Can Drug-Induced Yawning Serve as a Biomarker for Drug Safety and Effectiveness?

Abstract

Background/Objectives: Yawning, a common physiological behavior, has emerged as a potential biomarker for drug responsiveness and side effects. This scoping review synthesizes current evidence on drug-induced yawning (DIY), focusing on its neurobiological mechanisms and clinical implications. Methods: A scoping review (INPLASY registration number: INPLASY202540048) was conducted using PubMed, Scopus, and Web of Science, including studies published in the past decade. The review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane Handbook guidelines, ensuring systematic selection. Selected articles led to the analysis of 10 relevant studies encompassing 473 participants. Studies were evaluated for relevance to DIY, neurobiology, and clinical applications, with thematic analysis used to synthesize findings. Results: Four key themes emerged. (1) Yawning patterns: DIY involves frequent episodes (up to 80 yawns/day), varying by drug type and dosage. (2) Neurobiological mechanisms: Yawning is mediated by serotonin, dopamine, and oxytocin pathways, particularly via 5-HT2C and μ-opioid receptors. (3) Drug responsiveness: DIY is linked to SSRIs, opioids, and dopamine agonists. SSRIs induce yawning, while opioids suppress it, reflecting distinct neurochemical effects. (4) Clinical implications: Yawning may serve as a non-invasive biomarker for drug efficacy and side effects, particularly in opioid withdrawal and SSRI monitoring. Conclusions: DIY holds promise as a biomarker for drug safety and effectiveness, but research is limited by small sample sizes, methodological variability, and the absence of standardized yawning metrics. Future studies should establish consistent measures, account for interindividual variability, and evaluate DIY’s long-term clinical utility across diverse populations.

1. Introduction

Yawning is a universal and instinctive behavior observed across vertebrates, including humans, yet its precise functions and mechanisms remain incompletely understood [1,2]. Characterized by deep inhalation, brief apnea, and slow exhalation, yawning has traditionally been associated with boredom, fatigue, or transitions between arousal states [2,3,4,5,6]. However, contemporary research also highlights its relevance to pharmacological modulation, where drug-induced yawning (DIY) [7,8] provides a unique lens for studying yawning’s neurochemical underpinnings. Unlike physiological yawning, which is influenced by circadian rhythms [9] and social cues, DIY results from pharmacological activation or inhibition of specific neurotransmitter systems [10].

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and paroxetine, frequently induce yawning by enhancing serotonergic activity and incidence rates [11,12,13]. Dopamine agonists, including apomorphine and pramipexole, elicit yawning in a dose-dependent manner, highlighting the role of dopaminergic circuits [8,14,15,16]. In contrast, opioids suppress yawning by activating inhibitory pathways via μ-opioid receptors [17,18,19], further illustrating the receptor-specific nature of DIY. These consistent pharmacological patterns suggest that DIY could serve as a non-invasive biomarker of receptor activity, drug responsiveness, and even treatment tolerability.

One leading hypothesis, the brain-cooling theory, suggests that yawning facilitates cerebral heat exchange by increasing blood flow, particularly during heightened neural activity or exposure to environmental heat [20,21,22,23]. Alternatively, the arousal hypothesis proposes that yawning serves as a physiological “reset” to enhance vigilance [3,24,25,26,27]. While both theories are supported by empirical evidence, their relative importance remains debated, particularly regarding the limited effects of yawning on human brain temperature [21,22,28,29].

Yawning’s social dimension adds further complexity. Contagious yawning, triggered by observing or hearing others yawn, is hypothesized to promote social bonding and empathy through mirror neuron system activation [30,31,32]. Functional imaging studies reveal that contagious yawning engages brain regions associated with emotional and social processing, including the superior temporal sulcus, anterior cingulate cortex, and insula [24,33,34,35]. This behavior, observed in primates, dogs, and even cross-species interactions, suggests an evolutionary role in group coordination [30,36,37,38]. However, its precise function remains debated, with some studies attributing it to broader neurocognitive mechanisms unrelated to social bonding [2,4,39].

Pathological yawning, defined as three or more episodes within 15 min, is often linked to neurological disorders such as Parkinson’s disease, epilepsy, and migraines, as well as pharmacological agents targeting serotonergic and dopaminergic systems [40,41,42,43,44]. Given these drug-specific patterns, DIY has potential as a non-invasive biomarker for monitoring drug efficacy and adverse effects [7,39,40]. For instance, increased yawning frequency during SSRI treatment may reflect serotonergic activation [11,45], while excessive yawning during opioid withdrawal may indicate receptor desensitization [46,47]. In clinical trials, monitoring yawning behavior can offer real-time insights into drug pharmacodynamics, aiding in dose adjustments and optimizing therapeutic outcomes [7,46].

The neural control of yawning primarily involves subcortical structures, particularly the paraventricular nucleus (PVN) of the hypothalamus [47,48,49,50]. The PVN integrates signals from multiple neurotransmitter systems, including serotonin, dopamine, oxytocin, acetylcholine, and noradrenaline, which collectively regulate behaviors such as arousal, feeding, and emotional responses [51,52]. Dopamine D3 receptor activation and oxytocin release are key mediators of yawning, while serotonergic modulation via 5-HT1A and 5-HT2C receptors increases yawning frequency [1,47,53,54]. Conversely, noradrenaline exerts inhibitory effects, reducing yawning under heightened arousal states [3,4]. This intricate balance of excitatory and inhibitory pathways underpins yawning’s physiological regulation.

