Dexmedetomidine effects on metabolic rate over 5 days in humans

Clifton W Callaway; Alexandra J Weissman; Katharyn L Flickinger; Victor Wu; Jenna Monteleone; Ryann DeMaio; Mara Hierro; Daniel Neofes; Omarf Ortega-Reyes; Tao Sheng; Marianna Salinas; Paul Lerro; Francis X Guyette; Benjamin D H Gordon; Marie Mortreux; Kathleen Melanson; Daniel J Buysee; Philip E Empey

doi:10.1371/journal.pone.0359711

. 2026 Oct 27;21(10):e0359711. doi: 10.1371/journal.pone.0359711

Dexmedetomidine effects on metabolic rate over 5 days in humans

Clifton W Callaway ^1,^*, Alexandra J Weissman ¹, Katharyn L Flickinger ¹, Victor Wu ¹, Jenna Monteleone ¹, Ryann DeMaio ¹, Mara Hierro ¹, Daniel Neofes ², Omarf Ortega-Reyes ¹, Tao Sheng ¹, Marianna Salinas ¹, Paul Lerro ², Francis X Guyette ¹, Benjamin D H Gordon ², Marie Mortreux ³, Kathleen Melanson ³, Daniel J Buysee ⁴, Philip E Empey ⁵

Editor: Vincenzo Lionetti⁶

¹ Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

² Department of Health and Human Development, University of Pittsburgh School of Education, Pittsburgh, Pennsylvania, United States of America

³ Department of Nutrition, University of Rhode Island College of Health Sciences, Kingston, Rhode Island, United States of America

⁴ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

⁵ Center for Clinical Pharmaceutical Sciences, Department of Pharmacy, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States of Americaand Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States of America

⁶Scuola Superiore Sant'Anna, ITALY

^✉

* E-mail: callawaycw@upmc.edu

Competing Interests: The authors have declared that no competing interests exist.

Roles

Clifton W Callaway: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Alexandra J Weissman: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

Katharyn L Flickinger: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

Victor Wu: Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing

Jenna Monteleone: Data curation, Investigation, Writing – review & editing

Ryann DeMaio: Investigation, Writing – review & editing

Mara Hierro: Investigation, Writing – review & editing

Daniel Neofes: Investigation, Methodology, Writing – review & editing

Omarf Ortega-Reyes: Investigation, Writing – review & editing

Tao Sheng: Investigation, Writing – review & editing

Marianna Salinas: Investigation, Methodology, Writing – review & editing

Paul Lerro: Investigation, Writing – review & editing

Francis X Guyette: Conceptualization, Methodology, Writing – review & editing

Benjamin D H Gordon: Methodology, Resources, Writing – review & editing

Marie Mortreux: Conceptualization, Methodology, Resources, Software, Writing – review & editing

Kathleen Melanson: Conceptualization, Methodology, Resources, Writing – review & editing

Daniel J Buysee: Conceptualization, Methodology, Writing – review & editing

Philip E Empey: Conceptualization, Methodology, Resources, Writing – review & editing

Vincenzo Lionetti: Editor

PMCID: PMC13712702 PMID: 42945316

Abstract

The alpha-2-adrenergic agonist drug dexmedetomidine induces sleep-like sedation and reduces global metabolic rate. Drug-induced metabolic suppression sustained over days in humans could be a strategy for reducing energy expenditure (EE), oxygen consumption (VO₂), and carbon dioxide production (VCO₂) during prolonged rescue or austere conditions with limited life-support. We tested the feasibility of reducing EE, VO₂ and VCO₂ measured with intermittent indirect calorimetry using subcutaneous infusion of dexmedetomidine 1 µg/kg/hour for 18 hours per day over five days in healthy adults. Five participants received multiple days of dexmedetomidine in a laboratory setting, and five separate participants received placebo for one or five days. Relative to resting metabolic rate, dexmedetomidine infusion reduced VO₂ (effects, 95%CI, at 6-hour time epoch: −0.084 L/min, −0.145 to −0.023), VCO₂ (−0.067 L/min, −0.130 to −0.005) and EE (−577 kcal/day, −1016 to −137). Relative to placebo, dexmedetomidine produced light sedation (Richmond Agitation Sedation Score: −1.25; 95%CI −1.70 to −0.80 relative to placebo), with lower heart rate (−15 beats/minute; 95%CI −23 to −7) and core body temperature (−1.3ºC; 95%CI −1.7 to −0.8). Dexmedetomidine effects on all physiological variables decreased over time and were absent after day 2. Maximum and minimum plasma drug levels did not change over days. Participants reported rebound anxiety and insomnia after the study. Administering a sedating level of dexmedetomidine that reduces VO₂, VCO₂, and EE for 2 days was feasible in healthy adults. However, tolerance to drug effects develops by 3 days, which is a critical limitation for long-term use of this drug regimen.

Introduction

Controlling metabolic demand is a potential strategy to prolong survival when food or oxygen are limited. Many animals can enter a torpor or hibernation state during winter or starvation, with 70%−95% reductions of energy expenditure [1,2]. Reduced core body temperature is one hallmark of hibernation during which animals turn off the normal cold-induced thermogenesis reflexes that increase metabolic rate as body temperature falls [1]. Humans do not normally display the traits that allow hibernation, but many studies have explored whether features of hibernation could be adapted to humans for medical indications or for extreme activities or environments [3]. Immediate applications might include reducing organ metabolic demand during medical procedures or shock states, extending the time available for rescue or return after catastrophic life-support failure in spaceflight, or reducing oxygen (O₂) consumption and carbon dioxide (CO₂) accumulation during prolonged rescue from a closed space such as a submarine or cave [4,5]. Future applications might include intentional hibernation to conserve resources during long-duration spaceflight [6–8].

Anesthetic drugs can reduce metabolic rate in humans [9,10]. However, many of these drugs reduce respiration and require ventilatory support with prolonged use. We and others observed that alpha-2-adrenergic agonists can induce sleep-like sedation, reduce global metabolic rate, and suppress cold-induced thermogenesis, without impairing respiratory drive [11–14]. One such drug, dexmedetomidine, can be delivered parenterally to achieve reliable drug levels and has a short 2- to-3-hour half-life that allows for rapid recovery [15]. We demonstrated previously that subcutaneous dexmedetomidine infusion at 1.0 µg/kg/hour could reduce O₂ consumption and CO₂ excretion in healthy human participants without mechanical ventilatory support [15].

It is not known if a drug like dexmedetomidine is practical for prolonged reduction of metabolic demand in humans. Tolerance to alpha-2-adrenergic receptor agonists has been reported, and new side-effects may become apparent with repeated or prolonged administration. As a first step to explore prolonged administration, we conducted a 5-day laboratory study in healthy adult participants. In this study, participants received an 18-hour infusion of drug repeated daily for 5 days, allowing a 6-hour interruption in drug infusion for participants to eat, exercise and self-care. This study tested if prolonged dexmedetomidine infusions in spontaneously breathing, healthy humans can reduce O₂ consumption, CO₂ excretion, and energy expenditure (EE) over 5 days.

Materials and methods

The University of Pittsburgh Human Research Participant Protection Office approved this study, and all participants provided prospective written informed consent. Participants completed research activities between April 2024 and September 2025.

Study design

We assigned participants to receive either dexmedetomidine or saline placebo for 18 hours per day for up to 5 consecutive days. For safety, neither participants nor investigators were blinded to drug assignment.

The study protocol was designed with technical requirements for application in a target spaceflight mission [6–8]. Specifically, we required (1) minimally invasive drug delivery that could potentially be self-administered, (2) daily sedation interruptions to allow participants to toilet, eat and self-care, and (3) time each day for exercise to maintain muscle health. The first two requirements eliminate the need for catheters, parenteral feeding or assisted hygiene. The third requirement represents the fixed cost of current countermeasures to microgravity-associated muscle loss. We tested 18 hours of drug administration, 5 hours of recovery and 1 hour of supervised exercise as the first version of this protocol (S2 Fig).

Participants

We recruited healthy persons aged 18–55 years old through advertisements in our university research participant registry (Pitt+Me).

Screening

Potential participants provided medical history including medication use. We excluded persons with sleep disorders, psychiatric conditions, or medical conditions that might be adversely affected by altered diet and schedules in the laboratory (e.g., diabetes). We excluded persons taking medications that would interact with sleep or sedation (e.g., stimulants or anxiolytics). We measured height, weight and % body fat. We excluded persons with weight<55 kg or Body Mass Index >30. Participants completed the Epworth Sleepiness Scale, and we excluded persons with scores > 10, corresponding to excessive daytime sleepiness. We obtained a 12-lead electrocardiogram, and excluded persons with signs of AV conduction delays, QT prolongation or dysrhythmia. We measured grip strength using a handheld device (JAMAR, Chicago IL, USA). Participants completed a modified Bruce Protocol exercise treadmill test during which we monitored O₂ consumption (VO₂) and CO₂ excretion (VCO₂) with a metabolic cart (Parvo-medics Inc., Parvo TrueOne 2400, Sandy, UT, USA). We excluded participants with VO₂ < 20 percentile or >90 percentile of expected values for age and sex according to the ACSM charts [16].

Study days

We confirmed that participants capable of becoming pregnant had a negative urine pregnancy test at the beginning of all laboratory visits. We placed an intravenous catheter in one arm for blood draws. Participants swallowed a telemetry temperature measuring capsule prior to study start (eCelsius using research mode, BodyCap, Hèrouville Saint-Claire, France). If this capsule passed through the gastrointestinal tract prior to the end of the laboratory study, participants swallowed a replacement capsule. Time zero was defined as the time that participants started drug, which occurred between 10:30 and 12:00 local time.

