Circadian rhythm sleep disorders like Delayed Sleep-Wake Phase Disorder (DSWPD) involve a misalignment of the internal clock with desired sleep times. Pharmacological agents can help advance the sleep phase (shift the internal clock earlier) and reinforce circadian stability by strengthening or entraining rhythms. Below we explore key medications, supplements, and experimental compounds that influence circadian timing, focusing on their mechanisms (e.g. melatonin receptors, suprachiasmatic nucleus effects, neurotransmitters) and evidence of efficacy. Non-pharmacological measures (light therapy, behavioral interventions) are excluded as requested.

Melatonin and Melatonin Receptor Agonists

Melatonin (N-acetyl-5-methoxytryptamine) – the body’s natural “darkness hormone” – is central to pharmacological chronotherapy. It is secreted at night by the pineal gland, signaling the SCN (suprachiasmatic nucleus) that it is nighttime. Exogenous melatonin (available OTC in many countries) is a proven chronobiotic that can phase-advance circadian rhythms when taken in the early evening, a few hours before the endogenous melatonin rise. A meta-analysis in DSWPD patients showed melatonin on average shifted the dim-light melatonin onset ~1.2 hours earlier and advanced sleep onset by ~40 minutes ( The Use of Exogenous Melatonin in Delayed Sleep Phase Disorder: A Meta-analysis – PMC ). Melatonin also reduced sleep latency by ~23 minutes in DSWPD ( The Use of Exogenous Melatonin in Delayed Sleep Phase Disorder: A Meta-analysis – PMC ). Mechanism: Melatonin binds MT1 and MT2 receptors in the SCN. MT2 activation is thought to produce phase shifts in circadian timing, while MT1 contributes to acute sleepiness. By appropriately timing melatonin (typically 0.5–5 mg in late afternoon/early evening), patients with delayed phase can gradually shift their sleep-wake cycle earlier (Pharmacological Treatments of Sleep–Wake Disorders: Update 2023). Melatonin is generally safe and well-tolerated; it is considered first-line pharmacotherapy for DSWPD by sleep medicine experts (Pharmacological Treatments of Sleep–Wake Disorders: Update 2023).

Ramelteon (Rozerem) – an FDA-approved insomnia drug – is a selective MT1/MT2 receptor agonist that mimics melatonin’s action. Unlike melatonin (a supplement in the US), ramelteon is a prescription medication with consistent pharmacokinetics. Mechanism: Ramelteon binds melatonin receptors with high affinity to induce sleepiness and potentially shift the circadian phase. Although indicated for insomnia, it has been used off-label in circadian disorders. Case reports and small studies suggest ramelteon (taken in early evening) can successfully treat DSWPD by advancing sleep timing (Ramelteon for Delayed Sleep-wake Phase Disorder: A Case Report). In one case, a 15-year-old with DSWPD had her sleep-wake schedule normalized by 4 mg ramelteon at 7 PM nightly (Ramelteon for Delayed Sleep-wake Phase Disorder: A Case Report). Another report recommended strategically timed low-dose ramelteon (e.g. 0.5–1 mg in early evening) to phase-shift the clock with minimal next-day sedation (Ultra-low-dose early night ramelteon administration for the treatment …) (Pharmacological Treatments of Sleep–Wake Disorders: Update 2023). Ramelteon’s efficacy for circadian adjustment is attributed to MT2-mediated effects on the SCN similar to melatonin. Notably, ramelteon does not cause dependence and has a favorable safety profile, making it suitable for chronic use in circadian rhythm disorders.

Tasimelteon (Hetlioz) – a dual MT1/MT2 agonist specifically developed for circadian rhythm disorders – is FDA-approved for Non-24-Hour Sleep-Wake Disorder (especially in blind individuals). It has high affinity for MT2 receptors and a half-life designed to cover the nighttime. Mechanism: By activating melatonin receptors, tasimelteon can entrain a free-running circadian clock to the 24-hour day. Clinical trials in totally blind patients with Non-24 showed that nightly tasimelteon can synchronize the endogenous melatonin rhythm and sleep-wake cycle to a 24-h schedule (Tasimelteon for treating non-24-h sleep-wake rhythm disorder – PubMed) (Tasimelteon for treating non-24-h sleep-wake rhythm disorder – PubMed). In these studies, tasimelteon induced circadian entrainment and improved nighttime sleep and daytime alertness compared to placebo (Tasimelteon for treating non-24-h sleep-wake rhythm disorder – PubMed). Even upon discontinuation, a subset of patients maintained the entrainment, indicating a lasting effect (Tasimelteon for treating non-24-h sleep-wake rhythm disorder – PubMed). While tasimelteon’s approved use is Non-24 disorder, its pharmacology suggests it could benefit DSWPD or jet lag by shifting phase. Indeed, trials are exploring tasimelteon in DSWPD, and its ability to entrain rhythms may help stabilize sleep timing in those with chronic delays (Tasimelteon – an overview | ScienceDirect Topics). The main drawback is cost; thus, melatonin itself is often used first for sighted patients, but tasimelteon provides a validated option for circadian entrainment with an established efficacy and safety profile (Tasimelteon for treating non-24-h sleep-wake rhythm disorder – PubMed).

