Regulation of Energy ExpenditureEarly Phase 1NCT07030725
Menthol Stimulation of Brown Adipose Tissue in Humans: Aim 1
A Early Phase 1 study testing Menthol Gel in people with Regulation of Energy Expenditure, run by Indiana University at 1 site in United States.
Trial summary
Brown adipose tissue becomes activated during cold conditions to increase thermogenesis (i.e., energy expenditure). Topical menthol application increases resting energy expenditure but it is unclear whether brown adipose tissue activation contributes to this rise in the energy expenditure. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Regulation of Energy Expenditure
- What is being tested?
- Menthol Gel
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Mar 2025to 9 Jun 2025
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Fluency in English
- Participate in 150 minutes or more of at least moderate intensity exercise per week during the previous year. Assessment of moderate intensity physical activity will be determined via the International Physical Activity Questionnaire (i.e., IPAQ) (described in detail in Section 7.0). This questionnaire defines moderate intensity exercise as "activities that take moderate physical effort and make you breathe somewhat harder than normal".
- Body fat ≤ 30% as determined by DEXA scan
- Be cleared for physical activity according to the 2020 Physical Activity Readiness Questionnnaire (PAR-Q+).
Who cannot join
- Any autonomic cardiovascular, metabolic, neurologic, endocrine, or respiratory disease, that, in the opinion of the investigator, would exclude them from participation.
- Previously diagnosed liver and/or kidney dysfunction, including, but not limited to, acute and/or chronic kidney disease, cirrhosis, hepatitis, and fatty liver disease.
- Women who are pregnant or breastfeeding.
- Current use of tobacco or electronic cigarette, or regular (i.e., more than twice a week) use within the last 1 year.
- History of peripheral cold injury, skin disorder (eczema, psoriasis), or excessive tattooing.
- Known chronic (i.e., cancer, surgery) or acute conditions (i.e., diarrhea, constipation) of the rectum.
Show all 20Show fewer
- Menthol allergy (described in detail in Section 7.0 and 9.0). Menthol can cause skin irritation when applied topically, especially for people with sensitive skin or allergies. For this reason, recruited participants will be screened for a menthol allergy during the informed consent/screening visit. We will apply a small quantity of the cream (~2ml) to an isolated body area to limit skin exposure. In the case a rash develops during the application of the cream, research staff will irrigate the area to remove the substance and limit further exposure. A 24-hour follow-up phone call initiated by research staff will be implemented to follow-up on all adverse reactions. Detectable BAT activation during a localized cold stress test (i.e., face cooling test) (procedure described in detail in Section 7.0).
- Using medications with direct effects on the cardiovascular system including, but not limited to:
- Anticoagulants.
- Antiplatelet agents.
- ACE Inhibitors.
- Angiotensin II receptor blockers.
- Angiotensin-receptor neprilysin inhibitors.
- Beta blockers.
- Calcium, potassium, or sodium channel blockers.
- Cholesterol lowering medications.
- Digitalis preparations.
- Diuretics.
- Vasodilators.
- Anticholinergics.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Targeted TRPM8 Stimulation and Brown Adipose Tissue Activation in Humans
Brown adipose tissue becomes activated during cold conditions to increase thermogenesis (i.e., energy expenditure). Topical menthol application increases resting energy expenditure but it is unclear whether brown adipose tissue activation contributes to this rise in the energy expenditure. The overall goal with this project is to determine whether topical menthol application stimulates brown adipose tissue.
Read the detailed description
Brown adipose tissue (BAT) is an important organ in the regulation of energy balance, particularly in small mammals and infants. Until recently, BAT was thought to be nonexistent and thus metabolically irrelevant in adult humans, primarily due to the lack of methods capable of localizing and measuring its metabolic contribution. Since its discovery in adult humans, various reports have shown that BAT can be activated in response to cold exposure to increase non-shivering thermogenesis (NST). NST results primarily from the expression of uncoupling protein 1 (UCP1) in BAT, dissipating the energy of the proton motive force as heat, thus uncoupling it from mitochondrial respiration. Notably, activation of BAT augments glucose uptake, improving glucose regulation and insulin sensitivity. Whereas mild cold exposure and beta-3-adrenergic pharmacological stimulation have previously been used to augment BAT-induced thermogenesis, recent investigations have proposed novel methods for UCP1 expression.
Menthol, a chemical cooling agent naturally produced from mint oils, elicits a cold sensation when topically applied to the skin and is used clinically as a pain analgesic. This sensation is derived from the activation of cold-sensitive receptors known as transient receptor potential melastatin 8 (TRPM8), a primary sensor of thermal stimuli in the peripheral nervous system. While TRPM8 is predominately located on the cell membrane of sensory neurons, its expression has been recently detected on BAT, highlighting a potential alternative avenue for stimulating this highly thermogenic tissue. Previous reports have alluded to menthol's potential as a vehicle for BAT activation. Vizin et. al observed a persistent increase in energy expenditure following a short-term topical menthol intervention in a rodent model. Moreover, Valente et. al observed an increase in metabolic rate in humans following a single administration of menthol to the skin surface of the neck and of the right arm and leg. While both groups attribute their findings to menthol-induced BAT activation, there were no markers of BAT activation utilized in their investigations. Therefore, there is a significant scientific gap in the understanding of menthol-induced thermogenesis.
