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Jet lag

Jet lag, also known as jet lag disorder or desynchronosis, is a temporary sleep-wake disorder triggered by rapid travel across multiple time zones, which disrupts the body's internal circadian rhythm and leads to misalignment between the traveler's biological clock and the local day-night cycle.^[1] This condition primarily affects individuals flying east or west over long distances, with symptoms typically emerging within one to two days of arrival and lasting from a few days to a week, depending on the number of time zones crossed and individual factors.^[2] The most common symptoms of jet lag include daytime fatigue, insomnia or disrupted sleep patterns, irritability, difficulty concentrating, headaches, and gastrointestinal issues such as nausea or constipation, all stemming from the desynchronization of key physiological processes like melatonin production and core body temperature regulation.^[1] Eastward travel often exacerbates symptoms more severely than westward travel because it shortens the day and requires advancing the internal clock, which is biologically more challenging than delaying it.^[3] Risk factors include age (older adults recover more slowly), pre-existing sleep disorders, and the extent of time zone changes, with crossings of three or more zones increasing severity.^[2] Prevention and management strategies focus on gradually adjusting the circadian rhythm before, during, and after travel, such as timed exposure to light, maintaining hydration, strategic napping, and in some cases, the use of melatonin supplements to facilitate sleep onset at the destination time.^[1] While jet lag is generally self-limiting and not considered a serious medical condition, it can impair cognitive performance, mood, and overall well-being, particularly for frequent travelers like pilots or business professionals, highlighting its significance in occupational health and travel medicine.^[3]

History

Discovery

The rapid expansion of commercial aviation following World War II, with the introduction of faster propeller-driven aircraft and early jetliners, significantly increased transcontinental and transoceanic travel, allowing for the widespread observation of fatigue symptoms among passengers and crew that would later be identified as jet lag.^[4] The first documented cases of such fatigue emerged in the 1950s among pilots and flight crews on transatlantic routes, where long-duration flights across multiple time zones led to disrupted sleep and performance issues, as evidenced by aviation accident investigations attributing crashes to crew exhaustion. For instance, inquiry into a 1954 British Overseas Airways Corporation crash in Singapore suggested that pilot fatigue may have contributed after extended duty periods on international flights.^[5] Early scientific hypotheses linking these symptoms to circadian disruptions gained traction with Jürgen Aschoff's 1965 study on human circadian rhythms under isolation conditions, which demonstrated that internal biological clocks persist independently of external time cues and could desynchronize during rapid time zone shifts, providing a foundational framework for understanding jet lag.^[6] In the 1970s, researcher Charles Ehret at Argonne National Laboratory advanced these ideas through experiments on phase shifts in rodent circadian rhythms, extrapolating findings to human travelers and developing initial strategies to mitigate jet lag by aligning feeding and activity patterns with destination times.^[7]

Etymology

The term "jet lag" was first recorded in print on February 13, 1966, in a Los Angeles Times article by travel writer Horace Sutton, who described it as "a debility not unakin to a hangover" resulting from jet aircraft traveling so rapidly that they outpace the body's internal rhythms.^[8] This usage marked the introduction of a concise, evocative phrase to capture the malaise experienced by long-haul passengers, reflecting the rapid expansion of commercial jet travel in the post-World War II era. The etymology combines "jet," denoting the jet-engine aircraft that enabled transcontinental flights in hours rather than days, with "lag," signifying a delay or backwardness in the body's circadian adjustment to shifted time zones. Before "jet lag" became standard, the phenomenon lacked a unified English name; early aviation medicine referred to it as "time zone syndrome," a term appearing in scientific and popular discussions by the early 1960s to describe the disorientation from rapid east-west crossings.^[9] By the 1970s, "jet lag" had permeated popular culture and professional discourse, appearing frequently in media reports on celebrity travelers and business executives.^[10] Its adoption accelerated through aviation regulations; for instance, the UK's 1973 Bader Committee report on aircrew fatigue explicitly addressed "jet lag" in recommendations for flight scheduling to mitigate pilot desynchrony, influencing international guidelines.^[5] This period's surge in transoceanic tourism and the oil crisis-driven focus on crew efficiency solidified the term's dominance over earlier alternatives like "time zone syndrome."

