1 and MT2, in a region of the hypothalamus that controls circadian rhythms, and in some peripheral tissues. Supplemental melatonin modulates central nervous system activities via these MT1 and MT2 receptors.135 Drugs that target these receptors work similarly to melatonin, but may interact with the receptors in a slightly different fashion.

Targeting melatonin receptors may help modulate sleep rhythms. Note these therapeutics are not identical to supplemental melatonin. Rather, they are melatonin receptor agonists, meaning they mimic melatonin and bind to its receptor, activating it and inducing sleep.

Ramelteon (Rozerem) is an FDA-approved insomnia medication that binds to and activates melatonin receptors (MT1 and MT2).136 Ramelteon promotes sleep by regulating the sleep-wake cycle, not depressing the central nervous system.137 It is highly selective for the melatonin receptors MT1 and MT2, and has a half-life of just over one hour.120,138-140 Ramelteon can be used long-term, with no major safety issues noted. There is no evidence of dependence.137

In a study of adults aged 65 and older, this medication significantly reduced sleep latency over five weeks with no significant side effects.141 In another randomized, double-blind, placebo-controlled trial in adults aged 18‒64, subjects who received 8 or 16 mg of ramelteon had reductions in sleep latency and sleep onset.142

Tasimelteon (Hetlioz) is a high-affinity MT1-MT2 receptor agonist that regulates sleep and shifts circadian rhythms. It was originally developed to treat non-24-hour sleep-wake disorder, in which individuals cannot train the body clock to the 24-hour dark-light cycle. In one placebo-controlled clinical trial in healthy individuals, tasimelteon reduced sleep latency and increased sleep efficiency with no side effects.143

Animal research has demonstrated that the melatonin receptor MT2 promotes deep sleep.144,145 Drugs that specifically target the MT2 receptor are beginning to emerge, including IIK7 and UCM765. Animal research suggests these medications increase amount of deep sleep and reduce sleep latency in mice.144,145 However, further human research is needed to confirm safety, efficacy, and potency.146

Orexin Receptor Agonists

Suvorexant (Belsomra) is an FDA-approved medication that blocks the excitatory neuropeptides orexin A and orexin B, which promote wakefulness, from binding to their receptors. This helps to stabilize the sleep-wake cycle. Suvorexant suppresses waking after bedtime, improves sleep efficiency, increases total sleep time, and decreases sleep latency, although it may cause next-day drowsiness and impaired driving or cognitive funciton.137,147 Two randomized trials including 2,030 subjects demonstrated that 30‒40 mg suvorexant improved sleep maintenance, as compared with placebo.148 Another trial of 781 patients randomly assigned to receive 30 mg (elderly subjects) or 40 mg (nonelderly subjects) suvorexant or placebo indicated the drug was safe, tolerable, and helped enhance total sleep time.149 While preliminary research suggests this medication is safe and effective, long-term data are lacking.108

5-HT2 Receptor Antagonists

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter that plays a role in regulating sleep, appetite, thermoregulation, emotion, and cognition.150 It acts by binding to and activating various 5-HT receptors in the ventrolateral preoptic nucleus (VLPO), the main structure of neurons that trigger non-REM sleep.151,152 Impairments in 5-HT transmission have been linked to depression, anxiety, and sleep disorders. In one study, 5-HT deficient mice demonstrated a disrupted sleep-wake cycle with an increase in restless sleep (a period of sleep with frequent wakings).153

In animal research, sleep-promoting neurons in the VLPO can be characterized by their response to neurotransmitters such as noradrenaline and 5-HT. Those inhibited by 5-HT are known as Type 1 neurons, and those excited by 5-HT are known as Type 2. Type-2 neurons are involved in sleep initiation, and activating them activates Type-1 neurons. Type-1 are thought to be responsible for sleep maintenance, and their activation inhibits the brain’s arousal system.150

5-HT receptors 5-HT2A and 5-HT2C are of particular interest with regard to sleep. Activation of these receptors interferes with deep sleep.152 Therefore, some therapeutics attempted to reduce signaling through these receptors to facilitate high-quality sleep.154,155

While both animal and human data suggest blocking 5-HT2A/C signaling appears to be a promising mechanism for improving sleep quality, more research is needed.154,155

Propofol: Novel Use of an Anesthetic to Reset Sleep Rhythms

Propofol is a rapid, short-acting anesthetic often administered intravenously for the induction and maintenance of sedation during monitored anesthesia. While propofol is typically used for sedation for operations or medical procedures, some researchers have found that mild dosing regimens may help restore normal sleep rhythms.

Propofol induces a state of unconsciousness resembling non-REM sleep. Brain activity during anesthesia and sleep shares many similarities but also distinct differences.156 Interestingly, propofol sedation without surgery has been shown to alter diurnal melatonin secretion in animals, suggesting the drug can influence the body’s circadian clock system.157

In a randomized, placebo-controlled, double-blind clinical trial, subjects receiving a two-hour infusion of propofol for five consecutive nights showed improvement in sleep onset latency (ie, amount of time needed to fall asleep), quality of sleep, ease of waking up, and behavior after waking. These improvements persisted for six months, suggesting the benefits of propofol could continue after initial treatment. In addition, subjects showing no response to traditional agents, such as zopiclone (Imovane) or zolpidem, before study treatment were able to effectively use them on occasion after treatment, suggesting propofol restored the brain's response to conventional sleep aids.17 The study showed using propofol for a short period of time (at the same time each night) could help reset the body's natural circadian rhythm, providing long-term benefits for people with chronic refractory insomnia.

As of the time of this writing, no sleep centers that we are aware of are routinely offering propofol, which requires strict medical vigilance and adherence to safety protocols to avoid overdose. The novel use of propofol to reset sleep patterns, administered under carefully controlled clinical conditions, is an area of insomnia research that requires further study.