Behavioral Pharmacology of Orally Administered THC and D-limonene

The current clinical trial will investigate the effects of orally administered d-limonene (limonene), delta-9-tetrahydrocannabinol (THC) and the combination in healthy adult volunteers.

Study Overview

• Status: Recruiting
• Conditions: THC; Subjective Drug Effects; D-limonene
• Intervention / Treatment: Drug: Placebo; Drug: Delta-9-THC; Drug: D-Limonene

Detailed Description

The current clinical trial will investigate the interaction of orally administered d-limonene (limonene) and delta-9-tetrahydrocannabinol (THC). Limonene is a flavor/fragrance component common to many plants, including cannabis. The investigators have previously demonstrated that vaporized limonene can impact the acute effects of THC. The purpose of this study is to examine whether orally administered limonene modulates the acute effects of orally co-administered THC in a manner similar to when these substances are inhaled A controlled laboratory study will be completed at Johns Hopkins evaluating placebo, THC alone, and four ascending doses of d-limonene in combination with THC. Participants will be healthy adults with experience using cannabis. A total of 6 outpatient drug administration sessions will be conducted for each evaluable participant. The investigators will recruit study volunteers until 20 participants complete the protocol.

• Study Type: Interventional
• Enrollment (Estimated): 65
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Austin Zamarripa, PhD; Phone Number: 410-550-6969; Email: czamarr2@jhmi.edu
• Study Contact Backup: Name: Lauren S Pollak, MSc; Phone Number: 410-550-0586; Email: lschoen7@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Recruiting
      • Johns Hopkins Behavioral Pharmacology Research Unit
      • Contact: Austin Zamarripa
      • Principal Investigator: Austin Zamarripa, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Have provided written informed consent
• Be between the ages of 21 and 55
• Be in good general health based on a physical examination, medical history, vital signs, and screening urine and blood tests
• Test negative for drugs of abuse other than cannabis, including breath alcohol at the screening visit and at clinic admission
• Not be pregnant or nursing (if female). All females must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test at clinic admission.
• Have a body mass index (BMI) in the range of 18 to 36 kg/m2
• Blood pressure at Screening Visit does not exceed a systolic blood pressure (SBP) of 150 mmHg or a diastolic blood pressure (DBP) of 90 mmHg
• Have no allergies to any of the ingredients used to prepare (cellulose, THC, d-limonene).
• Report having used a high THC cannabis product in the past 3 years and having experienced anxiety after consuming cannabis at least once in lifetime.

Exclusion Criteria:

• Non-medical use of psychoactive drugs other than, nicotine, alcohol, or caffeine 3 month prior to the Screening Visit;
• History of or current evidence of significant medical (e.g. seizure disorder) or psychiatric illness (e.g. psychosis) judged by the investigator to put the participant at greater risk of experiencing an adverse event due to exposure or completion of other study procedures.
• Use of an over the counter (OTC), systemic or topical drug(s), herbal supplement(s), or vitamin(s) within 14 days of experimental sessions; which, in the opinion of the investigator or sponsor, will interfere with the study result or the safety of the subject.
• Use of a prescription medication (with the exception of birth control prescriptions) within 14 days of experimental sessions; which, in the opinion of the investigator or sponsor, will interfere with the study result or the safety of the subject.
• Average use of cannabis more than 2 times per week in the prior 3 months.
• History of clinically significant cardiac arrhythmias or vasospastic disease (e.g., Prinzmetal's angina).
• Enrolled in another clinical trial or have received any drug as part of a research study within 30 days prior to dosing.
• Individuals with anemia or who have donated blood in the prior 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Oral Placebo; Placebo (cellulose), via capsule	Drug: Placebo; Placebo (cellulose) administered via capsule
Experimental: Oral THC 30mg; 30mg pure THC in ethanol vehicle, via capsule	Drug: Delta-9-THC; Oral delta-9-THC in ethanol vehicle administered via capsule; Other Names: THC
Experimental: Oral THC 30mg + D-Limonene 25mg; 30mg pure THC in ethanol vehicle, via capsule 25mg pure D-Limonene, via capsule	Drug: Delta-9-THC; Oral delta-9-THC in ethanol vehicle administered via capsule; Other Names: THC; Drug: D-Limonene; Oral Limonene administered via capsule
Experimental: Oral THC 30mg + D-Limonene 50mg; 30mg pure THC in ethanol vehicle, via capsule 50mg pure D-Limonene, via capsule	Drug: Delta-9-THC; Oral delta-9-THC in ethanol vehicle administered via capsule; Other Names: THC; Drug: D-Limonene; Oral Limonene administered via capsule
Experimental: Oral THC 30mg + D-Limonene 100mg; 30mg pure THC in ethanol vehicle, via capsule 100mg pure D-Limonene, via capsule	Drug: Delta-9-THC; Oral delta-9-THC in ethanol vehicle administered via capsule; Other Names: THC; Drug: D-Limonene; Oral Limonene administered via capsule
Experimental: Oral THC 30mg + D-Limonene 200mg; 30mg pure THC in ethanol vehicle, via capsule 200mg pure D-Limonene, via capsule	Drug: Delta-9-THC; Oral delta-9-THC in ethanol vehicle administered via capsule; Other Names: THC; Drug: D-Limonene; Oral Limonene administered via capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective Drug Effect as assessed by Visual Analog Scale	Subjective drug effect will be measured on a 100 point visual analog scale (VAS) where 0 = no drug effect and 100 = strongest drug effect imaginable	8 hours after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective Drug Liking as assessed by Visual Analog Scale	Subjective drug liking will be measured on a 100 point visual analog scale (VAS) where 0 = no drug effect and 100 = strongest drug effect imaginable	8 hours after dosing
Subjective anxiety as assessed by Visual Analog Scale	Subjective anxiety will be measured on a 100 point visual analog scale (VAS) where 0 = no drug effect and 100 = strongest drug effect imaginable	8 hours after dosing
Subjective hunger as assessed by Visual Analog Scale	Subjective hunger will be measured on a 100 point visual analog scale (VAS) where 0 = no drug effect and 100 = strongest drug effect imaginable	8 hours after dosing
Subjective paranoia as assessed by Visual Analog Scale	Subjective paranoia will be measured on a 100 point visual analog scale (VAS) where 0 = no drug effect and 100 = strongest drug effect imaginable	8 hours after dosing

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Austin Zamarripa, PhD, Johns Hopkins School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2025
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: April 18, 2024
• First Submitted That Met QC Criteria: April 18, 2024
• First Posted (Actual): April 23, 2024

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Cannabinoids; Cyclohexane Monoterpenes; Monoterpenes; Dronabinol; Limonene
• Other Study ID Numbers: IRB00436545

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No