Despite the promising thermogenic potential of topical menthol application, the previously reported increase in metabolic rate may be attributed to other forms of thermogenesis, such as shivering thermogenesis and NST in skeletal muscle. Furthermore, methodological differences regarding application site/area, dosage of menthol, evaporative potential of the skin, and resting vasomotor tone complicate most studies in this field, providing limited clarity on the link between TRPM8 stimulation and UCP1-dependent NST. Due to this, proper characterization of menthol's influence, specifically on physiological responses that contribute to human thermoregulation, is warranted.
Specific Aim: Determine the specific thermogenic mechanism(s) underlying the increase in energy expenditure evoked by menthol induced TRPM8 activation.
Hypothesis: Topical menthol application to the anterior aspect of the thorax will increase thermogenesis (i.e., resting energy expenditure) via activation of BAT (i.e., supraclavicular skin temperature; indirect-noninvasive measure of BAT activity) and augmentation of skeletal muscle blood flow (i.e., estimated via changes in limb blood flow) versus application of a sham cream.
- Conditions
- Regulation of Energy Expenditure
- Being tested
- Menthol Gel, Sham, Time control
- Keywords
- menthol, brown adipose tissue, energy expenditure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Menthol GelDrug
Menthol (5% L-menthol) will be applied to the anterior thorax.
ShamDrug
Sham gel applied to the anterior thorax.
Time controlBehavioural
No gel applied to anterior thorax.
| Study group | Role | What they receive |
|---|---|---|
| Menthol | Experimental | Menthol (5% L-menthol) applied to the anterior upper body, excluding the arms, head, and neck. Receives: Drug: Menthol Gel |
| Sham | Sham comparator | A sham cream applied to the anterior upper body, excluding the arms, head, and neck. Receives: Drug: Sham |
| Time control | Other | No cream applied to the anterior upper body. Receives: Behavioral: Time control |
What is being measured
The primary outcome is the main question the study is designed to answer.
Resting energy expenditure
kcal/min
Measured: from prior to the interventions to 1 hour and 2 hours post gel application
Infrared thermography supraclavicular skin temperature
temperature in degrees C
Measured: from prior to the interventions to 1 hour and 2 hours post gel application
Shivering via electromyography
a percent of maximal activity
Measured: from prior to the interventions to 1 hour and 2 hours post gel application
Secondary outcomes (4)
Body temperatures
Combined intestinal and skin temperatures in degrees C
Measured: from prior to the interventions to 1 hour and 2 hours post gel application
Skin blood flow
red blood cell flux
Measured: from prior to the interventions to 1 hour and 2 hours post gel application
Cardiovascular measurements
heart rate in beats/min and blood pressure in millimeters of mercury
Measured: from prior to the interventions to 1 hour and 2 hours post gel application
Thermal perceptions
assessed using Likert Scales thermal discomfort (1=comfortable; 4=very uncomfortable) and thermal sensation (1=cold; 4=neutral; 7=hot)
Measured: from prior to the interventions to 1 hour and 2 hours post gel application
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jun 2025
- Study start27 Mar 2025
- Primary completion9 Jun 2025
- Study completion9 Jun 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Regulation of Energy ExpenditureStudies of the same condition, open and under way.
- More trials run by Indiana UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Blair D. Johnson, PhD, Indiana University
- Investigators
- Blair D Johnson, PhD, Principal investigator, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07030725
- Sponsor's protocol ID
- 24695
- Status last verified
- Aug 2026
- First submitted
- 7 Mar 2025
- Last updated
- 6 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeted TRPM8 Stimulation and Brown Adipose Tissue Activation in Humans
- ClinicalTrials.gov ID
- NCT07030725
- Acronym / sponsor ID
- 24695
- Conditions
- Regulation of Energy Expenditure
- Keywords
- menthol, brown adipose tissue, energy expenditure
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Study start
- 27 Mar 2025 (actual)
- Primary completion
- 9 Jun 2025 (actual)
- Study completion
- 9 Jun 2025 (actual)
- First posted
- 22 Jun 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Brown adipose tissue becomes activated during cold conditions to increase thermogenesis (i.e., energy expenditure). Topical menthol application increases resting energy expenditure but it is unclear whether brown adipose tissue activation contributes to this rise in the energy expenditure. The overall goal with this project is to determine whether topical menthol application stimulates brown adipose tissue.
Detailed description
Brown adipose tissue (BAT) is an important organ in the regulation of energy balance, particularly in small mammals and infants. Until recently, BAT was thought to be nonexistent and thus metabolically irrelevant in adult humans, primarily due to the lack of methods capable of localizing and measuring its metabolic contribution. Since its discovery in adult humans, various reports have shown that BAT can be activated in response to cold exposure to increase non-shivering thermogenesis (NST). NST results primarily from the expression of uncoupling protein 1 (UCP1) in BAT, dissipating the energy of the proton motive force as heat, thus uncoupling it from mitochondrial respiration. Notably, activation of BAT augments glucose uptake, improving glucose regulation and insulin sensitivity. Whereas mild cold exposure and beta-3-adrenergic pharmacological stimulation have previously been used to augment BAT-induced thermogenesis, recent investigations have proposed novel methods for UCP1 expression.