During drug infusion, participants were confined to the laboratory and allowed to sit or recline on a bed with a temperature-controlled surface set to 22–28ºC based on comfort. A medical water circulation cooling device (Arctic Sun, Franklin Lakes, NJ, USA) was used to control the bed surface temperature. Food and fluids were available ad libitum. Participants could ambulate to the toilet with assistance, or we provided them with a urinal. Urine output was collected in 24-hour blocks. Participants were weighed daily.

Drug administration

At time zero for each day, participants ingested 2 µg/kg dexmedetomidine or an identical volume (0.02 ml /kg) of saline. Drug was dripped under the tongue, held for 60 seconds and any remainder swallowed. Simultaneously, we started a syringe pump (MedFusion 3500 Syringe Pump, Medex Inc. Duluth, Georgia, USA) to deliver an infusion of dexmedetomidine 1 µg/kg/hour or saline at a rate of 1.5 ml / hour via a subcutaneous needle (Medtronic Minimed 6 mm or 9 mm Quick Set, Northridge, CA, USA) placed in the skin of the lower abdomen. Dexmedetomidine was the intravenous preparation which was diluted with 0.9% saline for the subcutaneous infusion.

We selected drug doses and routes based on our prior studies that measured dexmedetomidine levels after 1–4 µg/kg oral boluses and continuous subcutaneous infusions of 1 µg/kg/hour [14,15]. We selected subcutaneous infusions rather than intravenous infusions as part of the technical requirement for minimally invasive and self-administered drug delivery. We predicted that the regimen in this protocol would achieve sedating levels of drug within 1–2 hours and that participants would be able to participate in testing or exercise about 4 hours after stopping drug.

Post-drug waking and exercise

Drug infusions stopped after 18 hours. Researchers woke participants at 20 hours. Participants completed a supervised exercise protocol between 23 and 24 hours using a flywheel-based resistance device (kBox, Exxentric North America Inc., Portland, OR) and a handheld isometric exercise device (KINVENT, Montpellier, France) (S1 Table).

Measurements

We monitored heart rate constantly via a surface patch (ProPatch, Lifeware Inc., Pittsburgh, PA) and deep gastric temperature from the swallowed capsule. We recorded blood pressure from an arm cuff every hour. Researchers recorded the Richmond Agitation Sedation Score (RASS) every 4 hours [17]. RASS score of 0 corresponds to alert and calm, positive scores up to +4 indicate agitation, and negative scores ranges included drowsy (−1, eyes open to voice and remain open>10 seconds), light sedation (−2 eyes open to voice for <10 seconds), deep sedation (−3, movement or eye opening with no eye contact to voice), deep sedation (−4, eyes open or movement only to physical stimulation) and unarousable (−5).

Indirect calorimetry

We placed a clear plastic canopy over the participant while they were lying supine in the bed to capture exhaled breath and measure VO₂ and VCO₂ (Parvo TrueOne 2200 Metabolic Cart, Parvo Medics, Salt Lake, UT, USA) with one minute time resolution. When participants were sleeping, we were able to place the canopy with minimal disturbance other than requiring the participant to remain lying supine (S1 Fig). We obtained a resting metabolic rate (RMR) over one hour on the first day prior to any drug administration. On each day of drug administration, we measured metabolic rate at 6–7 hours (during infusion) and 17–18 hours (just before end of infusion) after drug start. We excluded measurements where the fraction of expired CO₂ < 0.5%, which corresponded to time when the canopy was not on the participant. At 23 hours after drug start, participants breathed into a facemask to collect VO₂ and VCO₂ while sitting quietly for 15 minutes and then continued to wear the facemask during a supervised exercise session between 23 and 24 hours. We excluded measurements where tidal volume was less than 300 ml, which corresponded to times when the mask was leaking or when the participant was trying to talk. Energy expenditure (EE) at each measurement was calculated from the Weir Equation: energy expenditure (kcal/24 hours) = 1440 (3.9 x VO₂ + 1.1 x VCO₂) [18].

We calculated the daily total energy expenditure (TEE) by extrapolating the measurements while under the canopy in each condition to the entire 24 hour period. Specifically, we multiplied the hourly EE measured at 6–7 hours (EE_6–7), 17–18 hours (EE_17–18) and at 23 hours sitting (EE_sitting) or exercising (EE_exercise) by the approximate number of hours in each condition. Dexmedetomidine participants spent 0–20 hours quietly sedated or sleeping (20 hours x average of EE_6–7 and EE_17–18), 20–23 hours sitting (3 hours x EE_sitting) and 23–24 hours exercising (1 hour x EE_exercise). Placebo participants spent 0–12 hours sitting or reclining in laboratory (12 hours x EE_6–7), 12–20 hours lying quietly or sleeping (8 hours x EE_17–18), 20–23 hours sitting (3 hours x EE_sitting) and 23–24 hours exercising (1 hour x EE_exercise). To confirm robustness of these results, we also calculated dexmedetomidine TEE using the same formula as used for placebo: 12 x (EE_6–7) +8 x (EE_17–18) + 3 x (EE_sitting) + 1 x (EE_exercise).

For comparison, we calculated the predicted RMR [19] and the predicted daily total energy expenditure (pTEE) [20] based on anthropometric measurements. We also considered an estimated daily total energy expenditure (eTEE) as 1.35 x the measured RMR.

As an additional measure of metabolic rate, dexmedetomidine participants ingested 1.25 g/kg doubly labeled water (DLW) 5 days prior to the laboratory study. DLW was 10% deuterium oxide (²H₂O) and water with ¹⁸O (H₂¹⁸O), diluted with local drinking water. We obtained plasma samples at baseline, 6–24 hours after ingestion, at the beginning of the laboratory stay, and 4–5 days into the laboratory stay. Using standard calculations [21], we compared the rate of disappearance of ²H and ¹⁸O from total body water. The excess rate of ¹⁸O disappearance is proportional to CO₂ excretion and total energy expenditure. For each participant, we calculated the pre-laboratory energy expenditure and the in-laboratory energy expenditure. One placebo participant also provided DLW data for comparison.

Safety parameters

A physician was present during all drug infusions. When heart rate was persistently below 35 beats per minute or systolic blood pressure below 80 mmHg, a study physician could pause dexmedetomidine infusion for 30 minutes and reevaluate. At that time, study drug could be paused for an additional 30 minutes, restarted or restarted at 0.5 µg/kg/hour. Physicians had option to terminate the drug infusion for any safety concerns. Research staff accompanied participants whenever they were ambulatory to prevent falls. Participants were warned and prepared for orthostatic symptoms, with staff reinforcing caution during transitions from supine to sitting to standing.

Drug levels

We collected plasma at 18 hours (peak) and 24 hours (trough) after start of drug infusion. Dexmedetomidine levels were measured using LC-MS/MS methods described previously [14,22].

Statistical analysis

This study was originally designed as a single-arm study in which every participant would receive drug, and drug effect would be quantified by the change in metabolic rate compared to baseline RMR. A target sample of 8 participants was selected to be able to detect a 30% decrease in metabolic rate after drug. After 5 participants received dexmedetomidine, there was clear evidence of tolerance to the drug, and the investigators stopped enrollment given that this new information informed the feasibility of the intervention and altered the risk profile for subsequent participants. We shared the interim findings with and solicited the opinion of participants who had completed screening but not yet participated in the drug phase when deciding to stop early. Placebo participants were added post hoc to clarify any laboratory-specific circadian or sleep-related changes in measures.

To analyze indirect calorimetry data, which was sampled intermittently, we defined five time epochs relative to the start of drug infusion: 0 hours (RMR during resting prior to drug), 6 and 18 hours (during drug or placebo infusion), 23:00–23:15 hours (sitting quietly after drug) and 23:16–24:00 hours (exercise). We created regression models during non-exercise epochs using random intercepts to account for clustering of repeated measurements within participants. The epochs with exercise were analyzed separately because activity level during that epoch was coached by the staff. For DLW data, we described the mean change in total energy expenditure for each participant with 95%CI.

Our planned primary analysis considered a model for energy expenditure, VO₂, VCO₂ and other secondary measures fit only to the participants who received dexmedetomidine with epoch and study day and their interaction as independent categorical factors. Drug effect was defined as the change in the physiological measure relative to baseline during epochs with drug infusion (6 or 18 hours). For RASS score, temperature, heart rate, systolic blood pressure and diastolic blood pressure, which were sampled continuously across study days, we also examined regression models using all hourly measurements instead of epochs to confirm the patterns of results.

We repeated these models in placebo participants to determine the pattern of changes in the absence of drug. A separate analysis including all drug and placebo participants considered a model with drug (dexmedetomidine or placebo), epoch, study day and their interaction as independent variables. Drug effect in that model was the defined as the effect of change from placebo to drug.

We compared marginal means from fit models with Bonferroni correction for multiple comparisons. For post-hoc comparison of observed values at each epoch and day versus baseline RMR, we compared means with Dunnett correction for multiple comparisons. After recognizing that drug effect changed over study days, we also contrasted means for observed values between drug and placebo for each epoch on the first study day alone. Values are reported as means with standard deviation (SD) or 95% confidence intervals (95%CI). An alpha-error rate of 0.05 was used to define significant changes. Statistical analysis was completed using Stata v19.5 (StataCorp, College Station, TX, USA) and graphs prepared using Prism v. 11.0 (GraphPad Software, Boston, MA, USA).

Results

Of 22 persons screened, 10 participated in laboratory stays. Characteristics of the participants are in Table 1. There were no large differences between characteristics of dexmedetomidine and placebo participants. Of these, 5 began and 4 completed a 5-day dexmedetomidine infusion, but one 5-day dexmedetomidine participant had to leave the laboratory early on study day 4 because of a family emergency unrelated to the study. One participant completed a 5-day placebo infusion, and another 4 participants completed a 1-day placebo infusion.

Table 1. Characteristics of participants.