Agomelatine (Valdoxan) – an antidepressant available in Europe – has unique chronobiotic properties as an MT1/MT2 agonist and a 5-HT2C antagonist. Although used for major depression, agomelatine’s melatonin agonism can resynchronize disrupted circadian rhythms. Mechanism: By activating melatonin receptors at night and blocking 5-HT2C, agomelatine increases nocturnal melatonin signaling and boosts daytime norepinephrine/dopamine release (via 5-HT2C blockade). This combination improves sleep quality and aligns circadian phase. Studies in depressed patients show agomelatine improves sleep efficiency and resets delayed circadian rhythms toward a normal phase (Agomelatine in Depressive Disorders: Its Novel Mechanisms of Action). In other words, it helps correct circadian dysregulation accompanying depression, which suggests potential use in primary circadian disorders. Small reports have noted agomelatine may help advance sleep timing and stabilize the sleep-wake cycle in patients with irregular rhythms. For example, agomelatine has been reported to normalize sleep onset and reduce evening anxiety in cases of circadian delay (though formal trials in DSWPD are lacking). Clinicians sometimes choose agomelatine for depressed patients who also have circadian phase delay, given its dual action on mood and circadian regulation (Full article: Agomelatine, melatonin and depressive disorder). While not yet standard for DSWPD, agomelatine represents a pharmacological bridge between mood regulation and circadian entrainment.

Table 1: Melatonin and Analogs with Circadian Phase-Shifting Effects

Agent	Type	Circadian Mechanism	Evidence in Phase Disorders
Melatonin	Endogenous hormone (OTC supplement)	MT<sub>1</sub>/MT<sub>2</sub> agonist at SCN; shifts circadian phase (MT<sub>2</sub>) and induces sleep (MT<sub>1</sub>)	Advances circadian markers ~1 hour in DSWPD; improves sleep onset latency​pmc.ncbi.nlm.nih.gov. Widely effective for phase advance in DSPS​mdpi.com.
Ramelteon	Selective melatonin receptor agonist (Rx)	High-affinity MT<sub>1</sub>/MT<sub>2</sub> agonist; mimics melatonin to promote earlier sleep onset and circadian shift	Case reports of DSWPD successfully treated (e.g. sleep schedule normalized in teens)​cpn.or.kr. Early-evening low doses used to induce phase advances​pmc.ncbi.nlm.nih.gov​mdpi.com.
Tasimelteon	Melatonin analog (Rx; FDA-approved for Non-24)	MT<sub>1</sub>/MT<sub>2</sub> agonist (higher MT<sub>2</sub> affinity); entrains free-running circadian clocks to 24h	Entrains rhythms in ~50% of blind Non-24 patients​pubmed.ncbi.nlm.nih.gov. Improves nighttime sleep and daytime alertness by stabilizing circadian phase​pubmed.ncbi.nlm.nih.gov. Being explored for DSWPD due to similar phase-shifting action.
Agomelatine	Melatonin agonist & 5-HT<sub>2C</sub> antagonist (Rx antidepressant)	MT<sub>1</sub>/MT<sub>2</sub> activation at night (resets clock); 5-HT<sub>2C</sub> block increases daytime monoamines, reinforcing diurnal rhythm	In depression, resynchronizes disrupted circadian rhythms​psychiatryonline.org. May aid circadian realignment in patients with sleep phase delay (off-label use, some case improvements noted).

Serotonergic Supplements and Precursors

Beyond melatonin itself, several nutritional supplements have been investigated for their ability to influence circadian timing, particularly by affecting serotonin and melatonin synthesis. Serotonin in the dorsal raphe modulates the SCN via non-photic pathways – stimulation of certain 5-HT receptors during the day can cause phase shifts (generally advances). Thus, raising serotonin levels or providing precursors might facilitate earlier circadian phases.

5-HTP (5-Hydroxytryptophan) – an over-the-counter amino acid supplement – is the direct precursor to serotonin. It crosses the blood–brain barrier and is decarboxylated to serotonin, potentially boosting melatonin production at night (since melatonin is synthesized from serotonin in the pineal). Mechanism: By increasing central serotonin availability, 5-HTP can indirectly enhance melatonin at night and also directly act on 5-HT receptors that influence the clock. In animal models, 5-HTP has shown chronobiotic potential: for example, giving 5-HTP to rats or hamsters can induce phase shifts in their activity rhythm. One report noted that 5-HTP accelerated re-entrainment to a 6-hour phase-advanced light cycle, simulating eastward jet lag ([PDF] The 5-HTP sip tryp: a timely word to the wise – ResearchGate). The 5-HTP-treated animals adjusted in fewer days than controls, suggesting it enhanced the circadian clock’s response to the new schedule ([PDF] The 5-HTP sip tryp: a timely word to the wise – ResearchGate). Another study found 5-HTP administration at certain circadian times led to phase advances of locomotor rhythms (likely via conversion to serotonin acting on SCN 5-HT1A/7 receptors). Human evidence: Formal trials are lacking, but some clinicians use 50–200 mg of 5-HTP in the late afternoon for patients with delayed sleep phase, hypothesizing it will promote an earlier rise in evening melatonin. At minimum, 5-HTP may improve sleep quality and is generally safe. While not a first-line chronotherapy, 5-HTP is a potential adjunct for phase advancing, working through the serotonergic->melatonergic pathway.