Therefore, the regulation of yawning is influenced by multiple neurotransmitter systems, including serotonin, dopamine, oxytocin, and opioids, each playing a distinct role in yawning induction or suppression. Pharmacological agents can logically modulate these pathways, with some drugs enhancing yawning frequency while others inhibit it through receptor-specific interactions.

Table 1. Neurotransmitter pathways, drug modulation, and yawning responses. This table summarizes key neurotransmitter systems involved in yawning, their associated receptors, and pharmacological agents that modulate yawning frequency.

Neurotransmitter System	Receptor(s) Involved	Yawning Effect	Drugs That Increase Yawning	Drugs That Decrease Yawning	References
Serotonin (5-HT)	5-HT2C, 5-HT1A	Increases yawning	SSRIs (e.g., Sertraline, Paroxetine), Buspirone (5-HT1A agonist)	5-HT2C Antagonists (e.g., Cyproheptadine)	[7,11,12,13,45,47,53,55,56]
Dopamine (DA)	D3, D2	Increases yawning	Dopamine Agonists (e.g., Apomorphine, Pramipexole)	Dopamine Antagonists (e.g., Haloperidol, Chlorpromazine)	[8,10,14,15,16,17,54,57]
Oxytocin (OXT)	Oxytocin Receptors	Facilitates yawning	Oxytocin administration (experimental)	Not well-studied	[47,58,59]
Opioids (μ-Opioid Receptors)	μ-opioid receptors	Suppresses yawning	Opioid Agonists (e.g., Morphine, Tilidine)	Opioid Antagonists (e.g., Naloxone, Naloxegol)	[17,19,60,61,62]

summarizes the key neurobiological mechanisms of yawning and their modulation by different drug classes.

Despite its promise as a biomarker, yawning research faces key challenges. Variability in yawning triggers across demographics, environmental conditions, and pharmacological contexts complicates its clinical utility [7,39,40]. Additionally, methodological inconsistencies in measuring yawning frequency and intensity hinder reproducibility [4,6,63,64]. Addressing these gaps requires rigorous investigation into yawning’s neurobiological pathways, standardization of assessment protocols, and identification of factors contributing to individual variability [65,66].

The observable nature of yawning positions it as a potential biomarker for drug efficacy and safety. Beyond its application in pharmacological monitoring, DIY may hold broader implications for personalized medicine. By correlating yawning patterns with individual neurochemical profiles, clinicians could potentially refine therapeutic strategies, minimizing adverse effects while optimizing treatment efficacy. Integrating yawning assessments into clinical practice could enhance drug monitoring, particularly for SSRIs and dopamine agonists [10,11].

This review synthesizes current evidence on DIY, with a particular focus on its neurobiological mechanisms, clinical implications, and potential as a biomarker. Specifically, we aim to:

• Compare yawning patterns under both physiological and pharmacological conditions, examining differences in frequency and timing.
• Explore the neurochemical mechanisms involved in yawning, with particular attention to the roles of serotonin, dopamine, and oxytocin.
• Investigate the relationship between DIY and clinical outcomes, including therapeutic efficacy and adverse effects.
• Discuss and propose standardized methods for assessing yawning in clinical and research settings.

We hypothesize that synthesizing existing evidence will clarify yawning’s neurobiological mechanisms and establish its potential as a biomarker. We propose that addressing current research gaps may advance personalized medicine and enhance understanding of yawning’s clinical significance.

2. Materials and Methods

2.1. Literature Search

A structured, two-phase literature search was conducted to differentiate physiological yawning from DIY. The study protocol (INPLASY registration number: INPLASY202540048) was followed. The first phase focused on mechanisms, frequency, and triggers of physiological yawning, while the second phase targeted DIY, emphasizing pharmacological effects. This approach enabled a comparative analysis of neurobiological pathways, drug-specific patterns, and clinical implications.

2.1.1. Systematic Search for Physiological Yawning

A systematic search of electronic databases was conducted to identify human studies investigating the neurobiological mechanisms of physiological yawning. Inclusion criteria ensured relevance to human neurobiology, while exclusion criteria filtered preclinical animal studies and non-relevant literature.

2.1.2. Systematic Search for Drug-Induced Yawning

The DIY search focused on studies evaluating yawning as a pharmacological effect (wanted or unwanted) of opioids, dopamine agonists, serotonin agonists, and related drugs. Preliminary searches helped refine keywords and MeSH terms, ensuring both sensitivity and specificity. The search iteratively adjusted Boolean operators, filters, and exclusion terms to optimize results.

2.2. Databases and Search Terms

2.2.1. Databases

The search was conducted using PubMed, Scopus, and Web of Science, chosen for their comprehensive biomedical and pharmacological literature coverage. Reference lists of included studies were also manually reviewed to identify additional relevant publications.

2.2.2. Search Terms and Operators

The search strategy combined Boolean operators (AND/OR), truncation symbols, and MeSH terms to ensure high specificity while capturing all relevant studies (See

Table 2. An example of PubMed database search results. This table presents key search terms and combinations used to identify literature related to yawning and its pharmacological modulation. Boolean operators and Medical Subject Headings (MeSH) were applied where relevant. To enhance clarity and avoid redundancy, combined queries are presented using reference numbers (e.g., #12 AND #4), and full search strings are omitted. #-’Search Number.