Circadian Rhythms

Biological basics

Circadian rhythms are endogenous, approximately 24-hour cycles that regulate various physiological and behavioral processes in living organisms, primarily orchestrated by the suprachiasmatic nucleus (SCN), a small cluster of neurons located in the anterior hypothalamus that serves as the master biological clock.^[11] The SCN coordinates these rhythms by integrating environmental signals and synchronizing peripheral clocks throughout the body, ensuring alignment with the external day-night cycle.^[12] Key physiological outputs of circadian rhythms include the core body temperature rhythm, which typically dips to its lowest point in the early morning hours and rises during the day; melatonin secretion from the pineal gland, peaking in the evening and night to promote sleep; and cortisol release from the adrenal glands, which surges in the early morning to facilitate wakefulness and energy mobilization.^[11] These rhythms maintain homeostasis by temporally organizing metabolic, hormonal, and neural activities.^[13] At the molecular level, circadian rhythms are driven by a transcriptional-translational feedback loop involving core clock genes. The CLOCK and BMAL1 proteins form a heterodimer that binds to E-box promoter elements, activating transcription of the PER (Period) and CRY (Cryptochrome) genes during the day.^[14] As PER and CRY proteins accumulate in the cytoplasm, they form complexes that translocate to the nucleus at night, where they inhibit the transcriptional activity of the CLOCK-BMAL1 complex, repressing their own expression and closing the loop; this oscillatory cycle, with degradation of PER and CRY allowing reactivation, generates the roughly 24-hour periodicity.^[15] A simplified representation of this feedback loop depicts CLOCK-BMAL1 activation during the subjective day leading to rising PER-CRY levels, followed by nuclear repression at night, with auxiliary loops involving REV-ERB and ROR genes stabilizing the rhythm.^[16] These internal rhythms are entrained to the external environment primarily through zeitgebers, or time-giving cues, with light being the dominant signal that resets the SCN via retinal ganglion cells projecting through the retinohypothalamic tract.^[12] Social cues, such as meal times and interpersonal interactions, also contribute to synchronization by influencing the sleep-wake cycle and reinforcing the light-driven rhythm.^[17]

Role in daily functioning

Circadian rhythms play a central role in regulating the sleep-wake cycle, promoting consolidated sleep during the night and wakefulness during the day in individuals entrained to a typical light-dark schedule. Optimal sleep onset aligns closely with the rise in endogenous melatonin secretion, known as the dim light melatonin onset (DLMO), which typically occurs between 9 and 11 PM in healthy adults with habitual bedtimes around 11 PM to midnight.^[18]^[19] This hormonal signal, produced by the pineal gland, facilitates the transition to sleep by lowering core body temperature and reducing alertness, ensuring restorative rest that supports overall recovery.^[20] These rhythms also profoundly influence cognitive performance throughout the day, with alertness and executive functions peaking in the mid-morning (around 10:00 AM) and early evening (around 4:00-7:00 PM). A notable dip in vigilance and reaction time often follows lunch, between 1:00 and 4:00 PM, reflecting an interaction between circadian processes and homeostatic sleep pressure, which can impair tasks requiring sustained attention.^[21]^[22] This pattern underscores how circadian alignment optimizes mental acuity during productive hours while predisposing individuals to temporary lulls in the afternoon. Beyond cognition, circadian rhythms coordinate essential physiological processes, timing digestion and nutrient absorption primarily to daytime activity when meals are consumed. Gastrointestinal motility, enzyme secretion, and nutrient uptake exhibit diurnal variations, with peak efficiency during waking hours to match feeding patterns and energy demands.^[23] Similarly, immune function is enhanced during sleep phases, as cytokine production and lymphocyte activity increase nocturnally, bolstering defenses against pathogens and promoting tissue repair under the influence of these rhythms.^[24]^[25] Individual differences in circadian rhythms, known as chronotypes, further shape daily functioning, with "morning larks" (early chronotypes) exhibiting earlier peaks in alertness and sleep propensity, while "night owls" (late chronotypes) show delayed timing and potentially greater flexibility—or rigidity—in adapting to schedule shifts. These variations, influenced by genetic factors, affect how readily one maintains optimal performance across the day.^[26]^[27]

Signs and Symptoms

Physical manifestations

Jet lag commonly manifests through a range of physical symptoms that disrupt normal bodily functions, primarily due to the misalignment of the body's internal clock with the new environment.^[1] Fatigue is one of the most prevalent symptoms, often presenting as profound daytime tiredness that impairs physical activity and recovery. Headaches frequently accompany this fatigue, resulting from disrupted sleep patterns and dehydration during travel.^[28] Digestive upset is also common, including issues such as constipation, diarrhea, or general gastrointestinal discomfort, which stem from irregular eating schedules and the stress of rapid time zone shifts.^[1] Sleep disturbances form a core physical component of jet lag, arising from a mismatched sleep drive relative to local time. Insomnia at night is typical, where individuals struggle to fall asleep despite feeling exhausted, due to the body's circadian rhythm signaling wakefulness.^[2] Conversely, excessive daytime sleepiness can lead to unintended naps or difficulty maintaining alertness, further compounding physical exhaustion. Sensory issues often intensify during air travel and contribute to jet lag's physical toll. Dry eyes and irritation result from the low humidity in airplane cabins, which can worsen with prolonged exposure.^[29] Dehydration, promoted by cabin conditions and factors like alcohol or caffeine consumption, exacerbates these symptoms and overall malaise, making recovery more challenging.^[1] The duration of these physical manifestations typically aligns with the extent of time zone crossing, lasting about one day per time zone traveled, though eastward journeys often require longer adjustment periods of 3-7 days compared to westward ones.^[2] Symptoms generally resolve as the circadian rhythm entrains to the new schedule, but individual variability in adaptation speed influences this timeline.^[3]