L-Tryptophan – an essential amino acid and precursor to 5-HTP – has also been tested. High-dose tryptophan (1–5 g at bedtime) has mild sedative effects and can hasten sleep onset. Its role in circadian phase is similar to 5-HTP’s: by increasing serotonin, it can promote melatonin synthesis. Early studies from the 1980s suggested tryptophan at night might advance sleep phase in DSPS patients slightly, although results were modest. Today 5-HTP (which is closer to the serotonin step) is more commonly used than tryptophan for this purpose, due to more predictable absorption.

Vitamin B12 (Methylcobalamin) – a coenzyme in many metabolic pathways – has an intriguing, though controversial, history in circadian therapy. Some early case series in the 1990s reported that high-dose B12 could improve sleep-wake rhythm disorders. The proposed mechanism was that B12 might enhance light sensitivity or dopamine function in the circadian system (one hypothesis: methylcobalamin may influence retinal or SCN response to light, or aid serotonin synthesis). Evidence: Initial uncontrolled observations found that 3–6 mg daily of B12 seemed to stabilize sleep timing in some patients with DSPS or irregular sleep cycles. However, controlled studies have largely not confirmed a benefit (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies) (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies). A Japanese trial in 50 DSPS patients found 3 mg B12 for 4 weeks was no better than placebo in shifting sleep phase (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies). Another study with 6 mg found a slight improvement at 4 weeks, but not by 8 weeks (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies). A 2019 review concluded: “Despite earlier reports of success, controlled studies have not confirmed the effectiveness of vitamin B12 in treating circadian rhythm sleep disorders” (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies). Implications: B12 is not a reliably effective chronotherapeutic, but it may help individuals who are deficient in B12 (since B12 deficiency can worsen sleep quality and contribute to fatigue). Some clinicians still empirically try high-dose methylcobalamin in DSWPD because it is low-risk; a minority of patients report feeling their sleep cycle advanced (possibly via a placebo or individual metabolic effect). In summary, B12 is not a first-line nor consistently effective phase-shifter according to current evidence (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies), but it remains of interest and is often discussed in the patient community.

Table 2: Supplements and Nutrients with Proposed Circadian Effects

Supplement	Proposed Mechanism	Circadian Effect and Data
5-HTP (5-Hydroxytryptophan)	Serotonin precursor → increases CNS 5-HT → more melatonin at night; 5-HT agonism of SCN (non-photic phase advance pathway)	Animal studies: enhances phase advances and speeds re-entrainment to shifted light schedules ([PDF] The 5-HTP sip tryp: a timely word to the wise – ResearchGate). Rationale for use in DSWPD to promote earlier melatonin onset. Limited clinical trial data (used off-label based on mechanism).
L-Tryptophan	Dietary amino acid → metabolized to 5-HTP/5-HT → boosts melatonin; mild hypnotic effect at high doses	Some older reports of modest improvement in sleep onset timing. Not strongly evidenced for circadian shift, but may aid sleep initiation. Supplanted by 5-HTP due to more direct action.
Vitamin B12 (Methylcobalamin)	Unclear – hypothesized to augment light sensitivity of circadian clock or neurotransmitter synthesis (e.g. dopamine, melatonin)	Early case reports suggested benefit in DSPS, but controlled trials found no significant phase-shifting effect (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies) (Vitamin B12 and Circadian Rhythm Sleep Disorders: Patient Treatments vs. Controlled Studies). May help if B12-deficient, but not a reliable chronotherapeutic in general.

Stimulant and Wake-Promoting Medications

Pharmacological stimulants do not directly reset the SCN’s phase like melatonin does, but they play an important role in managing circadian disorders by reinforcing the distinction between the biological day and night. By promoting alertness during intended awake hours (especially morning), these agents can help solidify the wake portion of the cycle, indirectly aiding circadian entrainment when combined with proper scheduling. They are especially useful in scenarios where the patient must be awake earlier than their body clock would normally allow (e.g. a DSWPD patient needing to function in the morning), or for shift-work disorder to maintain alertness at night. Note: Stimulants treat symptoms of misalignment (sleepiness at the wrong time) but do not themselves shift the internal clock – they should be used alongside core chronobiotic measures ( Therapeutics for Circadian Rhythm Sleep Disorders – PMC ).

Modafinil (Provigil) and its R-enantiomer Armodafinil (Nuvigil) are wake-promoting drugs approved for disorders of excessive sleepiness (narcolepsy, shift-work disorder). They enhance dopamine signaling (via DAT inhibition) and likely boost wake-promoting hypothalamic pathways (orexin and histamine systems). In circadian rhythm disorders: Modafinil is often prescribed to DSWPD patients who struggle with morning sleepiness, helping them wake up on time and stay alert through the day. By doing so, modafinil can facilitate adherence to an advanced schedule – e.g. a patient takes 50–200 mg upon waking at 6–7 AM, enabling them to avoid returning to sleep. Over days to weeks, this consistent earlier wakefulness (especially if paired with morning light exposure) will help entrain the circadian clock to an earlier time. Thus, modafinil indirectly supports phase advance by ensuring the patient experiences a strong, wakeful daytime. In Shift Work Sleep Disorder, modafinil (200 mg before a night shift) significantly improves alertness and performance during the night shift ( Therapeutics for Circadian Rhythm Sleep Disorders – PMC ). While it does not realign the internal clock to night work on its own, it mitigates the performance impairments of circadian misalignment. Clinical guidelines consider modafinil a standard option for shift-work disorder to counteract excessive sleepiness at night. Common stimulants like methylphenidate or amphetamine salts could similarly be used to promote wakefulness in circadian disorder patients, but modafinil’s longer duration and lower abuse potential make it preferred for this niche. In summary, wake-promoting agents strengthen the wake portion of the cycle, improve safety and functioning during misaligned periods, and can be part of a comprehensive approach (with melatonin or light) to shift the clock.