Search #	Query Description	Results
1	Yawning terms	1492
2	Physiological yawning	1
3	Drug-induced yawning	23
4	Cholinergic agents	99,626
5	Oxytocin	27,398
6	Nitric oxide and related compounds	213,251
7	Dopaminergic agents	170,515
8	Serotonergic agents	139,062
9	Opioids	166,108
10	GABAergic agents	54,959
11	Adrenergic agents	318,762
12	#1 + #3 (Yawning + Drug-induced yawning)	23
13	#12 AND #4 (Cholinergic agents)	5
14	#12 AND #5 (Oxytocin)	4
15	#12 AND #6 (Nitric oxide and related)	3
16	#12 AND #7 (Dopaminergic agents)	11
17	#12 AND #8 (Serotonergic agents)	5
18	#12 AND #9 (Opioids)	14
19	#12 AND #10 (GABAergic agents)	1
20	#12 AND #11 (Adrenergic agents)	1

).

2.3. Inclusion and Exclusion Criteria

Inclusion Criteria

• Peer-reviewed studies published within the last 10 years.
• Clinical and observational studies (case–control, cohort, and randomized controlled trials).
• Studies focusing on human participants.
• Research addressing yawning’s neurobiological mechanisms or pharmacological triggers.

Exclusion Criteria

• Studies without direct relevance to yawning or DIY.
• Animal studies, excluded to focus on clinical human applications. Since preclinical findings may not directly translate to human pharmacodynamics, animal models were omitted but may be referenced in the discussion for comparative insights.
• Non-peer-reviewed sources, including gray literature (conference abstracts, dissertations).
• Review articles, editorials, and opinion pieces.

Excluded studies were documented systematically, with 44 animal studies excluded due to their preclinical focus and 19 studies removed for exceeding the 10-year limit.

2.4. Study Selection Process

The study selection followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

• Identification: A total of 138 records were retrieved (PubMed: 23; Scopus: 64; Web of Science: 51). After duplicate removal, 92 unique articles remained.
• Screening: Titles and abstracts were independently screened by two reviewers based on inclusion/exclusion criteria.
• Full-Text Review: 10 articles were selected for the final analysis.

Disagreements were resolved through discussion or consultation with a third reviewer. Inter-rater reliability (Cohen’s kappa) was not statistically assessed, but consensus was reached through an iterative validation process.

2.5. Data Extraction and Analysis

2.5.1. Data Extraction

Key data were extracted from included studies into a structured spreadsheet, capturing study design and population; intervention details (e.g., drug type, dosage, duration); neurobiological mechanisms investigated; and outcomes related to yawning frequency, onset, and duration.

2.5.2. Comparative Analysis

Data were compared across physiological and pharmacological contexts to identify time of onset, frequency, and duration of yawning; similarities and differences in neurobiological triggers; and the impact of yawning on patient well-being.

2.5.3. Thematic Analysis

Thematic analysis was performed to synthesize key findings and elucidate mechanisms. Key themes were considered to be extracted and summarized descriptively: differentiation of physiological vs. drug-induced yawning; neurobiological pathways involving dopamine, serotonin, and oxytocin; correlation between yawning and drug responses; clinical implications of yawning as a biomarker for therapeutic efficacy and safety; and quantitative data, such as yawning frequency and timing. Although yawning frequency and timing were considered, they were analyzed within other themes rather than as a standalone category. While meta-analysis was not feasible due to heterogeneity, patterns and trends were highlighted to support qualitative findings.

2.6. Ethics

This review relied exclusively on publicly available, peer-reviewed data. Ethical concerns were minimal as no primary data collection or direct patient interaction occurred. Measures to mitigate bias included adherence to PRISMA guidelines, independent reviewer validation, and rigorous inclusion/exclusion criteria. The study protocol was registered and followed accordingly (INPLASY registration number: INPLASY202540048).

3. Results

3.1. Search Results

A systematic identification of relevant studies was conducted using multiple databases and registries, yielding a total of 138 records: 23 from PubMed, 64 from Scopus, and 51 from Web of Science. After removing 46 duplicate records, 92 unique records were screened. Of these, 82 studies were excluded based on predefined criteria, including 19 studies older than ten years, 44 animal studies, 9 that were not retrievable, 8 reviews, and 1 study unrelated to drug-induced effects. Ultimately, 10 studies were assessed for eligibility and included in the review. The study selection process is summarized in Figure 1, following the PRISMA guidelines. A completed PRISMA Checklist is provided in the Supplementary Materials.

3.2. Study Characteristics

The 10 included studies encompassed a total of 473 patients, comprising 290 males (61.3%) and 177 females (37.4%). These studies were geographically diverse and utilized varied study designs. Studies were conducted in the USA, Germany, Spain, France, Croatia, Brazil, and India, reflecting a broad spectrum of patient populations and clinical contexts. These studies were with various study designs including randomized controlled trials (two), a case–control study (one), case reports (five), a prospective study (one), and a cross-sectional study (one). Four studies investigated opioid-related yawning, three studies focused on serotonin-related effects, one examined oxytocin, and two explored mixed mechanisms. The characteristics of the 10 included studies are summarized in

Table 3. Characteristics of included studies. This table presents a summary of 10 included studies, detailing study design, sample size, geographic location, population characteristics, intervention type, yawning patterns, neurobiological mechanisms, drug responsiveness, and clinical implications.