N (%) or mean (SD)	Dexmedetomidine (n = 5)	Placebo (n = 5)	Standardized Mean Difference or Odds Ratio (OR) (95%CI)
Male Sex	4 (80%)	3 (60%)	OR 0.38 (0.02, 6.3)
Age in years	43 (15)	37 (7)	−0.51 (−1.75, 0.77)
Height in cm	177 (7)	178 (8)	0.14 (−1.1. 0.14)
Weight in kg	73.8 (8.7)	81.0 (13.6)	0.63 (−0.67,1.88)
BMI	23.7 (3.2)	25.4 (2.7)	0.58 (−0.71, 1.83)
VO₂ Max in ml/kg/min	39.0 (5.9)	38.0 (6.5)	−0.17 (−1.41, 1.08)
Grip score in N	77 (27)	74 (36)	−0.11 (−1.35, 1.13)
Resting SBP in mmHg	133 (12)	125 (12)	−0.72 (−1.98, 0.59)
Resting DBP in mmHg	82 (12)	74 (8)	−0.75 (−2.01, 0.56)
Resting HR in beats/min	62 (15)	69 (7)	0.58 (−0.71,1.83)
Predicted RMR (pRMR)^a in kcal/24 hr	1603 (208)	1677 (270)	0.31 (−0.95,1.55)
Predicted TEE (pTEE)^b in kcal/24 hr	2825 (341)	2910 (460)	0.21 (−1.04, 1.45)

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^a pRMR according to Mifflin St. Jeor 1990 [19].

^b pTEE according to Bajunaid 2025 [20].

When comparing the VO₂, VCO₂, and EE over the entire 5-day protocol to the baseline metabolic rate determined prior to any drug administration on day 1, during dexmedetomidine infusion, participants had lower marginal VO₂, VCO₂, and EE as indicated by the effects, 95%CI, of time epoch: for VO₂ (6 hour: −0.084 L/min, −0.145 to −0.023; 18 hour −0.072 L/min, −0.133 to −0.011), VCO₂ (6 hour: −0.067 L/min, −0.130 to −0.005; 18 hour: −0.065 L/min, −0.127 to −0.002) and EE (6 hour: −577 kcal/day, −1016 to −137; 18 hour: −510 kcal/day, −949 to −70) (Fig 1).

In placebo participants, there were no detectable effects of time epoch during placebo infusion for VO₂, VCO₂ and EE (S3 Fig).

Dexmedetomidine effects were maximal on the first day of drug infusion (Fig 1). Compared to placebo participants on day 1, dexmedetomidine participants had lower VO₂ (−28.7%), VCO₂ (−37.2%), and EE (−30.3%) at 6 hours and lower VCO₂ (−20.0%) at 18 hours (Table 2).

Table 2. Indirect calorimetry measurements on first day.

Mean (SD) or Mean Difference (95% CI)	Resting Metabolic Rate (RMR) (0 hours)	During Infusion (6–7 hours)	End of Infusion (17–18 hours)	Sitting (23 hours)	Exercise (23–24 hours)
Energy Expenditure (kcal/24 hour)
Dexmedetomidine	1879 (484)	1303 (156) ^**	1370 (185) ^**	2020 (506)	3320 (1398) ^**
Placebo	1737 (433)	1869 (386)	1567 (179)	2152 (422) ^**	4444 (946) ^**
Dexmedetomidine – Placebo	143 (−527,812)	−566 (−995,-137) ^*	−197 (−463,69)	−131 (−810,548)	−1124 (−2864,617)
% Change	+1.5%	−30.3% ^*	−12.6%	−6.1%	−25.3%
VO₂ (ml/kg/min)
Dexmedetomidine	273 (70)	189 (23) ^**	201 (27) ^**	288 (72)	466 (189) ^**
Placebo	251 (62)	265 (52)	225 (27)	309 (61) ^**	629 (134) ^**
Dexmedetomidine – Placebo	22 (−74,118)	−75 (−123,-16) ^*	−24 (−64,15)	−20 (−118,77)	−163 (−402,76)
% Change	+2.0%	−28.7% ^*	−10.7%	−6.8%	−25.9%
VCO₂ (ml/kg/min)
Dexmedetomidine	217 (58)	150 (17) ^**	152 (20) ^**	254 (64)	445 (213) ^**
Placebo	205 (54)	239 (60)	190 (20)	264 (55) ^**	575 (128) ^**
Dexmedetomidine – Placebo	12 (−70,94)	−89 (−153,-25) ^*	−38 (−67,-8) ^*	−11 (−98,76)	−130 (−386,127)
% Change	−2.5%	−37.2% ^*	−20.0% ^*	−3.8%	−22.6%

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Values are mean (SD) for 5 dexmedetomidine participants and 5 placebo participants

* Placebo different from Dexmedetomidine, mean comparisons p < 0.05

** Epoch Different from Baseline RMR, mean comparisons with Dunnett’s correction, p < 0.05

The dexmedetomidine-related decreases in VO₂, VCO₂ and EE diminished over study days (Fig 1), reflected by effects of study day in regressions and by the absence of decreases in VO₂, VCO₂ and EE relative to baseline RMR after day 2 (Fig 1). At 6 hours, VO₂, VCO₂ and EE were lower than baseline on days 1, but not on days 2, 3,4 or 5. At 18 hours, only VO₂ and EE were lower than baseline on day 2. None of the VO₂, VCO₂ or EE measurements were lower than baseline on days 3,4 or 5. VO₂ and EE did not differ from baseline RMR during quiet sitting at 23 hours across days, but VCO₂ was higher at 23 hours on days 4 and 5.

When comparing the VO₂, VCO₂, and EE over the entire 5-day protocol to the metabolic rate predicted by anthropometric formulas, dexmedetomidine reduced total energy expenditure but not resting energy expenditure. Predicted RMR for participants (Table 1) was similar to the measured resting energy expenditure at hour 0 on day 1 (Table 3). Over the multiple days of dexmedetomidine, the numerically lower measured total EE (1667 kcal/24 hours, SD 163) was not reliably different than observed RMR (1810 kcal/24 hours, SD 480) or predicted RMR (1603 kcal/24 hours, SD 208). However, the measured total EE was 40.7% lower than predicted total EE and 31.8% lower than estimated total EE (Table 3). In placebo participants confined to the laboratory, measured total EE that was lower than predicted or estimated total EE (−33.9% and −16.9% respectively). The numerically larger decreases after dexmedetomidine were not reliably different from the decreases after placebo (Table 3).

Table 3. Daily energy expenditure across all study days.

Mean (SD) in kcal / 24 hour, or Mean Difference (95% CI)	Dexmedetomidine	Placebo	Dexmedetomidine – Placebo	% Change from Placebo
Mean Energy Expenditure by Time Interval
During Infusion (6–7 hours)	1495 (197)	1968 (300)	−473 (−711, −234)	−24%*
End of Infusion (17–18 hours)	1468 (274)	1689 (192)	−221 (−399, −42)	−13%*
Sitting (23 hours)	2147 (572)	2393 (422)	−246 (−631, 139)	−10%
Exercise (23–24 hours)	3813 (1400)	4618 (925)	−805 (−1582, −29)	−17%*
Measured Total Energy Expenditure (mTEE)
Measured Total Energy Expenditure (mTEE) ^a	1649 (163)	1906 (295)	−257 (−623, 108)	−13%
Measured TEE vs. Predicted TEE
Predicted TEE (pTEE) ^b	2825 (341)	2910 (460)	−85 (−684, 515)	−3%
mTEE - pTEE	−1176 (−1547, −805)	−1003 (−1220, −787)	−173 (−545, 199)	−17%
% Change from pTEE	−42%*	−34%*
Measured TEE vs. Estimated TEE
Estimated TEE (eTEE) ^c	2444 (648)	2294 (579)	149 (−746, 1045)	+6%
mTEE - eTEE	−888 (−1591, −184)	−438 (−889, 12)	−450 (−1166, 266)	−103%
% Change from eTEE	−36%^*	−19%

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For Placebo, values are based on 1 day for four participants and 5 days for one participant (9 total days). For Dexmedetomidine, values are based on 3 days for one participant and 5 days for 4 participants (23 total days).

* Comparison of means, p < 0.05

a For placebo, mTEE = 12 x (6-hour EE) +8 x (18-hour EE) + 3 x (Sitting EE) + 1 x (Exercise EE). For dexmedetomidine, mTEE = 20 x ½ (6-hour EE + 18-hour EE) + 3 x (Sitting EE) + 1 x (Exercise EE)

^bpTEE according to Bajunaid 2025 [20]

^ceTEE = RMR x 1.35

Data from DLW for dexmedetomidine indicated a large decrease (−51.8%) from total EE during the 5 days prior to laboratory to days measured in the laboratory (Table 4). The pre-laboratory EE measured with DLW (mean 3193 kcal/24 hours, SD 395) was similar to the predicted total EE based on age, sex, body mass and size (mean 2810 kcal/24 hours, SD 364). For the single placebo participant who spent five full days confined to the laboratory, the decrease in total EE estimated with DLW was smaller (−6.4%).

Table 4. Double labeled water estimate of total energy expenditure.

Mean (SD) in kcal / 24 hour, or Mean Difference (95% CI)	Dexmedetomidine (n = 5)	Placebo (n = 1)	Dexmedetomidine – Placebo
Doubly Labeled Water (DLW) measured TEE
DLW-TEE prior to Lab	3193 (395)	3829	−636
DLW-TEE in Lab	1539 (348)	3584	−2045
(DLW-TEE)_{In Lab} – (DLW-TEE)_{Prior to Lab}	−1654 ^* (−2131, −1177)	−245	−1409
% Change	−52% ^*	−6%

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* Comparison, p < 0.05

Dexmedetomidine infusion produced light sedation with RASS scores less than zero during all drug-infusion epochs (Fig 2). For the entire day, dexmedetomidine was associated with decreased RASS compared to placebo (drug effect: −1.25; 95%CI −1.70 to −0.80). The mean RASS score for the day was lower after dexmedetomidine than after placebo on the first day but not on subsequent days (Fig 2). During dexmedetomidine infusion, participants were able to wake for toilet needs or to request food and drink. Most reported that they were sleeping or lightly dozing during drug infusion. Placebo participants only slept during local nighttime (approximately protocol hours 12–20).