Psychological effects

Jet lag induces a range of psychological symptoms stemming from circadian misalignment, including irritability, anxiety, and mood swings, which arise due to disruptions in neurotransmitter systems such as serotonin and dopamine that regulate emotional stability.^[30] These fluctuations occur as the body's internal clock struggles to adapt to rapid time zone shifts, leading to imbalanced release of mood-stabilizing chemicals and heightened emotional reactivity.^[31] Cognitive functions are also notably impaired, with travelers experiencing reduced concentration, memory lapses, and errors in decision-making as the brain's executive processes falter under sleep-wake cycle disruption.^[32] These effects manifest as difficulty sustaining attention on tasks and slower information processing, often compounding the emotional strain of travel.^[30] Such impairments are particularly evident in high-demand situations, where even mild desynchrony can lead to suboptimal judgment and forgetfulness.^[33] The severity of these psychological effects tends to be greater following eastward travel, as phase advances—shortening the circadian cycle—are harder for the body to achieve than phase delays in westward journeys.^[2] This directional difference amplifies mood instability and cognitive deficits due to more pronounced neurotransmitter imbalances and prolonged adaptation periods.^[34] Overall, these symptoms affect 60-70% of travelers crossing three or more time zones, based on surveys of international air passengers in the 2020s.^[35]

Relation to travel fatigue

Travel fatigue refers to the cumulative tiredness arising from the physical and environmental stressors of travel, such as prolonged motion, confinement in aircraft or vehicles, dehydration, irregular eating schedules, and sensory overload from crowded terminals or noisy cabins, occurring independently of time zone changes.^[2] This condition stems from the immediate demands of the journey itself, leading to symptoms like general exhaustion, headaches, and mild disorientation that affect travelers regardless of destination time differences.^[36] Jet lag and travel fatigue overlap in their disruption of sleep quality and induction of overall fatigue, yet jet lag uniquely incorporates a mismatch between the traveler's internal circadian rhythms and the external cues of the new time zone, exacerbating sleep-wake cycle irregularities.^[3] While both may manifest as daytime sleepiness or irritability, jet lag's circadian component results in more targeted issues like insomnia at night or alertness at inappropriate times, beyond the nonspecific weariness of travel fatigue.^[37] Symptom clusters unique to jet lag, including gastrointestinal disturbances and cognitive fog tied to physical manifestations and psychological effects, highlight this distinction without relying solely on journey-related exhaustion.^[1] A practical distinguishing test involves post-travel recovery: symptoms of pure travel fatigue typically resolve rapidly after adequate rest and a single good night's sleep, whereas jet lag persists for days—often one day per time zone crossed—until biological entrainment to local time occurs.^[38] This difference underscores that travel fatigue is transient and journey-linked, while jet lag requires active adjustment of internal clocks.

Causes and Mechanisms

Circadian desynchrony

Circadian desynchrony represents the core mechanism underlying jet lag, characterized by a temporary misalignment between the body's internal circadian timing system and the external zeitgebers, primarily the light-dark cycle, following rapid transmeridian travel. This desynchrony manifests as a transient uncoupling of peripheral circadian clocks—such as those in the liver and gut—from the central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus, leading to disrupted coordination across physiological processes.^[39] The SCN, as the master regulator, receives light input via the retinohypothalamic tract and coordinates peripheral oscillators through neural and hormonal signals, but abrupt time zone shifts overwhelm this synchronization, causing internal clock conflicts.^[40] Eastward travel exacerbates circadian desynchrony because it necessitates a phase advance (shortening the circadian period to align with an earlier local dawn), which is physiologically challenging as human endogenous rhythms naturally tend toward a slightly longer-than-24-hour cycle and resist compression. In contrast, westward travel induces a phase delay (lengthening the period to match a later local dusk), which is generally easier to achieve since it aligns with the intrinsic delay propensity of the circadian system. Approximately 75% of individuals report more severe symptoms with eastward flights due to this asymmetry in phase-shifting ease.^[2]^[41] The rate of circadian realignment is limited, with the human clock typically adjusting by about 1 hour per day for phase advances and 1.5 hours per day for phase delays, far slower than the instantaneous shift from long-haul flights spanning multiple time zones. Actigraphy-based studies from the 2010s illustrate this, showing that recovery from an 8-hour eastward shift often requires 5 to 10 days for sleep-wake cycles and circadian markers to stabilize, with symptoms persisting up to a week or more in severe cases. For instance, research on transmeridian travel across eight or more zones confirmed that full physiological resynchronization, including restored sleep efficiency, can take at least one week.^[42]^[43]