Caffeine – the ubiquitous stimulant – also deserves mention. Caffeine (100–300 mg in the morning or early afternoon) is frequently self-administered by individuals with delayed rhythms to combat grogginess. Taken strategically, caffeine can help maintain wakefulness after an abruptly advanced wake-up time. For example, a DSWPD patient trying to shift earlier might use a cup of coffee immediately on waking to reinforce that wake signal. Mechanism: Caffeine blocks adenosine receptors, reducing homeostatic sleep drive and acutely increasing alertness. Its circadian effects are complex – one study found that caffeine in the evening can delay the circadian clock by roughly 40 minutes (by delaying melatonin rise) (Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PubMed). However, when used only in the morning, caffeine is not known to significantly delay the circadian phase (since morning caffeine will be mostly metabolized by biological evening). In shift-work settings, combining caffeine with naps has been shown to improve alertness during night shifts ( Therapeutics for Circadian Rhythm Sleep Disorders – PMC ). In circadian therapy: patients are advised to use caffeine only at biologically appropriate times (morning/early-day) and to avoid it in the evening, to prevent inadvertent circadian delays. While caffeine is not a formal treatment, it is a supportive tool to maintain daytime alertness as the circadian adjustment takes place.

Overall, stimulants should be viewed as adjuncts – they improve wakefulness but do not fix circadian misalignment on their own ( Therapeutics for Circadian Rhythm Sleep Disorders – PMC ). In fact, if used improperly (e.g. taking a stimulant late at night when trying to advance one’s phase), they could worsen misalignment. When used in the morning/daytime, they can consolidate the “daytime” segment of the sleep-wake cycle. Long-term use should be monitored, and non-pharmacological strategies (morning light, structured schedules) should be paired to truly shift the circadian rhythm.

Sedatives and Sleep-Promoting Medications

Another set of pharmacological tools for circadian rhythm disorders are those that facilitate sleep onset or maintenance at the desired times. Like stimulants, traditional sedative-hypnotics do not directly alter the circadian clock’s phase, but they enforce a sleep period which, if timed correctly night after night, allows the circadian system to gradually adjust. These agents are particularly useful when a patient with DSWPD is trying to adopt an earlier bedtime than their body is used to – often they simply cannot fall asleep early due to misaligned internal signals. A prescribed hypnotic can bridge that gap by inducing sleep at the target bedtime.

Conventional Hypnotics (Benzodiazepine and Z-Drug Sedatives): Medications such as zolpidem, zaleplon, eszopiclone (nonbenzodiazepine “Z-drugs”) or short-acting benzodiazepines (e.g. triazolam) can be used at the patient’s desired bedtime to help initiate sleep. Mechanism: These drugs are GABAA receptor agonists, broadly inhibiting cortical arousal. While they do not act on circadian receptors, they ensure the patient is asleep during the intended night. Over successive nights, this can lead the circadian clock to shift earlier because the individual is consistently dark and asleep at that time (in effect, the behavior is imposing a new schedule that the circadian pacemaker will gradually follow). For DSWPD, a doctor might prescribe low-dose zolpidem or temazepam to be taken, say, at 10 PM nightly to enforce a 10 PM–6 AM sleep window. With concurrent morning light, the patient’s internal clock can move to align with this enforced schedule. Studies have shown that hypnotics improve sleep initiation in circadian disorders, though on their own they do not shift the endogenous rhythm ( Therapeutics for Circadian Rhythm Sleep Disorders – PMC ). In fact, animal experiments have indicated certain benzos can cause non-photic phase shifts (e.g. triazolam induces phase advances in hamsters when given during their subjective day (Phase-shifting effect of triazolam on the hamster’s circadian rhythm …)), but in humans the primary benefit is opportunistic – allowing sleep to occur at a biologically difficult time. Caution is needed: long-term use can lead to tolerance or dependency, and these drugs do not cure the circadian problem (the misalignment can recur if the medication is stopped without the circadian clock having fully adjusted).

Orexin Receptor Antagonists (DORAs): These are a newer class of sleep aids (e.g. Suvorexant, Lemborexant) that promote sleep by blocking orexin/hypocretin neuropeptides (which normally sustain wakefulness). By inhibiting the wake drive, DORAs facilitate natural sleep onset. In the context of circadian disorders, an orexin antagonist can be used in the evening to help a patient with a “night owl” clock feel sleepy at an earlier hour. Mechanism: By turning off the brain’s stabilizing wake signals, DORAs allow the body’s intrinsic sleep tendency (which might be low early at night for a DSWPD patient) to take over. There are case reports of combining an orexin antagonist with a melatonin agonist to treat stubborn DSWPD: the melatonin agonist shifts the clock, and the orexin blocker ensures sleep occurs (Prompt improvement of difficulty with sleep initiation and waking up …). For example, three DSWPD patients were successfully treated with suvorexant at bedtime plus ramelteon in early evening, leading to prompt improvement in sleep initiation and ability to wake on time (Prompt improvement of difficulty with sleep initiation and waking up …). In that combo, ramelteon provided the circadian phase advance, and suvorexant “glued” the patient’s sleep to the new earlier phase by preventing breakthrough alertness. Suvorexant alone does not shift circadian phase, but by consolidating sleep at the proper night phase it contributes to overall rhythm stability. The advantage of DORAs is that they generally preserve normal sleep architecture and have low risk of dependence compared to benzodiazepines. They can be used chronically if needed. Thus, for someone with a circadian misalignment who also has insomnia at desired bedtime, a DORA is a useful option to pharmacologically reinforce nighttime.

