Stress-Mimicking Drugs for Cannabis Use Disorder

(COBRAS Trial)

Recruiting at 1 trial location

Overseen By Mallory Cannon, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Florida State University

Must not be taking: Psychotropics, ACE inhibitors, ARBs, others

Disqualifiers: Psychosis, Bipolar, Cardiovascular, others

Compensation: Varies

Number of Visits: 5

Duration: 10-22 days

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how stress-mimicking drugs affect the desire to use cannabis in individuals with Cannabis Use Disorder. It tests hydrocortisone (a corticosteroid) and yohimbine (an alpha-2 adrenergic receptor antagonist), both separately and combined, to assess their impact on cannabis motivation and the body's natural cannabinoids. Participants will visit the lab four times to take the drugs and complete various tasks and interviews. The trial suits those who use cannabis almost daily and are generally healthy. As an Early Phase 1 trial, this research aims to understand how these treatments work in people, offering participants a chance to contribute to groundbreaking research.

Do I have to stop taking my current medications for the trial?

Yes, you will need to stop taking certain medications, especially if you are on daily psychotropic medications or specific heart and blood pressure medications like ACE inhibitors, ARBs, and beta-blockers.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Past research has used hydrocortisone to treat conditions like allergies and skin problems. It is generally safe but can worsen some infections. People should avoid using it for fungal infections unless approved by a doctor.

Yohimbine, however, presents more safety concerns. Studies have shown it can cause side effects such as irregular heartbeat, high blood pressure, anxiety, and nervousness. It is crucial to use yohimbine carefully and only under a doctor's guidance.

This trial is in its early stage, primarily assessing whether the treatments are safe and tolerated by people. While hydrocortisone is known for its safety, yohimbine is associated with several side effects. Participants should be aware of these potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the potential of using hydrocortisone and yohimbine hydrochloride for treating Cannabis Use Disorder because these treatments approach the issue from a unique angle. Unlike standard treatments that typically focus on behavioral therapy or medications targeting withdrawal symptoms, hydrocortisone and yohimbine mimic stress hormones, potentially altering the brain's response to cravings. This new mechanism of action could provide an innovative way to reduce reliance on cannabis by intervening in the body's stress pathways. By targeting the physiological aspects of addiction, these treatments might offer a new avenue for those struggling with cannabis dependency.

What evidence suggests that this trial's treatments could be effective for Cannabis Use Disorder?

This trial will evaluate the effects of hydrocortisone and yohimbine on Cannabis Use Disorder by mimicking stress. Participants in different arms of the trial will receive either hydrocortisone, yohimbine, a combination of both, or placebos. Research has shown that yohimbine causes stress reactions, which might help researchers understand how stress influences cannabis use. Some studies have also examined yohimbine for other purposes, such as weight loss and stress response, but its role in treating cannabis use remains under investigation. Hydrocortisone, a hormone that can also imitate stress, has an unknown effect on cannabis use motivation. Overall, the current understanding of these drugs in treating Cannabis Use Disorder focuses on their ability to mimic stress. ^{6 7 8 9 10}

Who Is on the Research Team?

Richard J Macatee, PhD

Principal Investigator

Florida State University

Are You a Good Fit for This Trial?

This trial is for individuals with severe Cannabis Use Disorder who use cannabis daily, can provide a THC-positive urine sample, and are able to understand the study's risks. They must be fluent in English and give written consent. People not meeting these criteria or having conditions that could interfere with the study cannot participate.

Inclusion Criteria

I use cannabis every day.

I can read and write in English.

I understand the study's risks and have signed the consent form.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person or by phone)

Treatment

Participants visit the lab four times to take one of four drug combinations, complete interviews, questionnaires, and computerized tasks, have their brain activity recorded with an EEG cap, and provide three blood samples

10-22 days

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Hydrocortisone Oral
• Yohimbine Hydrochloride

Trial Overview The study tests how two drugs (Hydrocortisone Oral and Yohimbine Hydrochloride) that mimic stress affect cannabis use motivation and the body's natural cannabinoids. It compares their effects both alone and combined against placebos over four lab visits involving interviews, tasks, EEG brain activity recording, and blood samples.