Double desynchrony

Double desynchrony in jet lag arises from the temporary internal misalignment between the central suprachiasmatic nucleus (SCN) clock and peripheral oscillators in organs such as the liver, gut, and pancreas, exacerbating the broader circadian desynchrony with the external environment.^[44] The SCN, as the master pacemaker, entrains more rapidly to shifted light-dark cycles, typically within 1-2 days, while peripheral clocks adjust more slowly, leading to phase differences of 2-6 hours or more during the initial recovery period.^[45] This incoherence can manifest as conflicting physiological signals, such as melatonin from the pineal gland promoting sleep while peripheral clocks in the gastrointestinal tract anticipate feeding during mismatched local times.^[44] The consequences of this internal desynchrony include disrupted hormonal and metabolic regulation, particularly affecting insulin dynamics. For instance, misaligned peripheral clocks in the liver and adipose tissue can impair insulin sensitivity, leading to transient glucose intolerance as the body's metabolic rhythms fail to synchronize with centrally driven cues.^[46] Such disruptions contribute to symptoms like gastrointestinal discomfort and fatigue beyond simple sleep misalignment.^[39] Seminal research in the 2000s, including studies by Joseph Takahashi and colleagues, demonstrated organ-specific circadian rhythms in mice using bioluminescent reporters, revealing that peripheral tissues like the liver re-entrain at rates distinct from the SCN following phase shifts simulating jet lag.^[45] Human parallels have been observed through blood markers, such as oscillating clock gene expression in peripheral blood mononuclear cells, which show delayed phase shifts compared to central melatonin rhythms after transmeridian travel.^[47] This internal desynchrony typically peaks between days 2 and 4 post-travel, when the lag between central and peripheral clocks is maximal, before resolving as slower-adjusting peripherals gradually realign, often taking up to 8 days for full coherence in animal models with human implications.^[48]

Entrainment challenges

Entrainment, the process by which the suprachiasmatic nucleus (SCN) in the hypothalamus adjusts the body's internal clock to align with a new environmental time zone, requires new zeitgebers such as light exposure and meal timing to override the previously established cues from the departure location. This reset involves gradual phase shifts in the SCN's oscillatory activity, typically occurring at a rate of about 1-1.5 hours per day in healthy adults, but disruptions during travel can prolong this adaptation period to several days or even weeks. One major barrier to effective entrainment is the presence of weak or conflicting zeitgebers in transit environments, such as the dim, artificial lighting in airplane cabins that fails to provide the strong photic signals needed for rapid phase adjustment. Additionally, social jet lag arising from irregular sleep and meal schedules upon arrival—often due to work demands or social obligations—further delays the SCN's resynchronization by reinforcing desynchronized peripheral clocks. These challenges are compounded by the internal discord of double desynchrony, where the core body clock lags behind the new local time, hindering overall rhythm realignment. The dynamics of entrainment can be qualitatively modeled using the phase response curve (PRC), which illustrates how zeitgebers like light influence the timing of circadian rhythms: exposure during the subjective evening or early night typically delays the phase (pushing the clock later), while morning light advances it (shifting the clock earlier), allowing travelers to strategically time exposures for faster adaptation. For eastward travel requiring phase advances, morning light is particularly effective, whereas westward trips benefit from evening exposure, though the curve's asymmetry means advances are generally slower and more challenging than delays. Age-related factors significantly impede entrainment efficiency, with older adults showing reduced phase-shifting capacity and taking longer to adapt—often 30-50% slower than younger individuals—due to diminished SCN responsiveness and reduced melatonin output that weakens the clock's plasticity.^[49] This age-dependent slowdown is attributed to accumulated cellular changes in the circadian system, making prolonged jet lag more common in the elderly and emphasizing the need for extended recovery periods.

Risk factors

Certain demographic characteristics heighten the risk of experiencing severe jet lag. Older adults, particularly those over 60 years, often face more pronounced symptoms and require extended recovery periods due to age-related changes in circadian adaptability.^[1] Sex differences in jet lag susceptibility are not fully established, but some recent studies in animal models suggest females may resynchronize faster to phase shifts, while others indicate greater vulnerability to chronic disruptions potentially linked to hormonal influences.^[50] Individuals with an evening chronotype, or "night owls," are especially vulnerable, as their delayed internal clocks amplify desynchrony during travel, particularly when heading eastward.^[51] Behavioral habits during and before travel can exacerbate jet lag severity. Dehydration, often worsened by alcohol and caffeine intake on flights, intensifies physical symptoms by further disrupting sleep and hydration balance.^[52] Irregular or insufficient sleep in the days leading up to departure increases propensity for the disorder by compounding pre-existing fatigue.^[53] Specific travel conditions also elevate risk. Crossing more than three time zones triggers significant circadian desynchrony, with eastward journeys generally producing more severe effects than westward ones due to the challenge of advancing the body's internal clock.^[35] Frequent flyers completing over four long-haul trips annually face heightened chronic risks from repeated disruptions.^[54] Survey data underscore the prevalence among long-haul passengers, with approximately 68% of international business travelers reporting jet lag disorder symptoms.^[35]