Sedating Antidepressants and Others: Certain sedative antidepressants (trazodone, mirtazapine, doxepin in low doses) or antihistamines (diphenhydramine, doxylamine) are also employed off-label to induce evening sleep in circadian disorders. While their mechanisms differ (antihistamine vs. serotonin antagonism), the concept is the same – facilitate sleep at the target bedtime. Trazodone, for instance, is often given to teens with DSWPD who cannot fall asleep early; it has no specific chronobiologic action but helps them feel drowsy at an earlier clock time. Over time, a stable regimen (e.g. 50 mg trazodone at 10 PM nightly) coupled with strict wake times can lead the internal clock to adjust. Sedating medications should be tailored to the individual (some may cause next-day grogginess which could defeat the purpose if taken too late or in too high a dose). Moreover, as with other symptomatic treatments, the circadian misalignment must also be addressed (with melatonin or light) for lasting success – using hypnotics alone without attempting to shift the clock often results in relapse if the drug is stopped ( Therapeutics for Circadian Rhythm Sleep Disorders – PMC ).

In summary, sleep-promoting medications “anchor” the sleep period at the desired time. They improve compliance with a new schedule and can increase the amplitude of the sleep-wake cycle (by avoiding late-night prolonged wakefulness). These agents should be used in concert with phase-shifting strategies and good sleep hygiene. Safety (tolerance, habit-forming potential, cognitive side effects) must be monitored, especially for long-term use.

Other Repurposed Drugs Affecting Circadian Timing

Researchers and clinicians have observed that certain drugs not originally developed for circadian disorders can nonetheless influence the body clock. These off-label or repurposed agents may act on neurotransmitter or molecular pathways that modulate circadian rhythms. Below are notable examples:

Lithium: A classic mood stabilizer for bipolar disorder, lithium has a well-documented effect on the circadian clock at the cellular level. Mechanism: Lithium lengthens the period of circadian rhythms by inhibiting glycogen synthase kinase-3β (GSK-3β), a kinase that phosphorylates core clock proteins (A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3 | Biochemistry (Moscow) ). By inhibiting GSK-3β, lithium stabilizes the active forms of CLOCK/BMAL1 (which drive the clock) and delays degradation of PER proteins, resulting in a longer circadian cycle. In various species – from fruit flies to mice to humans – lithium treatment causes the intrinsic circadian period to stretch slightly beyond 24 h (A Crosstalk between the Biorhythms and Gatekeepers of Longevity). In bipolar patients, lithium’s therapeutic effects have been partly attributed to “correcting” an unstable or hypersensitive circadian system. Clinically, lithium can shift circadian phase in some contexts: for instance, in a small trial with bipolar patients, lithium shifted the timing of activity rhythms earlier and reduced day-to-day variability (Lithium shifts circadian rhythms early in bipolar disorder and may …). Another study found that lithium treatment in bipolar disorder advanced the onset of daytime activity and reduced circadian disruption compared to baseline (Lithium shifts circadian rhythms early in bipolar disorder and may …). However, lithium is not routinely used for primary circadian rhythm disorders due to its side effect profile and monitoring needs. Its main role is in bipolar (where it likely contributes to mood stabilization by strengthening circadian amplitude and consistency). An interesting niche application was a case of a sighted non-24-hour sleep-wake disorder treated with lithium: given lithium’s period-lengthening effect, researchers hypothesized it might stabilize a free-running 25-hour cycle. There is a Science report that Rev-erbα, a core clock component, is a lithium-sensitive element of the clock mechanism (A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3 | Biochemistry (Moscow) ), underscoring lithium’s direct clock action. In summary, lithium demonstrates that pharmacologically targeting cell-intrinsic clock regulators is possible; it reinforces circadian rhythmicity and could, in theory, help patients with unstable circadian periods. But due to toxicity concerns, it’s reserved for those who also require mood stabilization.