How Is the Trial Designed?

Group I: 20mg hydrocortisone + 54mg yohimbine hcl Experimental Treatment 2 Interventions

20mg hydrocortisone, single oral dose 54mg yohimbine hcl, single oral dose

Group II: 20mg hydrocortisone + 54mg placebo Experimental Treatment 2 Interventions

20mg hydrocortisone, single oral dose 54mg cornstarch placebo, single oral dose

Group III: 20mg placebo + 54mg yohimbine hcl Active Control 2 Interventions

20mg cornstarch placebo, single oral dose 54mg yohimbine hcl, single oral dose

Group IV: 20mg placebo + 54mg placebo Placebo Group 2 Interventions

20mg cornstarch placebo, single oral dose 54mg cornstarch placebo, single oral dose

Who Is Running the Clinical Trial?

Florida State University

Lead Sponsor

Trials

234

Recruited

41,100+

Wayne State University

Collaborator

Trials

318

Recruited

111,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Auburn University

Collaborator

Trials

81

Recruited

14,600+

Published Research Related to This Trial

In a study involving nine normal volunteers, intravenous administration of low-dose yohimbine significantly increased plasma norepinephrine and cortisol levels, indicating its effectiveness in probing alpha 2-adrenergic receptor function.

Yohimbine also led to significant increases in systolic blood pressure and somatic symptoms, suggesting its impact on the hypothalamic-pituitary-adrenal axis and overall physiological responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous yohimbine. Selective enhancer of norepinephrine and cortisol secretion and systolic blood pressure in humans. Grunhaus, L., Tiongco, D., Zelnik, T., et al.[2019]

Yohimbine increases alcohol self-administration and reinstates alcohol-seeking behavior in rats, indicating its potential role in promoting addictive behaviors.

The CRF1 receptor antagonist antalarmin effectively attenuates the effects of yohimbine on alcohol self-administration and relapse, suggesting that targeting CRF1 receptors may be a promising strategy for treating alcohol addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Marinelli, PW., Funk, D., Juzytsch, W., et al.[2022]

Yohimbine, an alpha-2 adrenoreceptor antagonist, activates specific brain regions associated with stress, particularly the cortico-striato-thalamic areas, as shown through functional MRI in rats.

The study reveals that norepinephrine and dopamine play significant roles in yohimbine's effects, and that different neuropeptide systems, specifically CRF1R and OX1R, modulate stress responses through distinct neural pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine. Gozzi, A., Lepore, S., Vicentini, E., et al.[2021]

Both the CB1-receptor inverse agonist rimonabant and the neutral antagonist AM4113 effectively reduced drug-taking behavior and relapse cues related to nicotine and THC in squirrel monkeys, indicating their potential as treatments for tobacco and cannabis dependence.

Unlike rimonabant, AM4113 may offer a safer alternative for managing substance dependence without affecting behaviors reinforced by cocaine or food, suggesting a more targeted approach to treating addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys. Schindler, CW., Redhi, GH., Vemuri, K., et al.[2019]

Yohimbine, an alpha(2)-adrenoceptor antagonist, was found to significantly reinstate cocaine-seeking behavior in squirrel monkeys, indicating its role in stress-induced relapse, with effects observed regardless of the presence of cocaine-related cues.

The study also demonstrated that yohimbine increased physiological and behavioral stress markers, such as elevated cortisol levels and increased grooming behaviors, suggesting that noradrenergic mechanisms are involved in the stress response related to drug seeking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Lee, B., Tiefenbacher, S., Platt, DM., et al.[2015]

In a study involving 40 patients with major depression and 16 healthy controls, the alpha 2-adrenergic receptor antagonist yohimbine was found to significantly increase cortisol levels in depressed patients, indicating a heightened HPA axis response compared to healthy individuals.