Long-Term Health Effects

Mental health impacts

Chronic exposure to jet lag among frequent travelers, such as airline pilots and cabin crew, is linked to elevated risks of depression and anxiety disorders. A 2016 survey of commercial airline pilots revealed that those working longer duty hours per week were twice as likely to report symptoms of depression or anxiety compared to those with shorter hours.^[55] Similarly, a 2024 study of international flight attendants found they are twice as likely to experience anxiety and depression than the general population, with 40% reporting depressive symptomology attributable in part to irregular schedules and circadian disruption.^[56] The underlying mechanisms involve chronic circadian desynchrony, which interferes with serotonin signaling pathways in the brain, producing effects akin to those in seasonal affective disorder (SAD). In SAD, diminished daylight exposure reduces serotonin production, exacerbating depressive states; jet lag's repeated shifts in light-dark cycles similarly impair serotonin regulation, contributing to persistent mood dysregulation.^[57]^[58] This disruption can amplify vulnerability to psychiatric conditions over time, particularly in occupations requiring transmeridian travel. Longitudinal and cross-sectional evidence underscores these associations, with a 2024 analysis of over 7,000 pilots reporting a 23.3% prevalence of depression and anxiety, higher than general population averages and correlated with flight-related circadian challenges.^[59] A 2020 study of cabin crew further demonstrated positive correlations between occupational stressors, including repeated jet lag, and elevated levels of depression, anxiety, and stress, with existential fears linked to symptom severity.^[60] These mental health impacts are often reversible; symptoms tend to subside with retirement or schedule stabilization, enabling circadian realignment and improved serotonin homeostasis.

Metabolic disorders

Chronic jet lag, characterized by repeated disruptions to the body's circadian rhythms from frequent transmeridian travel, contributes to metabolic dysregulation by misaligning feeding-fasting cycles with internal clocks. This misalignment impairs the regulation of key hormones such as leptin and ghrelin, which control appetite and energy balance; specifically, circadian desynchrony leads to decreased leptin levels (indicating perceived energy deficit) and increased ghrelin (promoting hunger), fostering overeating and weight gain.^[61] Furthermore, these disruptions reduce insulin sensitivity, with studies showing approximately 15% increases in glucose and insulin responses during tolerance tests under misalignment conditions, thereby promoting insulin resistance and elevating the risk for type 2 diabetes.^[61] Rodent models provide direct evidence of these effects, demonstrating that simulated chronic jet lag induces glucose intolerance and altered body weight. In a 2024 study, male mice subjected to repeated 6-hour phase advances (mimicking eastward jet lag) exhibited significant weight gain and impaired glucose tolerance compared to controls, while females showed weight loss but preserved tolerance, highlighting sex-specific vulnerabilities in metabolic responses.^[62] Human data from simulations of shift-like jet lag, analogous to chronic travel disruption, further confirm these risks; for instance, individuals with pronounced social jet lag (a proxy for repeated circadian shifts) displayed HbA1c elevations of up to 1% in susceptible groups with type 1 diabetes, indicating worsened long-term glycemic control.^[63] The relationship follows a dose-response pattern, where greater exposure to circadian disruption correlates with heightened diabetes risk. Chronic shift work, comparable to accumulating >100 flight hours annually in frequent travelers, is associated with a 1.5-fold increased odds of type 2 diabetes after 10-14 years of exposure, underscoring the cumulative impact of repeated jet lag on metabolic health.^[64] These effects may overlap with inflammatory responses, as metabolic dysregulation amplifies immune-metabolic interactions.^[61]