First Author (Year)	Study Design	Sample Size	Geography	Population	Intervention/Drug	Yawning Patterns	Neurobiological Mechanisms	Drug Responsiveness	Clinical Implications
Béné, J (2014) [55]	Case Study	1	France	SSRI therapy patient	Paroxetine (SSRI)	Excessive daytime yawning associated with SSRIs	Serotonin receptor inhibitors	Yawning disappeared after SSRI discontinuation	Unwanted SSRI side effect
Gallup, AC (2015) [59]	Experimental	60	USA	Undergraduate students (general population)	Oxytocin	Contagious yawning documented via video	Oxytocin receptor involvement	Spontaneous yawning predictive value	Oxytocin ineffective in enhancing contagious yawning
Nazar, BP (2015) [56]	Case Study	2	Brazil	Patients with major or minor depressive disorder	Various SSRIs	Excessive yawning frequency (25–80 yawns/day)	Serotonin augmentation	Pattern unaffected by sedation or sleep disorders	Switching antidepressants resolved yawning
Petrić, D (2019) [45]	Case Study	1	Croatia	Psychiatric patient (moderate depressive episode)	Sertraline (SSRI)	Yawning correlated with sertraline dosage	Serotonin involvement confirmed	Discontinuation resolved yawning, maintaining psychiatric stability	Yawning as a side effect, not therapeutic marker
Bergeria, CL (2020) [67]	Survey	200	USA	Cannabis users	Cannabis	Not described	Not discussed	Cannabis reduced withdrawal symptoms but worsened yawning	Gender differences in cannabis efficacy
Dibaj, P (2020) [61]	Case Study	1	Germany	Sciatic pain patient	μ-opioid agonist	Moderate exercise-induced yawning, prevented by μ-opioid agonists	μ-opioid receptor activation	Yawning prevented by tilidine	Tilidine effective for yawning-fatigue syndrome
Dibaj, P (2021) [68]	Case Study	1	Germany	Fatigue syndrome patient	Tilidine (opioid)	Not described	Not discussed	Effective management of yawning-fatigue with tilidine	Increased exercise tolerance without yawning
Olmo, M (2021) [62]	Case Study	1	Spain	Opioid withdrawal patient	Naloxone, naloxegol	Severe yawning during opioid antagonist use	Not discussed	Yawning indicates acute opioid withdrawal syndrome	Marker for opioid withdrawal
Anagha, K (2021) [12]	Observational	100	India	SSRI users with depression, anxiety, and related disorders	Sertraline, escitalopram, fluoxetine	Common yawning as a side effect	SSRI-induced yawning noted	Yawning associated with multiple SSRIs	Distinctive side effect of SSRIs
Dunn, KE (2023) [69]	Experimental	106	USA	Morphine-maintained patients	Naloxone	Yawning linked to withdrawal symptoms	μ-opioid receptor involvement	Naloxone triggered yawning in morphine-maintained patients	Biomarker of opioid receptor antagonist effects

, detailing study design, sample size, geography, population, interventions, yawning patterns, and key neurobiological and clinical findings. This collected sample allowed for a comprehensive exploration of the mechanisms underlying both physiological and drug-induced yawning, as well as the clinical implications. However, the variability in study designs and sample sizes highlighted the need for standardized methodologies in yawning research.

3.3. Key Themes and Findings

Four primary themes emerged from the included studies: yawning patterns, neurobiological mechanisms, correlation with drug responsiveness, and clinical implications of yawning as a biomarker. Thematic analysis of the included studies is summarized in

Table 4. Thematic analysis of included studies. This table presents a summary of key themes identified across included studies, categorized into yawning patterns in drug-induced yawning, neurobiological mechanisms, correlation with drug responsiveness, and clinical implications as a biomarker. Each study’s findings are outlined, reflecting variations in methodology, intervention, and outcome measures.

First Author (Year)	Sample Size	Yawning Patterns in Drug-Induced Yawning	Neurobiological Mechanisms	Correlation with Drug Responsiveness	Clinical Implications as a Biomarker
Dunn, KE (2023) [69]	106	Within 15 min, ~51% of participants had peak ratings for SOWS, and ~48% for COWS. Symptoms included runny eyes, yawning, sweating, hot flashes, and pupil dilation.	γ-opioid receptor involvement in naloxone-precipitated withdrawal. Yawning identified as a sentinel symptom.	Naloxone administration induced withdrawal symptoms, including yawning, in morphine-maintained patients.	Yawning may indicate opioid receptor antagonist effects in individuals using morphine therapeutically or recreationally.
Dibaj, P (2021) [68]	1	Yawning pattern not described.	Neurobiological mechanism not discussed.	Yawning-fatigue syndrome successfully treated with tilidine.	Tilidine increased exercise tolerance, reducing yawning and fatigue episodes.
Olmo, M (2021) [62]	1	Not described.	Not discussed.	Shortly after opioid antagonist administration, yawning appeared alongside severe withdrawal symptoms.	Yawning, in conjunction with opioid withdrawal symptoms, may signal opioid cessation or dosage adjustments.
Anagha, K (2021) [12]	100	Yawning reported as a common SSRI side effect (47%). Characteristics not described.	SSRI involvement noted.	Yawning occurred in 47.2% of sertraline users, 51.3% of escitalopram users, and 25% of fluoxetine users.	Yawning was listed among common SSRI side effects, alongside somnolence, dry mouth, and fatigue.
Dibaj, P (2020) [61]	1	Yawning and fatigue occurred during moderate leg exercise but disappeared after μ-opioid agonist treatment.	μ-opioid receptor activation in the paraventricular nucleus inhibited yawning.	Yawning and fatigue prevented by subcutaneous injection of 3.75 mg piritramide.	Tilidine treatment before exercise prevented yawning and fatigue, supporting the role of opioid receptor modulation.
Bergeria, CL (2020) [67]	200	Not described.	Not discussed.	Some participants (n = 12) reported cannabis worsened opioid withdrawal symptoms, including yawning.	Cannabis may influence opioid withdrawal symptoms differently in men and women, with greater symptom relief in females.
Petrić, D (2019) [45]	1	Patient reported yawning began shortly after sertraline initiation: 2–3 yawns after 25 mg, 3–4 yawns after 50 mg.	Serotonin’s role in yawning supported by 5-HT2C receptor involvement.	Yawning onset correlated with sertraline dosage.	Yawning was an SSRI side effect rather than a sign of therapeutic efficacy.
Gallup, AC (2015) [59]	60	Yawning characterized by wide jaw opening, deep inhalation, brief hold, and short exhale.	Oxytocin receptor involvement noted.	A total of 33.3% of participants yawned while watching a video stimulus; spontaneous yawning predicted increased contagious yawning.	Oxytocin did not enhance contagious yawning, suggesting a limited role in yawning regulation.
Nazar, BP (2015) [56]	2	Yawning frequency increased to 80 yawns/day in one patient and 25 yawns/day in another. Occurred during social and professional settings.	Serotonin increase induced yawning, likely due to dopaminergic reduction in the basal ganglia or frontal lobe dysfunction.	Yawning occurred independently of sedation or sleep disorders in both patients.	Yawning-related distress was resolved by switching medications.
Béné, J (2014) [55]	1	Abnormal excessive daytime yawning, lasting several seconds and associated with jaw contractures.	Serotonin receptor inhibition.	Patient experienced excessive yawning after starting paroxetine 20 mg/day.	Yawning was an unwanted SSRI side effect, resolving after discontinuation.