Aripiprazole: This atypical antipsychotic (a dopamine D2 partial agonist and serotonin 5-HT1A partial agonist) has recently emerged as a surprising chronotherapeutic candidate. Clinicians in Japan observed that low-dose aripiprazole (1–2 mg, often given in morning) can markedly advance sleep timing in patients with delayed phase. Case reports and an open-label series found that in patients with DSWPD and co-morbid depression, adding aripiprazole led to earlier sleep onset and shorter total sleep time (correcting the prolonged nights) ( Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation – PMC ) ( Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation – PMC ). In a study of 12 DSPS patients, 0.5–3 mg aripiprazole daily advanced the circadian phase by approximately 1–2 hours on average over 4 weeks, while also improving depression in many cases ( Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation – PMC ) ( Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation – PMC ). How does aripiprazole, of all things, affect the clock? Mechanistically: It’s thought that aripiprazole’s partial agonism of dopamine receptors during the day may simulate the daytime activity of the dopaminergic system, thus reinforcing daytime signals. More importantly, aripiprazole is a 5-HT1A receptor partial agonist, and stimulation of 5-HT1A in the midbrain raphe is known to produce phase advances in the SCN (via non-photic pathways). Indeed, a Frontiers 2023 study showed aripiprazole acts directly on the SCN: it reduced the synchrony of SCN neurons and made the clock more sensitive to external light-dark cues (Aripiprazole disrupts cellular synchrony in the suprachiasmatic …) (Elucidating the mechanism of aripiprazole action in treating …). In mice, aripiprazole treatment enhanced entrainment to a new light-dark cycle, meaning the mice adjusted their activity to a shifted schedule faster than untreated mice (Aripiprazole disrupts cellular synchrony in the suprachiasmatic …). By disrupting the tightly coupled SCN cell network, aripiprazole might allow the clock to be “reset” more easily by environmental timing signals (light). This somewhat counterintuitive approach – loosening the SCN’s internal synchrony – appeared to help a patient with a persistent non-24h rhythm become entrained to 24h when given aripiprazole, as documented in a case report (Improvement of a patient’s circadian rhythm sleep disorders by …) (Improvement of a patient’s circadian rhythm sleep disorders by …). The authors of that report suggest aripiprazole could be a novel therapy for otherwise refractory circadian rhythm disorders (Elucidating the mechanism of aripiprazole action in treating …) (Improvement of a patient’s circadian rhythm sleep disorders by …). To summarize, aripiprazole (off-label at low doses) has demonstrated the ability to advance circadian phase and improve sleep-wake regularity, likely via serotonin and dopamine effects on the central clock. It is an exciting development, though more research is needed to establish safety and optimal dosing purely for circadian indications.

Others (Emerging off-label options): Some other drugs have small bits of evidence or theoretical backing for circadian effects:

• Beta-Blockers in the Evening: Typically beta-adrenergic blockers (like propranolol) suppress nighttime melatonin (since norepinephrine beta-1 receptors stimulate pineal melatonin release). While usually an unwanted side effect (beta blockers can cause insomnia), there were experiments using short-acting beta-blockers in late afternoon to allow an earlier melatonin onset rebound at night. However, this approach is not commonly used clinically for DSWPD because timing and individual response vary. More often, if a patient is on a beta-blocker and has sleep onset insomnia, one might switch medications or add evening melatonin.
• Vitamin D: There is interest in vitamin D’s role in the circadian system (vitamin D receptors are present in the SCN). Low vitamin D is correlated with poor sleep and possibly circadian rhythm disturbances. Supplementing D in deficient individuals might modestly improve sleep timing consistency, but direct phase shifting by vitamin D is not established.
• Chronotherapeutic Antidepressants: Beyond agomelatine (discussed earlier), certain antidepressants affect circadian rhythms. For example, SSRIs can shift circadian phase in animals (serotonin is involved in non-photic phase resetting). Some patients on SSRIs report changes in sleep timing (e.g. earlier waking or shifted REM timing), but these are side effects rather than reliable therapeutic effects. Tricyclics like nortriptyline have strong clock gene effects in some lab studies but are too non-specific to use for that purpose alone.

In practice, when treating a circadian disorder, psychiatrists might choose medications that also have chronobiological benefits if the patient needs pharmacotherapy for comorbid conditions. For instance, a DSWPD patient with depression might benefit from morning aripiprazole (for both mood augmentation and circadian advance) or nighttime agomelatine (for antidepressant and circadian alignment effects). Knowledge of these secondary properties helps personalize treatment.

Emerging and Experimental Chronobiotic Compounds

Significant research is ongoing to find direct pharmacological modulators of the core circadian clock – often termed “chronobiotics.” These go beyond melatonin analogs to target the molecular gears of the clock or its input pathways. While most are not yet in clinical use, they show how future medications might treat circadian rhythm disorders at a fundamental level. Here we highlight some cutting-edge examples:

Nobiletin: A natural polymethoxylated flavone derived from citrus peel, nobiletin has gained attention as a clock amplitude-enhancer. In a 2016 Cell Metabolism study, nobiletin was identified in a screening assay as a compound that increases the amplitude of PER2::Luc circadian oscillations in cells ( The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome – PMC ). It binds to and activates RORα/γ (nuclear receptors that drive expression of core clock genes) ( The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome – PMC ). By activating ROR, nobiletin strengthens the transcriptional feedback loops of the clock, effectively boosting rhythm robustness. In obese mice, nobiletin treatment restored dampened circadian gene expression and improved metabolic syndrome in a clock-dependent manner ( The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome – PMC ). Importantly, in those experiments nobiletin required an intact clock to exert benefits, indicating it was acting via circadian mechanisms ( The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome – PMC ). It has been called a “clock amplitude-enhancing small molecule” ( The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome – PMC ). This means nobiletin might not dramatically shift phase, but it stabilizes and reinforces circadian rhythms (which could help disorders characterized by weak or unstable rhythms, like irregular sleep-wake disorder). Preclinical studies show nobiletin-fed mice have higher amplitude activity rhythms and better alignment to environmental cycles (Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome) (Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome). A review in Molecules noted nobiletin’s “encouraging results in pre-clinical experiments” and deemed it a promising chronotherapeutic agent (Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome). As a dietary supplement, nobiletin is not yet widely available or tested in humans for circadian issues, but its dual metabolic and clock effects make it a compelling future nutraceutical for circadian health.