Cancer associations

Chronic jet lag, characterized by repeated disruptions to the circadian rhythm from transmeridian travel, has been hypothesized to elevate cancer risk primarily through the suppression of melatonin secretion induced by light exposure at inappropriate times. Melatonin, a hormone with documented oncostatic effects including inhibition of tumor cell proliferation and enhancement of immune surveillance, is particularly vulnerable to such desynchrony, potentially fostering an environment conducive to oncogenesis. The International Agency for Research on Cancer (IARC) classified shift work involving circadian disruption as a probable human carcinogen (Group 2A) in 2007, based on evidence from breast cancer epidemiology, and this framework has been conceptually extended to chronic jet lag due to analogous chronodisruption mechanisms.^[65] Epidemiological evidence linking chronic jet lag to cancer risk is most robust for breast and prostate cancers, often drawn from occupational cohorts like flight attendants who experience frequent time zone crossings. A 2006 meta-analysis of seven studies reported a standardized incidence ratio of 1.42 (95% CI: 1.18–1.70) for breast cancer among female flight attendants, indicating approximately a 1.5-fold increased risk relative to the general population, attributed partly to circadian misalignment beyond cosmic radiation exposure. Associations with prostate cancer have similarly emerged in male crew members, with odds ratios around 1.3 in comparable analyses. Although no specific 2023 World Health Organization update directly addresses jet lag, reaffirmations of IARC's 2019 monograph on night shift work underscore the broader implications for repeated circadian perturbations, while 2024 epidemiological reviews highlight elevated liver cancer risks in chronic jet lag models. A July 2025 study in animal models further demonstrated that chronic jet lag elevates glioma risk through altered molecular profiles in distinct brain regions.^[66]^[67]^[68]^[69] At the molecular level, circadian desynchrony impairs DNA repair pathways, such as nucleotide excision repair and double-strand break resolution, which exhibit rhythmic expression peaks that align with the sleep-wake cycle; misalignment leads to unrepaired genomic instability and mutagenesis. Core circadian clock genes, including PER2, regulate these processes and intersect with cancer pathways—PER2 mutations or downregulation, as observed in breast and colorectal tumors, disrupt p53-mediated apoptosis and cell cycle checkpoints, accelerating tumor initiation when combined with jet lag-like disruptions in animal models. These effects are particularly pronounced in hormone-sensitive cancers like breast and prostate, where clock gene dysregulation amplifies estrogen and androgen signaling aberrations.^[70]^[71]^[72] Despite these links, observational studies are confounded by lifestyle factors such as irregular sleep, alcohol use, and occupational stressors among frequent travelers. Nonetheless, 2025 cohort analyses, including those modeling glioma progression, demonstrate a dose-dependent risk wherein greater cumulative jet lag exposure correlates with heightened tumor gene expression and incidence, bolstering evidence for causality independent of confounders. These oncogenic risks share underlying hormonal disruptions, such as altered cortisol and sex steroid rhythms, with metabolic disorders.^[69]^[73]

Inflammatory responses

Chronic jet lag, characterized by repeated circadian desynchrony, triggers systemic inflammation by elevating pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). This occurs primarily through activation of the nuclear factor kappa B (NF-κB) pathway during misaligned sleep-wake cycles, where the circadian clock's normal suppression of NF-κB during rest phases is disrupted, leading to unchecked inflammatory gene expression.^[74]^[75] Evidence from biomarker analyses in travelers experiencing jet lag reveals significant post-disruption spikes in these cytokines, with increases of 15-29% in IL-6 and 3% in TNF-α levels, correlating with heightened risk for atherosclerosis via promotion of endothelial inflammation and plaque formation.^[76] Such acute inflammatory responses underscore the pathway's role in linking transient desynchrony to vascular pathology. Over the long term, cumulative jet lag exposure simulates chronic stress, fostering persistent cardiovascular inflammation through sustained cytokine elevation and immune dysregulation, as detailed in recent reviews.^[77] Inflammatory markers like C-reactive protein (CRP) exhibit dose-dependent rises proportional to the number of time zones crossed repeatedly, with circadian misalignment alone accounting for up to an 11% increase in 24-hour CRP levels independent of sleep loss.^[78] This chronic state amplifies risks for inflammatory-driven diseases, including acting as a promoter in cancer progression.^[79]

Management Strategies

Light therapy

Light therapy leverages timed exposure to bright light as a non-pharmacological intervention to expedite circadian realignment following transmeridian travel, addressing the desynchrony central to jet lag. The core principle relies on the phase response curve (PRC) to light, where exposure to bright light of at least 2,500 lux during the subjective morning advances the circadian phase, facilitating adaptation to eastward time shifts, while evening exposure delays the phase for westward shifts.^[80]^[81] This approach exploits light's role as the dominant zeitgeber in circadian entrainment, overriding internal clocks misaligned by rapid travel.^[80] Protocols for light therapy typically involve strategic pre-flight and post-arrival exposures to initiate and reinforce phase shifts. Pre-flight, individuals may use dawn simulation for about 1 hour upon waking to gradually advance or delay rhythms, often guided by apps or devices that mimic natural sunrise progression starting 3–5 days before departure.^[82]^[54] Post-arrival, seeking outdoor natural light during the target morning (for eastward travel) or evening (for westward) for 1–2 hours promotes faster adaptation, with indoor supplementation if sunlight is unavailable.^[80]^[82] Clinical trials demonstrate the efficacy of light therapy in mitigating jet lag symptoms, including fatigue, sleep disturbances, and cognitive impairment. A randomized study using light visors delivering timed bright light after westward travel across six time zones showed a greater circadian phase delay of approximately 1 hour compared to dim light controls, though no significant improvements in subjective sleep or alertness issues were reported.^[83] NASA research on shift workers, analogous to jet lag scenarios for astronauts, confirmed that scheduled light exposure enhances circadian adjustment and performance without disrupting sleep.^[84] Devices for light therapy often incorporate blue-enriched wavelengths (460–480 nm) to selectively stimulate intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate non-visual circadian responses.^[85] Common options include portable light boxes emitting 2,500–10,000 lux or wearable glasses like the goLITE, used for 20–30 minutes at prescribed times; evening use must be avoided to prevent unintended phase delays.^[86]^[87] These tools enable precise, portable application, particularly beneficial for frequent travelers.