, highlighting findings from each study.

Theme 1: Yawning Patterns in Drug-Induced Yawning

The studies revealed distinct patterns of yawning behavior linked to specific drugs and conditions. Gallup (2015) [59] documented yawning as a behavior characterized by jaw gaping, muscle contraction, and passive closure. Notably, contagious yawning was observed in 33.3% of participants during video exposure. Dibaj (2020) [61] reported yawning induced by moderate exercise, which was preventable with μ-opioid receptor agonists. Nazar (2015) [56] documented excessive yawning in antidepressant-treated patients, with frequencies reaching up to 80 yawns per day, unassociated with sedation or sleep disorders. Petrić (2019) [45] noted dose-dependent yawning in sertraline-treated patients, with 2–3 yawns following a 25 mg dose and 3–4 yawns after a 50 mg dose.

This diversity in yawning patterns highlights its multifaceted triggers and shows the need for standardized methodologies to capture its frequency and characteristics.

Theme 2: Neurobiological Mechanisms

The neurochemical pathways underlying yawning were a focal point.

Serotonin: Studies (e.g., Béné, 2014 [55]; Petrić, 2019 [45]; Nazar, 2015 [56]) consistently linked yawning to serotonergic augmentation, implicating serotonin receptor modulation in excessive yawning.

Dopamine: Dibaj (2020 [61], 2021 [68]) highlighted the inhibitory role of μ-opioid receptor activation in the paraventricular nucleus, which prevents yawning during exercise.

Oxytocin: Gallup (2015) [59] associated yawning with oxytocin receptor activity, suggesting a potential role in contagious yawning.

Opioid Receptors: Naloxone-triggered yawning in opioid withdrawal was observed by Dunn (2023) [69] and Olmo (2021) [62], implicating γ-opioid receptors.

These findings reinforce yawning as a behavior influenced by multiple overlapping neurotransmitter systems, with serotonin and dopamine playing dominant roles.

Theme 3: Correlation with Drug Responsiveness

Yawning was frequently correlated with drug action, providing insights into therapeutic responses.

Opioids: Yawning was a hallmark of opioid withdrawal, as noted by Olmo (2021) [62] and Dunn (2023) [69].

Antidepressants: Excessive yawning was a prominent side effect of SSRIs (e.g., paroxetine and sertraline), as documented by Béné (2014) [55] and Petrić (2019) [45]. Discontinuation of these drugs resolved the yawning, highlighting its role as a marker of serotonergic activity.

Cannabis: While Bergeria (2020) [67] noted improvements in withdrawal symptoms with cannabis use, yawning was reported as a worsening side effect in a subset of patients.

These findings emphasize yawning’s utility in reflecting neurochemical activity and drug effects, particularly in withdrawal syndromes and adverse reactions.

Theme 4: Clinical Implications of Yawning as a Biomarker

Yawning demonstrated significant potential as a non-invasive biomarker for drug efficacy and side effects.

Opioid Withdrawal: Yawning was a sensitive indicator of withdrawal severity, with immediate increases following naloxone administration (Dunn, 2023) [69].

Antidepressant Therapy: SSRIs consistently induced yawning, with patterns disappearing upon drug discontinuation (Béné, 2014 [55]; Petrić, 2019 [45]).

Clinical Monitoring: Gallup (2015) [59] suggested that spontaneous yawning during acclimation could predict susceptibility to contagious yawning, indicating its broader utility in behavioral monitoring.

These findings highlight yawning’s potential as a diagnostic tool across multiple pharmacological contexts, though standardization of assessment protocols remains essential.