REV-ERB Agonists (SR9009/SR9011): The REV-ERBα/β proteins are integral repressors in the circadian feedback loop (they suppress BMAL1 transcription during the day). Synthetic REV-ERB agonists like SR9009 and SR9011 bind to REV-ERB and enhance its repressive action, effectively turning off BMAL1-driven transcription. This can profoundly alter clock timing. In a landmark 2012 study, administration of SR9011 to mice was found to abolish locomotor activity during the time the drug was active, essentially pausing the clock’s output ( Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists – PMC ). Mice given a single injection of SR9009 or SR9011 in constant darkness experienced a loss of their next active period and a subsequent 1–3 hour delay in activity onset once activity resumed ( Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists – PMC ) ( Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists – PMC ). In other words, these compounds can delay the circadian phase (likely by acutely suppressing the clock’s drive). Repeated dosing of SR9009 was shown to shift circadian gene expression patterns in the brain and liver ( Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists – PMC ). Though such a strong clock modulation might be useful in resetting a rhythm, the effect in animals was essentially like inducing a transient state of circadian quiescence. This is potent but needs caution – in practice, a REV-ERB agonist could potentially treat jet lag by quickly delaying or advancing the clock if timed properly. It might also stabilize rhythms in shift work or for people who have internal period slightly longer than 24h by adjusting the clock speed. However, research also found these compounds influence many metabolic genes and even immune cells (e.g. SR9009 had anti-inflammatory effects independent of the clock in some studies (The Putatively Specific Synthetic REV-ERB Agonist SR9009 Inhibits …)). As of 2025, REV-ERB modulators are experimental; none are in human trials for circadian disorders yet. Nonetheless, they exemplify a molecular-target approach: instead of adjusting the clock via melatonin or light, directly tweak the core loop. In the future, refined REV-ERB agents or CRY stabilizers (compounds like KL001 that lengthen the clock period by stabilizing cryptochrome proteins) could form a new class of chronomedicines.

Phosphodiesterase (PDE) Inhibitors (e.g. Sildenafil): An intriguing discovery was that sildenafil (Viagra), a PDE5 inhibitor best known for erectile dysfunction, can enhance the circadian system’s response to light. Light is the primary entrainment signal to the SCN, and it triggers cGMP production in the SCN via nitric oxide signaling. By inhibiting the breakdown of cGMP, sildenafil amplifies the effect of light exposure. A seminal PNAS study demonstrated that hamsters given sildenafil adjusted to a 6-hour advanced light-dark schedule significantly faster than controls (Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PubMed). Specifically, after an abrupt 6-h advance (equivalent to flying eastward 6 time zones), control hamsters took ~12 days to re-entrain, whereas those injected with sildenafil re-entrained in ~8 days ( Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PMC ). Higher doses (10 mg/kg) achieved re-entrainment in ~6 days ( Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PMC ). Sildenafil on its own did not shift the clock, but when paired with the light cue it enhanced phase advances – a 50 lux light pulse at CT18 produced a ~150 minute advance with sildenafil vs ~76 minutes without ( Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PMC ). The drug effectively doubled the phase shift obtained from light ( Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PMC ). These results suggest PDE5 inhibition could be a therapy to speed up adjustment to jet lag or shift work (Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PubMed) (Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PubMed). An added bonus is that sildenafil’s effect was dose-dependent without permanently altering the period (once it wore off, normal rhythms continued). There’s even a whimsical note: this finding earned media attention as “Viagra for jet lag” (Another Use for Viagra: Curing Hamster Jet Lag). As for humans, no large trials yet, but given sildenafil’s safety profile in short-term use, a traveler might one day use a low dose when trying to adjust to a new time zone in conjunction with scheduled light exposure. It’s a prime example of repurposing a drug for an off-target but useful effect.

Other Clock-Modulating Compounds: Beyond the above, the circadian research field has identified numerous molecules affecting clock genes: Casein kinase inhibitors (like PF-670462) that can shift rhythms by preventing PER protein phosphorylation (thereby delaying the clock), CRY stabilizers (lengthen period), and partial agonists of neuropeptide receptors in the SCN (like VIP or AVP receptors) that could enhance SCN cell synchrony. Most of these are in preclinical phases. There is also exploration into histone deacetylase inhibitors and other epigenetic modifiers to tweak clock gene expression. For instance, valproic acid (an HDAC inhibitor) lengthens the circadian period in vitro; whether that can be harnessed therapeutically remains unclear.

Finally, an emerging concept is combo chronotherapy: using multiple agents targeting different aspects of the circadian system. We saw an example with ramelteon + suvorexant. Another might be combining a stimulant in the morning, melatonin in the evening – commonly done in practice. Future regimens might combine a core clock modulator (to adjust the molecular clock) with a receptor-level drug (like melatonin agonist) for synergistic resetting.