Melatonin supplementation

Melatonin supplementation involves the administration of exogenous melatonin, a hormone naturally produced by the pineal gland to regulate the sleep-wake cycle, to facilitate the realignment of the body's circadian rhythm following rapid travel across multiple time zones. By mimicking the endogenous melatonin signal, supplementation promotes phase shifts in the circadian clock, helping to synchronize sleep patterns with the destination's local time more rapidly. This approach is particularly useful for counteracting the desynchrony between internal rhythms and environmental cues like light-dark cycles.^[88] The mechanism relies on melatonin's ability to induce phase advances or delays depending on timing relative to the body's internal clock. Recommended doses range from 0.5 to 5 mg, administered 30 to 60 minutes before the desired bedtime at the destination. For eastward travel requiring a phase advance, intake occurs in the evening local time; for westward travel necessitating a phase delay, it is taken in the morning, though evidence supports stronger efficacy for eastward journeys where advancing the clock is physiologically more difficult. Timing precision is essential to achieve the intended shift and prevent counterproductive effects like grogginess or disrupted sleep.^[35]^[89] The American Academy of Sleep Medicine (AASM) endorses timed melatonin administration as a standard treatment for jet lag disorder, particularly for trips involving three or more time zones eastward. Supplements are typically synthetic, replicating the structure of natural melatonin derived from the pineal gland, and are favored for their consistent purity and bioavailability compared to animal- or plant-based natural sources. Recent considerations in dosing protocols emphasize adjustments based on individual chronotype to optimize efficacy, though core recommendations remain focused on short-term use limited to 3-5 days post-arrival.^[88] Meta-analyses, including the comprehensive Cochrane review, demonstrate that melatonin accelerates recovery from jet lag symptoms by 1-2 days compared to placebo, reducing overall severity and the duration of sleep disturbances, fatigue, and alertness issues. For instance, participants crossing five or more time zones reported about 50% fewer symptomatic days with supplementation. Side effects are generally mild and infrequent, primarily consisting of transient drowsiness or headache, supporting its safety for occasional use in healthy adults. Melatonin can complement light therapy by enhancing phase-shifting when combined strategically.^[90]^[91]

Pharmaceutical interventions

Pharmaceutical interventions for jet lag primarily target sleep disturbances and daytime alertness through prescription hypnotics and wakefulness-promoting agents, offering symptomatic relief during the acute phase of circadian misalignment. Hypnotics such as zolpidem, a non-benzodiazepine sedative, are commonly prescribed to facilitate sleep onset in travelers experiencing eastward or westward shifts of more than five time zones. Administered at doses of 5-10 mg before bedtime for a short duration of up to three nights, zolpidem has demonstrated efficacy in reducing sleep latency and improving overall sleep quality post-travel, with randomized controlled trials (RCTs) showing significant alleviation of insomnia symptoms compared to placebo.^[92]^[93]^[94] For managing daytime somnolence and fatigue, modafinil or its enantiomer armodafinil serves as a stimulant to enhance alertness without the jitteriness associated with caffeine. Dosed at 100-150 mg in the morning following arrival, these agents improve wakefulness and cognitive performance during the biological night, as evidenced by RCTs where armodafinil reduced perceived jet lag severity and enhanced participants' global impression of their condition on days 1 through 3 post-travel.^[95]^[35]^[96] Emerging options include melatonin receptor agonists like tasimelteon, a ramelteon analog approved for non-24-hour sleep-wake disorder, which is under active pursuit for jet lag indications following a 2025 federal appeals court ruling remanding the case to the FDA for further proceedings, including a hearing, due to the agency's arbitrary refusal to hold one, potentially leading to reconsideration of its supplemental application. RCTs on ramelteon, a related agonist, have shown it accelerates circadian re-entrainment after a 5-hour phase advance, reducing latency to persistent sleep by approximately 10-15 minutes over four nights at doses of 1-8 mg, though broader symptom relief varies.^[97]^[98]^[99] Overall, RCTs of these interventions, including hypnotics and stimulants, indicate reductions in jet lag symptoms, such as fatigue and sleep disruption, particularly in travelers crossing multiple time zones; however, benefits are most pronounced when limited to short-term use to mitigate risks of tolerance and dependency in frequent flyers.^[100] Contraindications include avoidance in elderly individuals due to heightened fall risk from impaired balance and coordination, with studies linking hypnotic use to a 1.5-2-fold increase in fracture incidence among those over 65. These drugs should be combined with non-pharmacological approaches for optimal outcomes, while melatonin supplementation remains a viable over-the-counter alternative for milder cases.^[101]^[102]^[103]