3.4. Narrative Synthesis of Findings and Reflections

The studies collectively reveal yawning as a complex, multifactorial behavior shaped by neurochemical, pharmacological, and physiological factors. While physiological yawning serves natural regulatory functions, DIY [7] reflects specific pharmacological effects, positioning it as a potential biomarker for assessing drug responsiveness. The consistent association between SSRIs and excessive yawning underscores the central role of serotonergic modulation [11], while yawning during opioid withdrawal [60] highlights its sensitivity to receptor interactions. These findings suggest that yawning could be a useful, non-invasive indicator for monitoring withdrawal severity, drug effects, and treatment responses. However, the variability in yawning patterns and inconsistencies in study methodologies highlight the need for standardized metrics to improve its clinical utility.

Our findings emphasized the dual nature of yawning as both a physiological behavior and a pharmacological phenomenon. The synthesis of findings highlighted yawning as a multi-faceted behavior regulated by distinct neurobiological mechanisms, including serotonergic, dopaminergic, and oxytocinergic pathways, each exerting context-dependent influences [38,40,47]. These insights could establish yawning as a valuable yet underutilized biomarker in clinical and pharmacological research.

The reviewed studies revealed distinct yawning patterns across physiological and drug-induced contexts. Physiological yawning [2] demonstrated predictable regularity, often linked to circadian rhythms and arousal states, whereas DIY [7] exhibited dose-dependent, context-specific characteristics. For instance, SSRIs such as paroxetine and sertraline consistently elicited excessive yawning [12], an effect attributed to their influence on serotonergic pathways. In contrast, opioids were primarily associated with yawning during withdrawal phases [67,69], reflecting the role of μ-opioid receptors in modulating this response. This divergence in yawning patterns highlights the importance of identifying specific yawning triggers to interpret their clinical relevance accurately.

The neurochemical basis of yawning further strengthens its potential as a proxy for central nervous system (CNS) activity. The dominant roles of serotonin and dopamine suggest that yawning may reflect real-time neurochemical fluctuations [1,70], yet the observed variability in yawning frequency across studies reinforces the necessity for standardized assessment methodologies. Without uniform criteria for defining yawning episodes, comparing results across different studies remains a challenge.

The findings also strongly supported yawning as a clinically significant marker of drug responsiveness. In multiple studies, SSRIs induced yawning [11] in a subset of patients, with symptoms resolving upon drug discontinuation, suggesting that yawning may serve as an early indicator of serotonergic overstimulation and worth looking further into it in depression [71]. This could allow clinicians to tailor antidepressant therapy more effectively, minimizing adverse effects. Similarly, opioid withdrawal studies [60] demonstrated yawning’s sensitivity to receptor interactions, with rapid onset following naloxone administration, reinforcing its role as a reliable, observable symptom for monitoring withdrawal severity and optimizing treatment strategies.

However, not all studies confirmed proposed mechanistic hypotheses. For example, Gallup (2015) [59] challenged the role of oxytocin in contagious yawning, demonstrating that findings in this area remain inconclusive. This underscores the importance of rigorous experimental controls, larger sample sizes, and reproducibility in future research.

While the results highlighted yawning as a promising biomarker, significant challenges remain. Variability in definitions, triggers, and assessment methodologies complicates data interpretation, limiting yawning’s immediate clinical applicability. For instance, while most studies quantified yawning frequency, few examined yawning intensity or associated behaviors, leaving critical gaps in understanding. To fully harness yawning’s diagnostic potential, standardized protocols must be established, accounting for patient demographics, environmental conditions, and drug-specific responses.

Beyond pharmacology, yawning also presents intriguing behavioral and social implications [30]. Contagious yawning, for example, may provide insight into neurocognitive processes such as empathy and social bonding [30]. Expanding research into evolutionary and behavioral perspectives could further enrich understanding of yawning’s broader physiological and psychological roles.

To bridge existing knowledge gaps, future research should prioritize longitudinal studies to assess yawning patterns over extended periods, particularly in chronic conditions and long-term drug use. Investigations into less-explored neurobiological pathways, such as oxytocinergic and adrenergic systems, are warranted to develop a more comprehensive framework for yawning regulation. Additionally, incorporating yawning as an outcome measure in CNS drug trials will be essential to validate its biomarker potential. An unexplored yet promising avenue is the examination of how yawning correlates with individual neurochemical profiles, which could pave the way for personalized medicine approaches, optimizing treatment selection and minimizing adverse effects.

In summary, our results showed that yawning represents a unique intersection of physiology, neurochemistry, and behavior. By integrating these domains, future research has the potential to unlock its full diagnostic utility, advancing both clinical practice and scientific understanding. These findings collectively illustrate the complexity of yawning as both a physiological response and a pharmacological phenomenon. In the following discussion, we critically evaluate the methodological strengths and limitations of this review and interpret these findings in the context of the existing literature, highlighting their implications for clinical practice and future research.

4. Discussion

4.1. Discussion of the Applied Method

4.1.1. Scoping Review Design

This scoping review followed a structured and systematic methodology to synthesize current knowledge on DIY. Utilizing PRISMA guidelines [72], the review ensured transparency and reproducibility through comprehensive database searches (PubMed, Scopus, Web of Science) and predefined inclusion/exclusion criteria. Studies were selected based on clearly defined parameters, emphasizing peer-reviewed, English-language human research to ensure clinical relevance. However, the exclusion of animal studies and gray literature, while preserving methodological rigor, may have introduced language and publication bias. The exclusion of animal studies might also have limited insights into mechanistic pathways often elucidated in preclinical models. Data extraction followed a standardized narrative synthesis framework, enabling consistent comparisons and thematic organization across diverse studies. This methodological consistency facilitated identification of key neurobiological pathways relevant to yawning and its pharmacological modulation.