Table 3: Novel and Investigational Chronobiotic Compounds

Compound	Target/Mechanism	Findings (Preclinical)
Nobiletin	Activates RORα/γ (nuclear receptors) → boosts BMAL1/CLOCK output; increases circadian amplitude	In obese mice, increased circadian amplitude of behavior and metabolism ([

        The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome - PMC
    ](https://pmc.ncbi.nlm.nih.gov/articles/PMC4832569/#:~:text=Dysregulation%20of%20circadian%20rhythms%20is,We%20identified)). Improved alignment of activity to day/night and rescued clock-impaired phenotypes. Proposed as a *clock amplitude enhancer* for strengthening weak rhythms ([Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome](https://www.mdpi.com/1420-3049/27/22/7727#:~:text=of%20the%20circadian%20clock,potential%20as%20a%20chronotherapeutic%20agent)). |

| REV-ERB Agonists (e.g. SR9009) | Bind REV-ERBα/β → repress BMAL1 transcription strongly (dampens clock oscillations) | In mice, a single dose abolished the upcoming active phase and delayed circadian activity by 1–3 h ( Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists – PMC ). Repeated dosing shifted clock gene expression and reduced overall locomotor activity (essentially “pausing” the clock). Potential to realign or compress the circadian cycle, though with broad effects on metabolism ( Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists – PMC ). | | Sildenafil (PDE5 inhibitor) | Elevates cGMP levels in SCN → potentiates light-induced phase resetting (photic entrainment pathway) | Hamsters adjusted to a 6-h advance 33% faster with sildenafil (8 days vs 12) ( Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PMC ). Light pulse phase advances were roughly doubled in magnitude with sildenafil co-administration ( Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PMC ). Suggests use for rapid jet lag recovery by enhancing environmental cues (Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules – PubMed). | | Aripiprazole | Dopamine D2 partial agonist; 5-HT1A partial agonist; destabilizes SCN neuronal synchrony | Mice on aripiprazole showed improved entrainment to shifted light cycles (Aripiprazole disrupts cellular synchrony in the suprachiasmatic …). Case series in humans: low-dose aripiprazole advanced sleep phase ~1–2 h and reduced late-night sleep in DSWPD ( Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation – PMC ) ( Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation – PMC ). Mechanism likely via serotonin activation causing non-photic phase advance and making SCN more responsive to re-scheduling (Aripiprazole disrupts cellular synchrony in the suprachiasmatic …) (Elucidating the mechanism of aripiprazole action in treating …). | | Lithium | Inhibits GSK-3β → stabilizes CLOCK/BMAL1, lengthens circadian period; also upregulates Rev-erbα | Lengthens circadian period in cells and animals (e.g. causes free-running period to prolong by ~1 hour) (A chemical biology approach reveals period shortening of … – PNAS). Clinically observed to reduce circadian variability in bipolar patients and possibly advance activity rhythms (Lithium shifts circadian rhythms early in bipolar disorder and may …). Not typically used solely for circadian issues due to side effects. |

Conclusion

In managing circadian rhythm sleep disorders like DSWPD, pharmacological interventions offer valuable tools to manipulate the body’s clock. Melatonin and its analogs remain the cornerstone for actively shifting circadian phase earlier, directly targeting the SCN’s melatonin receptors to signal an earlier night. Other agents, from wake-promoting stimulants to sedative hypnotics, reinforce the desired sleep-wake schedule – essentially propping up the circadian rhythm by enforcing clear periods of wakefulness and sleep. These help increase the amplitude and stability of the rhythm, even if they don’t by themselves change the clock’s timing. Emerging therapies are moving toward clock-targeted drugs – aiming at the molecular gears (like ROR, REV-ERB, kinases) or signal pathways (like serotonin or cGMP) that govern circadian regulation. Early results in animals are promising, showing that we may someday pharmacologically entrain or adjust human clocks with precision.

For now, clinicians treating DSWPD or related conditions often employ a combination approach: an evening chronobiotic (e.g. melatonin) to shift the phase, morning alerting strategy (bright light and/or a stimulant) to reinforce the new phase, and possibly a short-term hypnotic to ensure sleep onset at the intended earlier bedtime. Each drug plays a part in moving the patient from a delayed schedule to a conventional one and keeping them aligned. Importantly, these pharmacological approaches have to be individualized – factors like a patient’s work demands, response to medications, and any comorbidities guide the regimen chosen.

It should be emphasized that circadian rhythm modulation is an active area of research. The pipeline of novel agents (melatonin agonists, receptor antagonists, and clock modulators) holds promise for those who do not respond to current treatments. As our understanding of circadian biology deepens, it opens opportunities to treat not only sleep phase disorders but also the many health issues linked to circadian disruption (metabolic syndrome, mood disorders, etc.) using timed pharmacotherapy. In practice, a successful outcome for a DSWPD patient might involve, for example, 2 mg of melatonin at 7 PM daily to advance the clock (Pharmacological Treatments of Sleep–Wake Disorders: Update 2023), 200 mg of modafinil at 7 AM to ensure morning alertness, and good sleep hygiene, gradually leading to an earlier stable sleep schedule. If needed, adjuncts like low-dose aripiprazole or B12 can be tried, though evidence may be limited.

In summary, a range of pharmacological agents – from FDA-approved drugs to experimental compounds – have shown potential to shift circadian phase and stabilize rhythms. When used thoughtfully (often in combination), these agents can significantly improve the alignment of the internal clock with the desired schedule, alleviating the insomnia and daytime impairment that characterize circadian rhythm sleep disorders. As new research emerges, we anticipate even more targeted chronotherapeutics to complement the current arsenal of melatonin-based treatments, moving closer to the goal of precision circadian medicine.