Behavioral adjustments

Behavioral adjustments for jet lag focus on lifestyle habits implemented before, during, and after travel to align the body's circadian rhythm with the destination time zone without relying on medical interventions. Pre-flight preparation is key, involving a gradual shift in sleep schedule by advancing or delaying bedtime and wake time by about one hour per day for up to three days prior to departure, depending on the direction and extent of time zone crossing. For eastward travel, this means going to bed and waking earlier; for westward, later. Additionally, maintaining hydration by drinking ample water and opting for light meals rich in fruits and vegetables in the days leading up to the flight can mitigate dehydration risks and digestive discomfort exacerbated by travel.^[104]^[105]^[106] During the flight, strategic behaviors help preserve energy and reduce fatigue accumulation. Travelers should aim for short naps of less than two hours, ideally under 30 minutes and timed at least eight hours before the intended bedtime at the destination, to avoid deep sleep cycles that prolong adjustment. Regular movement, such as standing, stretching, or walking the aisle every hour, combats physical stiffness and promotes circulation, while continuing hydration with water and consuming small, light meals prevents gastrointestinal issues and supports overall alertness.^[104]^[105] Upon arrival, immediate adoption of the local time through synchronized meals, physical activity, and sleep routines accelerates recovery. Eating and exercising according to the destination's schedule reinforces the circadian shift, and any necessary naps should be limited to under 30 minutes to prevent interference with nighttime sleep. For short trips lasting less than 48 hours, it is often advisable to maintain the home time zone schedule for sleep and meals to avoid unnecessary disruption to the internal clock. In 2025, mobile applications like Timeshifter provide personalized plans based on flight details and individual chronotypes to guide these behavioral adjustments effectively.^[104]^[105]^[107]^[108]

References

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Jet lag disorder - Symptoms and causes - Mayo Clinic
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Aug 11, 2022 · This type of disturbance also includes the so-called jet lag, classified as acute desynchronosis—damage to circadian rhythms caused by a rapid ...
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Circadian rhythm is the 24-hour internal clock in our brain that regulates cycles of alertness and sleepiness by responding to light changes in our environment.
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New perspectives on the role of melatonin in human sleep, circadian ...
The sleep–wake cycle is the most overt circadian rhythm ... There is compelling evidence indicating that melatonin effectively advances sleep onset and wake times ...
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Melatonin helps control your circadian rhythm. This is your sleep-wake cycle that happens automatically about every 24 hours. Melatonin helps your body get ...
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An early afternoon period of reduced alertness and performance commonly referred to as the postlunch ... A time of peak alertness occurs in the early evening and ...Sleep, Biological Rhythms... · Introduction · Abstract<|control11|><|separator|>
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Circadian rhythms: a regulator of gastrointestinal health and ...
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Sleep and immune function - PMC - PubMed Central - NIH
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Chronotype, circadian rhythm, and psychiatric disorders
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Passengers and crew members frequently report fatigue, dizziness, headaches, sinus and ear problems, dry eyes, and sore throats during and after air travel.<|control11|><|separator|>
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Jet lag is defined as a disruption in circadian rhythm caused by crossing time zones, resulting in a mismatch between internal biological time and external ...
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Jan 23, 2020 · ... dopamine transporter (DAT) expression differentially express ... effects of jet lag on mental health are modest. In 2017, commercial ...
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Jet lag is characterized by a constellation of symptoms including: fatigue, irritability, gastrointestinal issues, reduced mental and physical acuity, and poor ...
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Feb 2, 2021 · Sleep and circadian clock disruption generally alter cognitive performance (alertness, attention, memory, higher-order executive functions such as response ...
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Jun 15, 2022 · Eastward travel requires a phase advance which is associated with greater circadian disruption and sleep loss. Consistent with past research ( ...
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Jul 14, 2021 · The subsequent travel fatigue and jet lag experienced result in a myriad of shared symptoms, such as daytime fatigue, decreased concentration ...
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Jul 31, 2019 · Delays and advances in the timing of the circadian system can be facilitated by appropriately timed light exposure, melatonin ingestion, and/or ...
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Timeshifter® | Jet lag app | Jet lag is history.
Rating 4.7 (2,590) · Free · TravelLight is the most important time cue for resetting your circadian clock. The right light exposure at the right time can significantly accelerate your adaption.