4.1.2. Strengths and Limitations

A major strength of this review was its adherence to the PRISMA framework [72], which enhanced methodological transparency and reproducibility. The multi-database search strategy provided broad coverage of both pharmacological and neurobiological literature, thereby reducing selection bias. Additionally, systematic removal of duplicates and inclusion of diverse study designs—ranging from randomized controlled trials (RCTs) to observational studies and case reports—ensured a comprehensive and balanced evidence base.

Inter-rater reliability checks during study selection and data extraction minimized subjectivity and error. The scoping review design was especially suitable for exploring the relatively underexamined topic of DIY, allowing the identification of emerging patterns, conceptual inconsistencies, and research gaps.

Nevertheless, several limitations must be acknowledged. Restricting inclusion to English-language publications likely introduced language bias, potentially omitting valuable findings reported in other languages. The absence of gray literature and unpublished studies may have amplified publication bias, particularly with underreporting of null or negative findings. Furthermore, heterogeneity in study designs, target populations, outcome measures, and yawning definitions posed significant challenges to synthesis and generalizability. The lack of standardized yawning measurement tools [73,74,75] further hindered the ability to quantitatively aggregate findings across studies.

4.1.3. Recommendations for Future Methodology

Future reviews should consider broader inclusion criteria that accommodate multilingual sources and gray literature. Collaborative translation tools or multilingual research teams could help mitigate language bias. Inclusion of unpublished data and negative findings would support a more balanced understanding of yawning as a drug-related phenomenon.

Standardization remains a critical priority. Consistent operational definitions should distinguish spontaneous, drug-induced, and pathological yawning, while validated measurement instruments, such as video-based analysis, wearable sensors, or EMG, are needed to enhance accuracy and reproducibility. Methodologies should also control for confounding contextual factors such as circadian rhythms, ambient temperature, posture, and social setting.

To improve efficiency and consistency in evidence mapping, the use of AI-enhanced tools (e.g., Rayyan) and machine learning algorithms for citation tracking and study selection is recommended. Ultimately, methodological refinement will be essential for validating yawning as a reliable clinical or experimental biomarker and enabling its integration into broader pharmacodynamic research frameworks.

4.2. Discussion of Findings: Neurobiological and Pharmacological Insights

This scoping review provides novel insights into DIY, highlighting its neurobiological complexity and pharmacological significance. Yawning, a stereotyped behavior characterized by jaw opening, deep inhalation, and passive closure, is increasingly recognized as a neurobehavioral response to acute neuromodulatory changes [70].

The frequency and severity of DIY vary substantially. While some patients experience transient or mild episodes, others report pathological patterns exceeding 80 yawns per day, particularly in response to serotonergic agents like SSRIs [11,43]. This wide range underscores the importance of contextualizing yawning within the pharmacological, physiological, and individual clinical profiles of patients.

4.2.1. Neurotransmitter Systems in Yawning

Yawning behavior is regulated by a complex network of subcortical structures, with the PVN of the hypothalamus playing a central integrative role [50]. The PVN processes input from several neurotransmitter systems, which act in synergy or opposition to modulate yawning behavior.

Dopaminergic signaling, especially through D2 and D3 receptor activation, is a well-established trigger. Dopamine agonists such as apomorphine and pramipexole reliably induce yawning in a dose-dependent fashion [8,10,14,15,16,57].

Serotonergic pathways also contribute significantly, particularly through 5-HT1A and 5-HT2C receptors. Agents such as SSRIs (e.g., sertraline, paroxetine) and 5-HT1A partial agonists (e.g., buspirone) are frequently associated with excessive yawning [11,12,13,45,47,53,55,56].

Oxytocin, although less extensively studied, has been shown to facilitate yawning, likely via its action in the PVN. Experimental rodent studies demonstrate yawning following oxytocin administration [58], and recent work also points to a role in modulating social-affiliative behaviors relevant to yawning responses [59].

The opioid system, acting through μ-opioid receptors, generally suppresses yawning. Agonists such as morphine and tilidine inhibit yawning, whereas opioid antagonists like naloxone and naloxegol can provoke it, particularly in withdrawal states [17,18,19,60,61,62].

Other neurotransmitter systems, including cholinergic pathways, particularly in the brainstem, may also play modulatory roles, though they are less frequently addressed in human studies. It is also important to note that these systems most likely interact dynamically, and yawning can reflect neurochemical adaptations to acute and long-term effects of drugs.

4.2.2. Patterns and Presentation of DIY

DIY may manifest as a benign or pathological condition. DIY varies from mild, sporadic episodes to pathological patterns exceeding 80 yawns per day [11,16,43]. Case reports and clinical studies describe patterns ranging from occasional yawns to clusters of over 30 yawns within 10 min of SSRI or dopaminergic drug administration [12,22]. Opioid administration tends to suppress yawning, but abrupt withdrawal often leads to its sudden reappearance [27,29,64].

The criteria for pathological yawning remain inconsistent. While some studies define it as three or more yawns within a 15 min period [15,16,19], others offer no formal threshold. This heterogeneity underscores the urgent need for consensus on operational definitions and standardized measurement tools.

In addition, yawning responsiveness varies across individuals. Biological factors such as age, sex, neurochemical sensitivity, and genetic predispositions contribute to this variability [58]. Controlled experimental settings and consistent classification of yawning intensity, frequency, and duration are crucial for assessing pharmacological impact and pharmacologically relevant thresholds.