Menthol, a chemical cooling agent naturally produced from mint oils, elicits a cold sensation when topically applied to the skin and is used clinically as a pain analgesic. This sensation is derived from the activation of cold-sensitive receptors known as transient receptor potential melastatin 8 (TRPM8), a primary sensor of thermal stimuli in the peripheral nervous system. While TRPM8 is predominately located on the cell membrane of sensory neurons, its expression has been recently detected on BAT, highlighting a potential alternative avenue for stimulating this highly thermogenic tissue. Previous reports have alluded to menthol's potential as a vehicle for BAT activation. Vizin et. al observed a persistent increase in energy expenditure following a short-term topical menthol intervention in a rodent model. Moreover, Valente et. al observed an increase in metabolic rate in humans following a single administration of menthol to the skin surface of the neck and of the right arm and leg. While both groups attribute their findings to menthol-induced BAT activation, there were no markers of BAT activation utilized in their investigations. Therefore, there is a significant scientific gap in the understanding of menthol-induced thermogenesis.
Despite the promising thermogenic potential of topical menthol application, the previously reported increase in metabolic rate may be attributed to other forms of thermogenesis, such as shivering thermogenesis and NST in skeletal muscle. Furthermore, methodological differences regarding application site/area, dosage of menthol, evaporative potential of the skin, and resting vasomotor tone complicate most studies in this field, providing limited clarity on the link between TRPM8 stimulation and UCP1-dependent NST. Due to this, proper characterization of menthol's influence, specifically on physiological responses that contribute to human thermoregulation, is warranted.
Specific Aim: Determine the specific thermogenic mechanism(s) underlying the increase in energy expenditure evoked by menthol induced TRPM8 activation.
Hypothesis: Topical menthol application to the anterior aspect of the thorax will increase thermogenesis (i.e., resting energy expenditure) via activation of BAT (i.e., supraclavicular skin temperature; indirect-noninvasive measure of BAT activity) and augmentation of skeletal muscle blood flow (i.e., estimated via changes in limb blood flow) versus application of a sham cream.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Menthol | Experimental | Drug: Menthol GelMenthol (5% L-menthol) applied to the anterior upper body, excluding the arms, head, and neck. |
| Sham | Sham comparator | Drug: ShamA sham cream applied to the anterior upper body, excluding the arms, head, and neck. |
| Time control | Other | Behavioral: Time controlNo cream applied to the anterior upper body. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Fluency in English
- Participate in 150 minutes or more of at least moderate intensity exercise per week during the previous year. Assessment of moderate intensity physical activity will be determined via the International Physical Activity Questionnaire (i.e., IPAQ) (described in detail in Section 7.0). This questionnaire defines moderate intensity exercise as "activities that take moderate physical effort and make you breathe somewhat harder than normal".
- Body fat ≤ 30% as determined by DEXA scan
- Be cleared for physical activity according to the 2020 Physical Activity Readiness Questionnnaire (PAR-Q+).
Key exclusion criteria (20 listed)
- Any autonomic cardiovascular, metabolic, neurologic, endocrine, or respiratory disease, that, in the opinion of the investigator, would exclude them from participation.
- Previously diagnosed liver and/or kidney dysfunction, including, but not limited to, acute and/or chronic kidney disease, cirrhosis, hepatitis, and fatty liver disease.
- Women who are pregnant or breastfeeding.
- Current use of tobacco or electronic cigarette, or regular (i.e., more than twice a week) use within the last 1 year.
- History of peripheral cold injury, skin disorder (eczema, psoriasis), or excessive tattooing.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Menthol GelMenthol (5% L-menthol) will be applied to the anterior thorax. | Drug | Menthol |
| ShamSham gel applied to the anterior thorax. | Drug | Sham |
| Time controlNo gel applied to anterior thorax. | Behavioural | Time control |
Primary outcome
Resting energy expenditure
Time frame: from prior to the interventions to 1 hour and 2 hours post gel application
kcal/min
Infrared thermography supraclavicular skin temperature
Time frame: from prior to the interventions to 1 hour and 2 hours post gel application
temperature in degrees C
Shivering via electromyography
Time frame: from prior to the interventions to 1 hour and 2 hours post gel application
a percent of maximal activity
4 secondary outcomes
Body temperatures
Time frame: from prior to the interventions to 1 hour and 2 hours post gel application
Skin blood flow
Time frame: from prior to the interventions to 1 hour and 2 hours post gel application
Cardiovascular measurements
Time frame: from prior to the interventions to 1 hour and 2 hours post gel application
Thermal perceptions
Time frame: from prior to the interventions to 1 hour and 2 hours post gel application
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2026.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Blair D Johnson, PhD principal investigator
Indiana University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Menthol Gel in people with Regulation of Energy Expenditure, run by Indiana University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Resting energy expenditure (time frame: from prior to the interventions to 1 hour and 2 hours post gel application). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2026.