Dexmedetomidine infusion was associated with a decrease in core body temperature (−1.3ºC; 95%CI −1.7 to −0.8) and heart rate (−15 beats/minute; 95%CI −23 to −7) relative to placebo (Fig 2). Core body temperature showed circadian variation with a decline during sleep in placebo participants. Mean core temperature for the day was lower after dexmedetomidine relative to placebo on days 1 and 2, but not subsequent days. Mean heart rate for the day was lower than placebo on day 1, but not on subsequent days. We did not detect consistent differences between dexmedetomidine and placebo in systolic blood pressure (+5 mmHg; −6–16) or diastolic blood pressure (0 mmHg; −9–8).

Fig 2 shows drug onset over days. Participants reported feeling subjective drug effects by 1 hour after starting infusions. On days 1 and 2, participants were sedated (RASS < −1) by 3 hours and heart rate decreased from 0 to 3 hours. First RASS scores and the numerical values of heart rate were higher on days 3–5. Recovery of heart rate and RASS from 18 to 21 hours did not appear to vary over days.

There was no detectable effect of study day on plasma levels of dexmedetomidine at the end of infusions (mean 1.55 ng/dl, SD 0.55; ß_day = −0.045, 95%CI −0.152 to 0.062). (Fig 3) Plasma drug levels declined to mean 0.55 ng/dl (SD 0.38) by 24 hours after drug start (6 hours after drug stop) each day, and these levels also did not change over days of infusion (ß_day = −0.063, 95%CI −0.134 to 0.008).

Fig 3 — Mean and 95% CI plasma dexmedetomidine levels (ng/ml) are plotted for each study day (1-5). Peak values were collected at 18 hours at the end of drug infusion. Trough values were collected at 24 hours, which is 6 hours after stopping drug, just before starting next day drug infusion.

Body weight and urine output changed little over days of drug infusion (S2 Table). Blood and urine chemistry had no systematic changes over the course of the study (S2 Table).

There were few adverse events. All dexmedetomidine participants reported orthostatic symptoms, primarily light-headedness or nausea, when standing, which resolved in minutes without treatment or vanished immediately when patients reclined. One participant had persistently low heart rate on the first day of infusion, and the dexmedetomidine dose was reduced to 0.5 µg/kg/hour. This pause was made solely based on the numerical value of the heart rate. The participant had no symptoms or decrease in blood pressure. This participant tolerated the 1 µg/kg/hour dose on subsequent laboratory days. There were no episodes of hypotension or other events requiring treatment during infusions.

All dexmedetomidine participants reported trouble sleeping or anxiety on the first 1–2 days after the laboratory stay. All but one took 0.5 mg – 1.0 mg lorazepam to assist with sleep or anxiety on the first post-study day. One participant sought emergency medical care for presyncope symptoms when he engaged in an athletic event 3 days after the laboratory stay. Vital signs were normal for this participant during that presentation and were attributed to dehydration. All participants reported that restlessness and inability to sleep was worst on the first night after leaving the laboratory. Three reported that sleep duration was normal by the third night after leaving the laboratory, and two did not provide any daily report.

Discussion

This study demonstrated that administering a sedating level of dexmedetomidine infusion for 18 out of 24 hours for multiple days was feasible in healthy adults. Dexmedetomidine reduced EE during quiet resting by 30.3% and VO₂ by 28.7% relative to placebo on the first day. Total EE decreased by 42% relative to predicted total EE over the whole session, though simply confining participants to the laboratory reduced total EE by 34% relative to predicted total EE even with placebo administration. Most adverse events were expected and consistent with the known effects of this drug.

While drug effects were robust for at least 2 days in all participants, our data show the development of tolerance to dexmedetomidine after 3 days. The participants reported subjective rebound or withdrawal symptoms for 1–3 days after the infusion. We considered this tolerance to be a critical limiting factor for using this specific drug strategy, and we stopped the study early when this tolerance and rebound became clear. Even in the laboratory, VCO₂ increased during sitting at 23 hours on days 4 and 5 (Fig 1). Though not statistically different, numerical values for mean VO₂ and EE were also higher at 23 hours on days 4 and 5, and failure to detect increases in these variables may just be a result of the small number of participants. We suspect that this pattern of increasing metabolic rate at 23 hours is an early sign of the rebound restlessness that participants reported on the post-laboratory days. At a minimum, this pattern indicates that drug effects wore off more quickly and participants were less sedated by 23 hours on days 4 and 5 than they were on prior days.

Tolerance to dexmedetomidine infusion is unlikely to be related to pharmacokinetic changes because peak and trough plasma levels changed little over the 5 days of infusion (Fig 3). The slight increase in peak levels on day 2 probably reflects the accumulation of drug from the previous day rather than a change in volume of distribution. The similar trough levels across all days do not support any increase in clearance. Like other G-protein coupled receptors, alpha-2-adrenergic receptors may undergo phosphorylation or uncoupling within minutes followed by internalization or reduced numbers over hours to days of in response to agonist binding resulting in functional desensitization over time [23,24]. This pharmacodynamic change would explain our results.

Our study provides information about the time-course for developing tolerance to dexmedetomidine in humans, which may be useful for several clinical settings. When dexmedetomidine is used as a sedative, the infusion dose can be titrated to achieve the desired effect. However, our data suggest that a need to increase doses after 2 or more days of infusion may represent tolerance that will lead to withdrawal symptoms when the drug is stopped. Some studies describe protocols for weaning or transitioning to other drugs to prevent dexmedetomidine withdrawal syndrome [25–27].

Using a single dose of drug for all participants ignores between-individual variation in response. In a separate cohort, we observed that a small number of participants were agitated or restless with this dose [15]. At the same time, we had to reduce the dose in some people because of worrisome bradycardia. Our protocol did not allow titration of dose, which is routine when dexmedetomidine is used in medical settings. A protocol in which the drug is titrated to a set sedation level or heart rate might provide different results. To minimize blood draws in this study, we only collected plasma at two time points which does not completely define the drug kinetics. Nevertheless, we did observe some between participant variation in drug levels.

These data suggest that dexmedetomidine reduces EE and VO₂ during the 5-day protocol both by reducing metabolic rate during rest and by increasing sleep time per day. Dexmedetomidine decreases VO₂ and EE by about 30% relative to waking (6-hour data in Fig 1) and by about 10% relative to sleeping (18-hour data in Fig 1). At the same time dexmedetomidine increased the total amount of time spent sleeping almost 3-fold from 6–8 hours to 20 hours (RASS data in Fig 2). The combination of lower metabolic rate during sleep and increased sleep time resulted in the large reduction of total EE relative to predicted EE or relative to the EE measured during the prior week using doubly labeled water (Table 3). Some reduction in total EE was evident even after placebo, which reflects the lower total activity when participants were confined to the laboratory compared to their normal daily activity.

Comparison over time between participants receiving dexmedetomidine and participants receiving placebo was a secondary aim of this study that was limited because only one placebo participant spent multiple days in the laboratory. That subject did not show large changes in metabolic rate from day to day, but we cannot exclude the possibility that other participants would have had different patterns over time. The comparison of metabolic rates between placebo and five dexmedetomidine on the first protocol day is based on five participants in each group and more reliable.

The purpose of this investigation was to determine whether a drug-induced decrease in metabolic rate could be maintained for multiple days in healthy humans. Such a reduction would be useful to conserve resources and reduce payload for long-duration spaceflight [6–8] or to improve survivability during long-duration rescues from catastrophic failure of life-support [4,5]. Our results indicate that the current regimen is insufficient for more than 3 days of metabolic suppression. Increasing the dose of drug over time or reducing the daily 6-hour drug interruption might increase the desired effect, but these interventions also would be expected to accelerate drug tolerance. This might worsen the withdrawal symptoms at the end of the study.

Achieving reductions of metabolic rate greater than observed in this study may require other drug classes or larger manipulations of body temperature. We selected an alpha-2-adrenergic agonist for this study because of properties discovered about these drugs during medical use. However, these drugs do not specifically target physiological mechanisms employed by animals that hibernate. Manipulating neuropeptides, adenosine, or endocrine pathways that are implicated in hibernation might better mimic hibernation changes in humans [28,29].

The largest limitation of this study is the small number of participants. The point estimates for metabolic rate and for drug effect on metabolic rate may lack precision. Nevertheless, the sample was sufficient to detect dexmedetomidine-induced reductions in EE and the development of drug tolerance. These data are sufficient to conclude that drug-induced metabolic reduction in humans is technically possible, and that future studies should explore different drugs or dosing regiments for long-term applications.

A second limitation of this study is that we measured baseline EE, VO₂ and VCO₂ during the resting state in the laboratory prior to drug administration, which may underestimate the resting metabolic rate that would be observed under stressful situations. Future studies might explore both the resting metabolic rate and any drug effect on metabolic rate in settings that more directly mimic the intended use cases.

This study and related studies in this project [13–15] provide practical lessons for future studies that attempt to mimic animal hibernation and provide a model for how to test metabolic manipulation drugs as they become available. First, short-term experiments can screen for drugs that increase the proportion of total time spent in sleep and also decrease metabolic rate during sleep to levels at or below resting metabolic rate. The short-term experiments also can detect suppression of cold-induced thermogenesis: decreasing core body temperature when heat flux is held constant is one sign of decreased resting metabolic rate. Second, the total energy expenditure is the sum of energy expenditure in all of the behavioral conditions throughout the day: wake, sleep and exercise. Required activities like exercise, eating and toileting have fixed energy costs for any practical implementation. Accounting for all the states during the day is required to determine if a drug provides a net reduction in energy expenditure. Third, there is some reduction in energy expenditure simply from confinement to the laboratory. Studies that compare free living energy expenditure in fit and active adults with drug-states in the laboratory may overestimate the energy reduction attributable to drug unless in-lab control participants are included. Fourth, multi-day studies are required to assess whether tolerance develops to any drug-induced sleep or metabolic rate reduction. The data in this study revealed that participants had less sedation from dexmedetomidine after day 2, which is a serious barrier to implementation. This fact would not have been evident from only short-term laboratory studies.