4.2.3. Yawning as a Neurobehavioral Feedback Mechanism

Yawning may serve as a behavioral marker of acute neurochemical imbalance and the brain’s compensatory efforts to restore homeostasis. Receptor-specific activation (e.g., D2/D3, 5-HT1A) initiates yawning, but sustained or repeated stimulation may lead to receptor desensitization or regulatory feedback inhibition [16,53].

For instance, dopaminergic yawning—triggered by agonists such as apomorphine—might reflect transient overactivation of motivational and arousal circuits [14,15]. Serotonergic yawning, often seen during SSRI titration, may indicate feedback adjustments in brainstem and hypothalamic arousal pathways [11,13,55]. Oxytocin-mediated yawning, while less clearly mapped, appears linked to affiliative signaling and stress regulation [58,59].

These feedback loops suggest that yawning could act as an observable, adaptive response to acute neuromodulatory perturbations. This interpretation supports the emerging view of yawning as a dynamic behavioral indicator of neurotransmitter system activity [28,47].

4.2.4. Yawning as a Pharmacodynamic Biomarker

The reproducibility of yawning responses across various pharmacological agents strengthens the case for its use as a pharmacodynamic biomarker. Drug classes that consistently induce or suppress yawning, such as SSRIs, dopamine agonists, and opioid antagonists demonstrate well-characterized, dose-responsive patterns [8,11,14,16,45,60].

Yawning offers practical advantages: it is non-invasive, easily observable, and relatively low-cost to assess in both clinical and experimental settings. Quantifying yawning onset, frequency, and severity in response to pharmacological interventions could assist in real-time monitoring of central nervous system activity, drug adherence, or side effect development. These features support its integration into personalized medicine strategies (e.g., to enhance drug monitoring and dose optimization) and early-phase clinical trials.

4.2.5. Clinical and Translational Potential

Yawning has promising applications in clinical pharmacology and neuroscience. During SSRI initiation, yawning may indicate effective engagement of the serotonergic system [11,12,13,45], while yawning during naloxone challenge often signals opioid withdrawal [46,47,60].

Incorporating yawning metrics into treatment protocols could help monitor medication effects, inform dose adjustments, and preempt adverse reactions. For example, wearable devices with facial movement tracking could detect abnormal yawning frequencies in real-world settings, an approach already explored in driver drowsiness research [76,77].

Nevertheless, widespread clinical use is limited by the lack of standardized tools, inconsistent reporting, and methodological variability across studies. Future research must focus on validating yawning as a behavioral biomarker through large-scale trials and controlled experiments. Once standardized, DIY tracking could enhance drug development pipelines and support tailored interventions for neuropsychiatric and pain-related conditions.

4.3. Methodological Considerations and Future Directions

Several methodological limitations emerged from this review and must be acknowledged. Variability in study designs, sample populations, yawning definitions, and outcome measures significantly hinders cross-study comparability and meta-analytic synthesis. In many cases, findings are based on case reports or small observational studies, reducing the robustness of conclusions. Furthermore, the exclusion of non-English publications and gray literature introduces language and publication bias, limiting the comprehensiveness of the evidence base.

To overcome these limitations and strengthen future yawning research, several key directions should be pursued.

First, researchers should aim to broaden the scope of literature inclusion by incorporating studies published in multiple languages and considering relevant gray literature. This will help mitigate selection and publication bias and ensure a more comprehensive evidence base.

Second, there is a pressing need for standardized definitions of yawning, including clear behavioral criteria that distinguish between spontaneous, drug-induced, and pathological yawning. Establishing consistent diagnostic thresholds will improve cross-study reliability.

Third, validated and reproducible measurement protocols must be developed to assess yawning frequency, duration, and intensity objectively. These protocols should ideally be adaptable across clinical and experimental settings.

Fourth, longitudinal study designs are needed to track yawning patterns over extended periods, especially in the context of chronic drug exposure or withdrawal. Such designs will provide insight into temporal fluctuations and treatment-related changes in yawning behavior.

Fifth, researchers should expand their focus beyond serotonin and dopamine to include less-explored neurotransmitter systems, particularly oxytocinergic and adrenergic pathways. This will enrich the neurobiological understanding of yawning. Finally, integrating yawning assessments into clinical trials of CNS-active medications will help validate its utility as a pharmacodynamic marker of drug response and side effects.

Future research should also control for confounding variables known to influence yawning behavior, such as circadian timing, ambient temperature, body posture, and social context. Consistent application of well-defined behavioral criteria—such as mouth opening, deep inhalation, and associated facial expressions—will further support standardized classification and reporting.

To improve detection accuracy, studies should adopt advanced technologies, including video-based observation protocols, wearable sensors, facial recognition software, surface electromyography (EMG), and neuroimaging techniques (e.g., fMRI, PET). These tools can provide high-resolution, objective data and facilitate a deeper understanding of the neurophysiological correlates of yawning.

Yawning lies at a unique intersection between physiology, neurochemistry, and clinical pharmacology. With rigorous methodological standardization and integration of modern analytic tools, yawning has the potential to become a valuable, non-invasive biomarker of central nervous system function, drug efficacy, and patient-specific treatment responsiveness. This approach aligns closely with emerging frameworks in personalized medicine.

Our research group is actively developing remote monitoring tools, wearable technologies, and automated measurement protocols to support reproducible yawning detection in both laboratory and naturalistic settings. These innovations will support future efforts to validate yawning as a clinically meaningful biomarker for evaluating drug safety, efficacy, and neurobehavioral health.