In conclusion, we demonstrated that dexmedetomidine can be administered to healthy humans without respiratory support for 18 hours/day over 5 days. Tolerance to most physiological effects of dexmedetomidine develops after 2 days, and participants report some rebound symptoms. Nevertheless, this drug regimen does reduce total energy expenditure, O₂ consumption and CO₂ production for at least 2 days. This regimen might be useful to prolong survival during emergency situations with limited air or resources.

Supporting information

S1 Fig. Canopy for indirect calorimetry.

This picture shows the canopy system used to collect exhaled breath for indirect calorimetry placed over one of the authors in the laboratory in the same configuration used for participants. Participants would lie supine under the canopy during testing for about one hour. When participants were sedated or sleeping, we were able to place the canopy over the participant with minimal disturbance aside from repositioning to supine. Participants could sleep or lie quietly throughout the data collection. For exercise testing at protocol hour 23, we used a traditional face mask to collect exhaled breath.

(TIFF)

pone.0359711.s001.tiff^{(19.2MB, tiff)}

S2 Fig. Protocol timeline.

Timeline for drug administration and testing during daily protocol for A. Dexmedetomidine participants and B. Placebo participants. The daily protocol was repeated each day in dexmedetomidine participants and in one of the placebo participants. Time 0 was the time of drug start, which was typically between 10 am and noon local time. Indirect calorimetry to determine VO₂, along with VCO₂ and energy expenditure are indicated as “VO₂.” Baseline indirect calorimetry was performed prior to drug administration on day 1. Plasma was collected to measure peak drug levels at the end of drug infusion (18 hours) and trough drug levels just prior to starting the next day drug (24 hours). In all subjects, heart rate, blood pressure, sedation scales (RASS), and pulse oximetry were measured during drug infusions and recovery. Dexmedetomidine participants were sedated to quiet resting or sleeping from hours 0–20. Placebo participants were not sedated but quietly resting in the laboratory from hours 0–12, until they went to sleep, typically from hours 12–20. We woke all participants at hour 20 and conducted supervised exercise beginning at hour 23. Indirect calorimetry at hour 23 was collected both while sitting quietly during the first 15 minutes of the supervised exercise, and during exercise.

(TIFF)

pone.0359711.s002.tiff^{(1MB, tiff)}

S3 Fig. Placebo EE, VO2, VCO2 over 5 days.

Mean and 95% confidence intervals for EE (top row), VO₂ (middle row) and VCO₂ (bottom row) from indirect calorimetry are plotted for each time point prior to exercise (6, 18 and 23 hours on left, middle and right column respectively) for all five participants who received placebo on study day 1 (left column). The horizontal lines indicate the 95% confidence intervals for the RMR determined on study day 1 prior to starting drug. Measured values did not differ from baseline. The individual values from the one participant who received placebo for study days 1–5 are plotted as line graphs (right column).

(TIFF)

pone.0359711.s003.tiff^{(1.2MB, tiff)}

S1 Table. Exercise protocol.

(DOCX)

pone.0359711.s004.docx^{(18.8KB, docx)}

S2 Table. Body weight, oral intake, serum and urine chemistry during dexmedetomidine infusion.

(DOCX)

pone.0359711.s005.docx^{(21.2KB, docx)}

Data Availability

All relevant data are available at the following DOI: https://doi.org/10.5281/zenodo.23082735.

Funding Statement

This work was supported by National Aeronautics and Space Administration award NNX16AO69A to the Translational Research Institute for Space Health at the Baylor College of Medicine with subawards to CWC and KF (https://www.nasa.gov/hrp/the-translational-research-institute-for-space-health-trish/) and by National Institutes of Health S10 OD028540 to the University of Pittsburgh Small Molecule Biomarkers Core (https://www.biomarkers.pitt.edu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0359711.r001

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Reviewer #1: I am pleased to have had the opportunity to peer-review this study. This is a highly interesting paper that examines the effects of continuous subcutaneous administration of dexmedetomidine (DEX) over five days on metabolic rate in healthy adults. The finding that tolerance to DEX’s metabolic inhibitory and sedative effects develops by the third day, despite stable plasma drug concentrations over the five-day period, is a crucial insight into the characteristics of this drug.

However, there are several serious concerns regarding the handling of data from the placebo group and indirect calorimetry data, and I request revisions and explanations on the following points.

Specific Comments

1. the Handling of Data from the Placebo Group

In the Results section, the authors state that four of the five participants in the placebo group stayed for only one day, while only one stayed for five days. Despite this, the Supplemental Figure includes error bars for the data from days 2–5. How were the error bars calculated for the data from days 2–5, where the sample size is n = 1? It is impossible to calculate statistical variance when there is only one data point. I believe these error bars need to be corrected, as they could lead readers to the serious Misunderstanding that there were multiple participants in the placebo group from the second day onward and that the error bars represent their variability.

Furthermore, the fact that the placebo group consisted of n=1 from days 2 through 5 significantly limits the reliability of statistical comparisons over time between the two groups. Please clearly state this as a major limitation of the study in the Discussion section.

2. Conversion to a 24-Hour Equivalent for Indirect Calorimetry

The author measured the metabolic rate intermittently during the 6th and 18th hours and estimated the total energy expenditure over 24 hours by applying the values to the formula in footnote a of Table 3. What is the basis for this formula? Also, why were different formulas used for the DEX group and the placebo group? Isn’t it inappropriate to compare data calculated using different formulas?

3. About Rebound Symptoms

It is reported that subjects complained of anxiety and insomnia due to rebound effects after the trial ended, and many required lorazepam. From the perspective of clinical safety and transparency, please add more specific details in the “Results” section regarding the timeline of these withdrawal symptoms (e.g., on which day they peaked and on which day they completely resolved). This information will serve as an important safety indicator for future researchers designing long-term α₂-agonist protocols.

4. On the Mechanism of Metabolic Inhibition by DEX

Based on the authors’ data, it is clear that DEX suppresses metabolism, but it is unclear whether DEX directly suppresses metabolism or whether the decrease in metabolism is due to reduced patient activity resulting from its sedative effects. Please state the authors’ opinion on this matter.

5. minor comments

1) Table 3 For placebo, values are based on 3 days for one participant and 5 days for 4 participants (23 total days).: Isn't “placebo” a typo for “DEX”?

2) Figure 2 Why doesn't the DEX group have RASS data for 23 hours?

3) The authors write that they woke the participants after 20 hours, but was the 18-hour calorimetry conducted while the patients were asleep? Is the canopy designed to allow measurements whether the patient is sleeping or exercising? A photo of the product might help readers visualize it.

Reviewer #2: Thank you for the opportunity to review the manuscript “Dexmedetomidine effects on metabolic rate over 5 days in humans“. Callaway et al. analyzed the effect of dexmedetomidine on metabolic rate and found that VO2, VCO2 and EE were reduced within the first two days of application compared to placebo treated controls. However, dexmedetomidine effects vanished after day 2, although plasma concentrations remained identical. This study nicely provides important data concerning effects of dexmedetomidine on different metabolic measures and its potential use to induce internal hibernation, however, needs clarification at some points.

Please find my comments attached:

• In medical settings, continuous intravenous application of dexmedetomidine is used and subcutaneous infusion is only used off-label in special situations, e.g. palliative care. Please clarify why subcutaneous application has been used and additional oral intake rather than boli subcutaneously at the beginning. Please provide more information on pharmacokinetics, possibly from your earlier studies.

• Did you screen for other medical conditions, e.g. liver cirrhosis, that can potentially influence the effect of dexmedetomidine? Despite there do not seem to be any group differences for baseline characteristics, please provide an appropriate statistic (Table 1) and add measurement units.

• If dexmedetomidine is applied for different scenarios, outside the direct therapy in the ICU setting, people would probably have a higher baseline excitement and subsequently higher baseline levels of EE, VO2 and VCO2. Do you have any data if dexmedetomidine has the same effect in these exceptional situations compared to “normal” laboratory days where even “placebo” people have a lower resting rates?

• The tolerance and rebound effect seem to be a major limitation for the use of dexmedetomidine in the proposed context. However, if it is supposed to be used for a definite short amount of time, e.g. three days, would it make sense to increase dosage to maintain the goal of “hibernation”? Where would such scenarios of an infusion of sedating substances make sense (outside a defined ICU setting, which is not the aim of this study)? Please clarify what situations you aim for?

• Although statistics seem to be appropriate, please state more clearly where you compare what timepoints and which groups. For example, it is hard to follow for the description of the results of Figure 1. Is the marginal reduction of VO2 relative to baseline RMR for day 1 or for all 5 days of follow-up (e.g. effects, 95%CI, of time epoch: 6 hour: -0.084 L/min, -0.145 to -0.023; 18 hour -0.072 L/min, -0.133 to -0.011)?

• Why did you apply dexmedetomidine for 18 hours and then pause for 6 hours and did not use any other time frames. Why was dexmedetomidine not infused continuously over five days without any breaks to test if metabolic rates could be reduced. I assume that this setup should represent possible scenarios, i.e. space ship/submarine, where people should still be able to exercise to reduce muscle wasting or similar appearances. Please discuss this more clearly so that the reader can get an idea for what exact situations you consider using dexmedetomidine and why this setup/infusion regime was chosen.

• People have a rebound effect of about 2-3 days. How long does it take until you see an effect of the drug when starting the daily experiments and how long does it take until the drug wears off (based on clinical observations such as RAAS)? Does this change over the course of days? If tolerance is seen, probably the drug will need more time/accumulation until an effect is seen, however, the time until it wears off should be shortened.

• Please provide an overview figure for the setup and the different timepoints. When does infusion start? When does it stop? When do people do exercise, etc. This would help the reader to get a better idea of the experimental setup.

• Safety: How often did the infusion need to be paused due to side effects? Is it only the one patient where infusion had to be reduced at the first day? Was the patient clinically symptomatic due to the bradycardia?

• Why was only one patient of the placebo group followed up over five days (and the others only one day)? Potentially, five consecutive days in a laboratory setting can have effects on the metabolic rates and the overall state of participants.

• Why was VCO2 increased after 23 hours at the last two days and not during the earlier days? Do you have any explanation why EE was not influenced? In the results section it is stated that VCO2 is increased after 18 hours for the last two days (instead of 23 hours as shown in Figure 1). Please double check.

• Table 2: Include p-values and what statistical tests were used

• Please clarify why measured and predicted PMR was used and what the differences are.

• Considering Table 4: Please mark for transparency reasons that the placebo group includes only one person at this point.

• Unfortunately, Figure 3 is not included

• Please double-check phrasing at some points, i.e. “5 completed a 5-day dexmedetomidine infusions and 1 participant completed a 5-day placebo infusion 5 completed 5 days of Dexdor, one had a family emergency and left one day early”. Therefore, it does not seem like 5 participants completed the 5 day infusions when 1 participant dropped out early.

• Double-check spelling and grammar throughout the manuscript

• How can you state that lower food intake was seen after dexmedetomidine infusion when no baseline was assessed? Was this compared to placebo? Or just a clinical observation

• Please specify your exercise protocol, i.e. as supplemental material.

• Please state limitations more clearly, and add that this is a small sample size and data is therefore, mainly hypothesis-generating

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Reviewer #2: No

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PLoS One. 2026 Oct 27;21(10):e0359711. doi: 10.1371/journal.pone.0359711.r002

Author response to Decision Letter 1

14 Sep 2026

7 September 2026

Dear PLOS One:

Thank you for reviewing our manuscript “Dexmedetomidine effects on metabolic rate over 5 days in humans“ for PLOS One. We have considered all of the comments from the peer reviewers and modified our manuscript to address each one. These helpful suggestions have improved the paper, and we hope that you find it suitable now for publication in the journal.

The table below has point-by-point responses to each comment. A marked-up copy of the manuscript is submitted which has track-changes to show where each modification was made.

We also modified fonts and headings according the PLOS One style sheets.

Sincerely,

Clifton Callaway, MD, PhD

Reviewer or Editorial Comment

Authors’ Response

Change in Manuscript

Editorial Comments:

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

We made a number of typographical edits to be consistent with the PLOS style sheets.

We reformatted the revised manuscript to match the style. “FIGURE” was changed to “Fig” and “TABLE” to “Table” throughout. Figure legends were moved to be in-line with text. Supplemental information was relabeled “S1 Table,” etc. Headings were formatted per the style sheet.

Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript.

We removed the funding information in the Acknowledgements. There are no other acknowledgements, so this section was deleted.

DELETED ACKNOWLEDGEMENTS:

“Acknowledgements. This work was supported by NASA award…”

The grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match…please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

We correct the funding information to be consistent.

CHANGED FUNDING INFORMATION IN SUBMISSION

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ADDED THIS SENTENCE:

“The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

Please expand the acronym “NIH” (as indicated in your financial disclosure) so that it states the name of your funders in full.

NIH is the National Institutes of Health

CHANGED “NIH” to “National Institutes of Health”

We strongly recommend all authors decide on a data sharing plan before acceptance,

We have decided to place the raw data in Zenodo where it can be accessed freely. This plan is consistent with the Open Data policies of our funder.

DATA SHARING PLAN - deposit data to Zenodo

Please upload a copy of Figure 3

Apologies that this figure was not included in the previous PDF

FIGURE 3 is uploaded to system

your supplementary tables are included in the manuscript file. Please remove them and upload them with the file type 'Supporting Information'.

The Supplementary Tables is separated into a different file, now included in the “Supporting information”

MOVED Supplementary Table to the Supporting Information

Your supplementary figures are uploaded with the file type 'Figure'. Please amend the file type to 'Supporting Information'.

We revised the file types and names per the PLOS style sheet.

CHANGED the file type for Supplementary Figures to Supporting Information

Reviewer 1:

Supplemental Figure. I believe these error bars need to be corrected,

We agree this figure is deceptive: we used the same code as Figure 1 in an attempt to make the figures look alike, which drew error bars from a regression rather than the raw values. i.e. the original figure extrapolated errors from Day 1 data. Since the placebo data is not structured the same as the dexmedetomidine data, this was a mistake.

To correct this, we made an entirely new figure with 95% confidence interval bars calculated directly from the placebo data for Day 1 (n=5 participants) and with a line graph showing the individual values for the one placebo participant who stayed in the lab for 5 days (n=1) ADDED NEW SUPPLEMENTAL FIGURE 3.

CHANGED SUPPLEMENTAL FIGURE 3 LEGEND:

“S3 Fig. Placebo EE, VO2, VCO2 over 5 Days. Mean and 95% confidence intervals for EE (top row), VO2 (middle row) and VCO2 (bottom row) from indirect calorimetry are plotted for each time point prior to exercise (6, 18 and 23 hours on left, middle and right column respectively) on for all five participants who received placebo on each study day 1 (left column). (1-5). The horizontal lines indicate the 95% confidence intervals for the RMR determined on study day 1 prior to starting drug. Measured values did not differ from baseline. The individual values from the one participant who received placebo for study days 1-5 are plotted as line graphs (right column). “

We agree with this limitation, and emphasize that the primary comparison is from baseline. The comparison of placebo versus drug on subsequent days was an additional exploratory aspect f the study.

ADD TO DISCUSSION: “Comparison over time between participants receiving dexmedetomidine and participants receiving placebo was a secondary aim of this study that was limited because only one placebo participant spent multiple days in the laboratory. That subject did not show large changes in metabolic rate from day to day, but we cannot exclude the possibility that other participants would have had different patterns over time. The comparison of metabolic rates between placebo and five dexmedetomidine on the first protocol day is based on five participants in each group and more reliable.”

Estimated the total energy expenditure over 24 hours by applying the values to the formula in footnote a of Table 3. What is the basis for this formula? Also, why were different formulas used for the DEX group and the placebo group? Isn’t it inappropriate to compare data calculated using different formulas? Our approach is to multiply the hourly EE rate estimated during each type of activity x the hours spent in that activity.

Different formulas for placebo and dexmedetomidine reflect the fact that dexmedetomidine participants were sedated the entire time between 0 and 20 hours, whereas placebo participants were awake while sitting/reclining between 0 and 12 hours and sleeping between 12 and 20 hours. We believe the displayed formulas most accurately represent the actual activity for participants during the protocol and are the best estimates from indirect calorimetry of the total 24 hours EE. We tried using the same formulas for estimating the total EE in dexmedetomidine and placebo participants, and this provided a similar pattern of results. This is added to the RESULTS

ADDED TO METHODS: “We calculated the daily total energy expenditure (TEE) by extrapolating the measurements while under the canopy in each condition to the entire 24 hours period. Specifically, we multiplied the hourly EE measured at 6-7 hours (EE6-7), 17-18 hours (EE17-18) and at 23 hours sitting (EEsitting) or exercising (EEexercise) by the approximate number of hours in each condition. Dexmedetomidine participants spent 0-20 hours quietly sedated or sleeping (20 hours x average of EE6-7 and EE17-18), 20-23 hours sitting (3 hours x EEsitting) and 23-24 hours exercising (1 hour x EEexercise). Placebo participants spent 0-12 hours sitting or reclining in laboratory (12 hours x EE6-7), 12-20 hours lying quietly or sleeping (8 hours x EE17-18), 20-23 hours sitting (3 hours x EEsitting) and 23-24 hours exercising (1 hour x EEexercise). To confirm robustness of these results, we also calculated dexmedetomidine TEE using the same formula as used for placebo: 12 x (EE6-7) +8 x (EE17-18) + 3 x (EEsitting) + 1 x (EEexercise).”

… more specific details in the “Results” section regarding the timeline of these withdrawal symptoms (e.g., on which day they peaked and on which day they completely resolved).

Unfortunately, we did not anticipate the subjective withdrawal symptoms and there was no structured instrument about anxiety or restlessness completed after the participants left the laboratory. Our observations are based on anecdotal reports from each participant, and the questions we did ask about sleep duration and quality. Two participants failed to answer the post-laboratory sleep questions, so these data are incomplete.

ADD TO RESULTS: “Participants reported restlessness and inability to sleep that was worst on the first night after leaving the laboratory. Three reported that sleep duration was normal by the third night after leaving the laboratory, and two did not provide any daily report.”

It is unclear whether DEX directly suppresses metabolism or whether the decrease in metabolism is due to reduced patient activity resulting from its sedative effects. Please state the authors’ opinion on this matter

We believe that both sedation and reduced resting metabolic rate contribute to the observed effects. We add this more clearly in the Discussion

CLARIFY IN DISCUSSION: “These data suggest that dexmedetomidine reduces of EE and VO2 during the 5-day protocol results from both reduction of metabolic rate during rest and from increased sleep time per day. Dexmedetomidine decreases VO2 and EE by about 30% relative to waking (6-hour data in FIGURE 1) and by about 10% relative to sleeping (18-hour data in FIGURE 1). At the same time dexmedetomidine increased the total amount of time spent sleeping almost 3-fold from 6-8 hours to 20 hours (RASS data in FIGURE 2).”

Table 3 For placebo, values are based on 3 days for one participant and 5 days for 4 participants (23 total days).: Isn't “placebo” a typo for “DEX”?

This is a typo.

CHANGED TABLE 3 FOOTNOTES: “For Dexmedetomidine, values are based on 3 days for one participant and 5 days for 4 participants (23 total days).”

Figure 2 Why doesn't the DEX group have RASS data for 23 hours?

At 23-24 hours, all participants were engaged in the supervised exercise, and RASS scores were not recorded, because they should all be RASS=0. The one line for Placebo Day 1 where RASS=0 for hours 23-24 was graphed because values of 0 were entered into the database for one of those participants.

ADD TO FIGURE LEGEND: “RASS was not documented and assumed to be 0 during supervised exercise at hour 23. “

The authors write that they woke the participants after 20 hours, but was the 18-hour calorimetry conducted while the patients were asleep? Is the canopy designed to allow measurements whether the patient is sleeping or exercising? A photo of the product might help readers visualize it.

The reviewer is correct: the canopy was placed over the sleeping participant with effort to minimally disturb the participant. All participants were able to sleep under the canopy. We added a Figure of one of the investigators lying under the canopy to demonstrate its placement.

ADD TO METHODS: “When participants were sleeping, we were able to place the canopy with minimal disturbance other than requiring the participant to remain lying supine”.

ADD TO SUPPLEMENT:

S1 Fig.

ADD TO FIGURE LEGENDS:

“S1 Fig. This picture shows the canopy system used to collect exhaled breath for indirect calorimetry placed over one of the authors in the laboratory in the same configuration used for participants. Participants would lie supine under the canopy during testing for about one hour. When participants were sedated or sleeping, we were able to place the canopy over the participant with minimal disturbance aside from repositioning to supine. Participants could sleep or lie quietly throughout the data collection. For exercise testing at protocol hour 23, we used a traditional face mask to collect exhaled breath.”

Reviewer 2:

Please clarify why subcutaneous application has been used and additional oral intake rather than boli subcutaneously at the beginning. Please provide more information on pharmacokinetics, possibly from your earlier studies.

We selected the current dosing regimen based on prior studies [REFS 14-15] that examined sublingual loading doses of 1-4 µg/kg and subcutaneous infusions of 1 µg/kg/hr. Subcutaneous bolus doses are a great idea for an alternative regimen, but we have not tested this to date.

ADDED TO METHODS: “We selected drug doses and routes based on our prior studies that measured dexmedetomidine levels after 1-4 µg/kg oral boluses and continuous subcutaneous infusions of 1 µg/kg/hour [14,15]. We selected subcutaneous infusions rather than intravenous infusions as part of the technical requirement for minimally invasive and self-administered drug delivery. We predicted that the regimen in this protocol would achieve sedating levels of drug within 1-2 hours and that participants would be able to participate in testing or exercise about 4 hours after stopping drug..”

Did you screen for other medical conditions, e.g. liver cirrhosis, that can potentially influence the effect of dexmedetomidine? Despite there do not seem to be any group differences for baseline characteristics, please provide an appropriate statistic (Table 1) and add measurement units.

We recruited participants who self-reported themselves to be healthy, and who reported no other organ problems on the PAR-Q survey. After inclusion in the study, we obtained the baseline laboratory data in the Supplemental Table, which suggests no major laboratory abnormality. Specifically, there were no elevations of creatinine to suggest renal dysfunction or transaminases, canalicular enzymes, or bilirubin to suggest liver dysfunction.

ADDED TO SUPPLEMENTAL TABLE: AST, ALT, Alk Phos, Bilirubin, Prealbumin.

ADDED TO TABLE 1: Standardized mean differences for continuous variables and odds ratios for binary variable (sex).

ADDED TO RESULTS: “There were no large differences between characteristics of dexmedetomidine and placebo participants.”

Do you have any data if dexmedetomidine has the same effect in these exceptional situations compared to “normal” laboratory days where even “placebo” people have a lower resting rates?

We agree that the effect of the sedative drug might be more pronounced when participants are in stressful situations. The resting state in the laboratory may underestimate the baseline EE, VO2 and VCO2 prior to drug in those settings, but we are not aware of data directly addressing this.

ADDED TO DISCUSSION: “We measured baseline EE, VO2 and VCO2 during the resting state in the laboratory prior to drug administration, which may underestimate the resting metabolic rate that would be observed under stressful situations. Future studies might explore both the resting metabolic rate and any drug effect on metabolic rate in settings that more directly mimic the intended use cases”

However, if it is supposed to be used for a definite short amount of time, e.g. three days, would it make sense to increase dosage to maintain the goal of “hibernation”? Where would such scenarios of an infusion of sedating substances make sense (outside a defined ICU setting, which is not the aim of this study)? Please clarify what situations you aim for?

ADDED TO THE METHODS (mentioned above): “The technical requirements…”

ADD TO THE DISCUSSION:

“The purpose of this investigation was to determine whether a drug-induced decrease in metabolic rate could be maintained for multiple days in healthy humans. Such a reduction would be useful to conserve resources and reduce payload for long-duration spaceflight [6-8] or to improve survivability during long-duration rescues from catastrophic failure of life-support [4-5]. Our results indicate that the current regimen is insufficient for more than 3 days of metabolic suppression. Increasing the dose of drug over time or reducing the daily 6-hour drug interruption might increase the desired effect, but these interventions also would be expected to accelerate drug tolerance. This might worsen the withdrawal symptoms at the end of the study.”

State more clearly where you compare what timepoints and which groups. For example, it is hard to follow for the description of the results of Figure 1. Is the marginal reduction of VO2 relative to baseline RMR for day 1 or for all 5 days of follow-up (e.g. effects, 95%CI, of time epoch: 6 hour: -0.084 L/min, -0.145 to -0.023; 18 hour -0.072 L/min, -0.133 to -0.011)?

We added more clear statements at the opening of each paragraph of the Results to declare which comparisons the numbers describe. ADD TO RESULTS:

“When comparing the VO2 , VCO2 , and EE over the entire 5-day protocol to the baseline metabolic rate determined prior to any drug administration on day 1,…”.

AND

“Compared Relative to placebo participants on day 1, dexmedetomidine participants had lower VO2 (-28.7%), VCO2 (-37.2%), and EE (-30.3%) at 6 hours and lower VCO2 (-20.0%) at 18 hours (TABLE 2). “

AND

“When comparing the VO2 , VCO2 , and EE over the entire 5-day protocol to the metabolic rate predicted by anthropometric formulas, dexmedetomidine reduced total energy expenditure but not resting energy expenditure. “

Why did you apply dexmedetomidine for 18 hours and then pause for 6 hours and did not use any other time frames. Why was dexmedetomidine not infused continuously over five days without any breaks to test if metabolic rates could be reduced. This regimen was our first proof-of-concept test of metabolic suppression for multiple days in humans. We added to the methods the rationale for the design we selected. ADDED TO METHODS: “The study protocol was designed with technical requirements for application in a target spaceflight mission [6-8]. Specifically, we required (1) minimally invasive drug delivery that could potentially be self-administered, (2) daily sedation interruptions to allow participants to toilet, eat and self-care, and (3) time each day for exercise to maintain muscle health. The first two requirements eliminate the need for catheters, parenteral feeding or assisted hygiene. The third requirement represents the fixed cost of current countermeasures to microgravity-associated muscle loss. We tested 18 hours of drug administration, 5 hours of recovery and 1 hour of supervised exercise as the first version of this protocol.”

AND

“We selected drug doses and routes based on our prior studies that measured dexmedetomidine levels after 1-4 µg/kg oral boluses and continuous subcutaneous infusions of 1 µg/kg/hour [14,15]. We selected subcutaneous infusions rather than intravenous infusions as part of the technical requirement for minimally invasive and self-administered drug delivery. We predicted that the regimen in this protocol would achieve sedating levels of drug within 1-2 hours and that participants would be able to participate in testing or exercise about 4 hours after stopping drug.”

People have a rebound effect of about 2-3 days. How long does it take until you see an effect of the drug when starting the daily experiments and how long does it take until the drug wears off (based on clinical observations such as RAAS)? Does this change over the course of days? I ADDED TO RESULTS: “Figure 2 shows drug onset over days. Participants reported feeling subjective drug effects by 1 hour after starting infusions. On days 1 and 2, participants were sedated (RASS<-1) by 3 hours and heart rate decreased from 0 to 3 hours. First RASS scores and the numerical values of heart rate were higher on days 3-5. Recovery of heart rate and RASS from 18 to 21 hours did not appear to vary over days.”

Please provide an overview figure for the setup and the different timepoints. When does infusion start? When does it stop? When do people do exercise, etc. We added a figure of the study timeline and measurements.

ADDED SUPLEMENTAL FIGURE 2: Study Timeline

ADDED FIGURE LEGEND:

“Supplemental Figure 2. Timeline for drug administration and testing during daily protocol for A. Dexmedetomidine participants and B. Placebo participants. The daily protocol was repeated each day in dexmedetomidine participants and in one of the placebo participants. Time 0 was the time of drug start, which was typically between 10 am and noon local time. Indirect calorimetry to determine VO2, along with VCO2 and energy expenditure are indicated as “VO2.” Baseline indirect calorimetry was performed prior to drug administration on day 1. Plasma was collected to measure peak drug levels at the end of drug infusion (18 hours) and trough drug levels just prior to starting the next day drug (24 hours). In all subjects, heart rate, blood pressure, sedation scales (RASS), and pulse oximetry were measured during drug infusions and recovery. Dexmedetomidine participants were sedated to quiet resting or sleeping from hours 0 to 20. Placebo participants were not sedated but quietly resting in the laboratory from hours 0-12, until they went to sleep, typically from hours 12-20. We woke all participants at hour 20 and conducted supervised exercise beginning at hour 23. Indirect calorimetry at hour 23 was collected both while sitting quietly during the first 15 minutes of the supervised exercise, and during exercise.”

How often did the infusion need to be paused due to side effects? Is it only the one patient where infusion had to be reduced at the first day? Was the patient clinically symptomatic due to the bradycardia? Only one participant required infusion to be paused and reduced because of bradycardia. This pause was made solely based on the numerical value of the heart rate, which we chose a priori as a safety measure as described in the Methods. The participant had no symptoms or decrease in blood pressure.

ADD TO RESULTS:

“This pause was made solely based on the numerical value of the heart rate. The participant had no symptoms or decrease in blood pressure.“

and

“There were no episodes of hypotension or other events requiring treatment during infusions.”

Why was only one patient of the placebo group followed up over five days (and the others only one day)?

The primary design of this study was a single-arm comparison of baseline versus drug in the five participants. The additional placebo patients were enrolled as an add-on to explore how the laboratory setting alone affected the metabolic measurements. Unfortunately, we did not have funding for 5-day monitoring of all placebo participants. The one placebo participant who stayed for 5 days showed little day to day variation in measurements, suggesting to us that the one-day observations in the other placebo participants were representative.

DESCRIBED IN METHODS:

“This study was originally designed as a single-arm study in which every participant would receive drug, and drug effect would be quantified by the change in metabolic rate compared to baseline RMR. “

AND

“Placebo participants were added post hoc to clarify any laboratory-specific circadian or sleep-related changes in measures.”

Why was VCO2 increased after 23 hours at the last two days and not during the earlier days? Do you have any explanation why EE was not influenced?

This difference is likely a result of our small sample size. All of the variables, EE, VO2 and VCO2 were numerically higher on days 4 and 5 at 23 hours with mean values at or above the upper 95% confidence interval for the baseline values (dashed lines in Figure 1). Only the VCO2 increase achieved statistical significance on days 4 and 5 because the VCO2 values in the laboratory during sitting at 23 hours were already closer to the upper 95% confidence interval of the baseline VCO2. EE and VO2 values during sitting were closer to the mean baseline values. We suspect a larger sample size would have statistically confirmed the EE and VO2 increase.

We suspect that this increase in VCO2 (and the trend to an increase in EE and VO2) is an early sign of the rebound restlessness and sleep disruption that participants reported on the post-laboratory days. At a minimum, this pattern indicates that drug effects wore off more quickly and participants were less sedated by 23 hours on days 4 and 5 than they were on prior days.

ADDED TO DISCUSSION: “Even in the laboratory, VCO2 increased during sitting at 23 hours on days 4 and 5 (Figure 1). Though not statistically different, numerical values for mean VO2 and EE were also higher at 23 hours on days 4 and 5, and failure to detect increases in these variables may just be a result of the small number of participants. We suspect that this pattern of increasing metabolic rate at 23 hours is an early sign of the rebound restlessness that participants reported on the post-laboratory days. At a minimum, this pattern indicates that drug effects wore off more quickly and participants were less sedated by 23 hours on days 4 and 5 than they were on prior days.”

In the results section it is stated that VCO2 is increased after 18 hours for the last two days (instead of 23 hours as shown in Figure 1). The reviewer is correct that this is a mistake in our written description of FIGURE 1: the figure is correct. We correct our written description. CHANGE RESULTS: “VO2 and EE did not differ from baseline RMR during quiet sitting at 18 23 hours across days, but VCO2 was higher at 18 23 hours on days 4 and 5.”

Table 2: Include p-values and what statistical tests were used

ADDED TO Table 2 footnotes:

“* Placebo different from Dexmedetomidine, mean comparisons p<0.05

** Epoch Different from Baseline RMR, mean comparisons with Dunnett’s correction, p<0.05”

Please clarify why measured and predicted PMR was used and what the differences are. Table 3

ADD TO RESULTS:

Considering Table 4: Please mark for transparency reasons that the placebo group includes only one person at this point. For transparency, we add the number of participants in each group to the column headers in Table 4.

TABLE 4. We add numbers to the headers for the column “Dexmedetomidine (n=5)” and “Placebo (n=1)”

Unfortunately, Figure 3 is not included

We apologize this was not included in the original submission, and confirm that it is now correctly uploaded.

FIGURE 3 is now uploaded into the editorial system.

“5 completed a 5-day dexmedetomidine infusions and 1 participant completed a 5-day placebo infusion 5 completed 5 days of Dexdor, one had a family emergency and left one day early”. Therefore, it does not seem like 5 participants completed the 5 day infusions when 1 participant dropped out early.

The reviewer is correct: only 4/5 completed the 5 days of dexmedetomidine. We clarify this in the text.

RESULTS FIRST PARAGAPH CHANGE TO:” Of these, 5 began and 4 completed a 5-day dexmedetomidine infusion, but one 5-day dexmedetomidine participant had to leave the laboratory early on study day 4 because of a family emergency unrelated to the study. One participant completed a 5-day placebo infusion, and another 4 participants completed a 1-day placebo infusion.”

Double-check spelling and grammar throughout the manuscript Acknowledged.

Spelling and grammar checked.

How can you state that lower food intake was seen after dexmedetomidine infusion when no baseline was assessed? Was this compared to placebo? Or just a clinical observation

We did collect food diaries and appetite scales during a day in the week prior to the laboratory stay and during the laboratory stay. These data are complex to interpret because individuals varied greatly in usual diet and because both nausea and sleep affected reporting and eating. These data do not add directly to the current analysis of metabolic rate, and a full analysis and discussion would require a lot of space and be a distraction from the current paper. Therefore, we will save these observations as the topic of another report.

DELETED FROM RESULTS: “Participants had reduced appetite and food intake while receiving dexmedetomidine. “

Please specify your exercise protocol, i.e. as supplemental material.

We developed an exercise protocol that covered all muscle groups using a flywheel device and isometric device that have been used in spaceflight. We attach that protocol in the Supplemental Material and call it out in the Methods.

ADDED TO METHODS: “Participants completed a supervised exercise protocol between 23 and 24 hours using a flywheel-based resistance device (kBox, Exxentric North America Inc., Portland, OR) and a handheld isometric exercise device (KINVENT, Montpellier, France) (S1 Table).”

ADDED TO SUPPLEMENTAL MATERIAL: S1 Table. Exercise regimen

Please state limitations more clearly, and add that this is a small sample size and data is therefore, mainly hypothesis-generating

We added additional text to acknowledge the limitations.

ADDED TO DISCUSSION: “The largest limitation of this study is the small number of participants. The point estimates for metabolic rate and for drug effect on metabolic rate may lack precision. Nevertheless, the sample was sufficient to detect dexmedetomidine-induced reductions in EE and the development of drug tolerance. These data are sufficient to conclude that drug-induced metabolic reduction in humans is possible, and that future studies should explore different drugs or dosing regiments for long-term applications.

A second limitation of this study is that we measured baseline EE, VO2 and VCO2 during the resting state in the laboratory prior to drug administration, which may underestimate the resting metabolic rate that would be observed under stressful situations. Future studies might explore both the resting metabolic rate and any drug effect on metabolic rate in settings that more directly mimic the intended use cases.”

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PLoS One. doi: 10.1371/journal.pone.0359711.r003

Decision Letter 1

Vincenzo Lionetti

17 Sep 2026

<p>Dexmedetomidine effects on metabolic rate over 5 days in humans

PONE-D-26-31594R1

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PLoS One. doi: 10.1371/journal.pone.0359711.r004

Acceptance letter

Vincenzo Lionetti

PONE-D-26-31594R1

PLOS One

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Canopy for indirect calorimetry.

(TIFF)

pone.0359711.s001.tiff^{(19.2MB, tiff)}

S2 Fig. Protocol timeline.

(TIFF)

pone.0359711.s002.tiff^{(1MB, tiff)}

S3 Fig. Placebo EE, VO2, VCO2 over 5 days.

(TIFF)

pone.0359711.s003.tiff^{(1.2MB, tiff)}

S1 Table. Exercise protocol.

(DOCX)

pone.0359711.s004.docx^{(18.8KB, docx)}

S2 Table. Body weight, oral intake, serum and urine chemistry during dexmedetomidine infusion.

(DOCX)

pone.0359711.s005.docx^{(21.2KB, docx)}

Attachment

Submitted filename: PLOSone_Response to Reviews.docx

pone.0359711.s006.docx^{(35KB, docx)}

Data Availability Statement

All relevant data are available at the following DOI: https://doi.org/10.5281/zenodo.23082735.

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PERMALINK

Dexmedetomidine effects on metabolic rate over 5 days in humans

Clifton W Callaway

Alexandra J Weissman

Katharyn L Flickinger

Victor Wu

Jenna Monteleone

Ryann DeMaio

Mara Hierro

Daniel Neofes

Omarf Ortega-Reyes

Tao Sheng

Marianna Salinas

Paul Lerro

Francis X Guyette

Benjamin D H Gordon

Marie Mortreux

Kathleen Melanson

Daniel J Buysee

Philip E Empey

Roles

Abstract

Introduction

Materials and methods

Study design

Participants

Screening

Study days

Drug administration

Post-drug waking and exercise

Measurements

Indirect calorimetry

Safety parameters

Drug levels

Statistical analysis

Results

Table 1. Characteristics of participants.

Fig 1. EE, VO2, VCO2 after Dexmedetomidine Compared to Baseline RMR over 5 Days.

Table 2. Indirect calorimetry measurements on first day.

Table 3. Daily energy expenditure across all study days.

Table 4. Double labeled water estimate of total energy expenditure.

Fig 2. Sedation, temperature and heart rate after dexmedetomidine or placebo over 5 days.

Fig 3. Peak and trough dexmedetomidine levels over 5 days.

Discussion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Vincenzo Lionetti

Roles

Author response to Decision Letter 1

Decision Letter 1

Vincenzo Lionetti

Roles

Acceptance letter

Vincenzo Lionetti

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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