The results suggest that patients with depression may have a subsensitivity of postsynaptic alpha 2-adrenergic receptors, as evidenced by their exaggerated cortisol response to yohimbine, which could be linked to the neurotransmitter imbalances associated with depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine. Price, LH., Charney, DS., Rubin, AL., et al.[2019]

In a study with rats, the anxiogenic drug yohimbine significantly increased cocaine-seeking behavior when combined with drug-associated cues, showing a 10-13 times higher response compared to extinction levels.

The findings suggest that stress and drug cues interact to enhance cravings for cocaine, indicating that effective treatment strategies for addiction should address both stress and cue exposure simultaneously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine. Feltenstein, MW., See, RE.[2013]

In a study involving 12 daily cannabis users, tiagabine (12 mg/day) did not significantly reduce cannabis self-administration or alter the effects of cannabis, suggesting it may not be an effective treatment for cannabis use disorder (CUD).

Participants experienced some negative effects from tiagabine, including increased cravings for cannabis and reduced sleep quality, indicating that tiagabine may not be a suitable stand-alone therapy for CUD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of tiagabine maintenance on cannabis effects and related behaviors in daily cannabis users. Wesley, MJ., Westgate, PM., Stoops, WW., et al.[2020]

Chronic exposure to THC during adolescence in rats led to increased anxiety-like behavior, suggesting that THC may have lasting effects on mental health.

Rats treated with THC showed a heightened vulnerability to relapse into heroin seeking behavior as adults, indicating that early THC exposure may increase the risk of addiction to other substances later in life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats. Stopponi, S., Soverchia, L., Ubaldi, M., et al.[2014]

In a study with male Long-Evans rats trained to self-administer cocaine, it was found that blocking dopamine D1/5 receptors effectively prevented the reinstatement of cocaine-seeking behavior induced by the stressors corticotropin-releasing factor (CRF) and yohimbine.

The results indicate that the reinstatement of cocaine seeking is specifically mediated by D1/5 receptor transmission, while D2/3 receptors do not play a significant role in this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reinstatement of cocaine seeking in rats by the pharmacological stressors, corticotropin-releasing factor and yohimbine: role for D1/5 dopamine receptors. Brown, ZJ., Kupferschmidt, DA., Erb, S.[2021]

Yohimbine, an α2-adrenoceptor antagonist, activates specific brain regions associated with stress and impulsivity, which may contribute to alcohol seeking behavior in abstinent rats, highlighting its role in stress-induced relapse.

The study found that yohimbine administered in a non-drug context primarily activated the prefrontal cortex and extended amygdala, while in a drug-associated context, it engaged additional brain regions, suggesting different neural mechanisms depending on the context of administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pattern of neural activation following yohimbine-induced reinstatement of alcohol seeking in rats. Walker, LC., Kastman, HE., Lawrence, AJ.[2021]

Citations

1. withpower.com withpower.com/trial/early-phase-1-cannabis-use-disorders-7-2024-1df45

Stress-Mimicking Drugs for Cannabis Use Disorder The research does not provide direct evidence supporting the effectiveness of Hydrocortisone Oral and Yohimbine Hydrochloride for treating Cannabis Use Disorder ...

2. cannabisevidence.org cannabisevidence.org/registered-ongoing-studies/

Registered Ongoing Studies Despite strong indicators of the efficacy of this CM intervention, there remained room for improvement in increasing rates of treatment response and reducing ...

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/portal/utils/pageresolver.fcgi?recordid=68a7563bb42eb438be6878db

3-[2(S) - NCBI No information is available for this page.

4. go.drugbank.com go.drugbank.com/conditions/DBCOND0039373

Cannabis Use Disorders (DBCOND0039373) Associated Data ; NCT05765409. Assessment of the Effectiveness of an Integrative Therapy for Cannabis Misuse in Adolescents, No drug interventions ; NCT02932215.

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/72/NCT04737772/Prot_SAP_000.pdf

A Brief Behavioral Intervention for Quitline Callers Who ... If successful, this study could lead to improved tobacco cessation outcomes for those who also use cannabis, which would lead to improved health and longer ...

6. imgcdn.mckesson.com imgcdn.mckesson.com/CumulusWeb/Click_and_learn/SDS_9PFIZ_SOLU-CORTEF_AOV_VL.pdf

SAFETY DATA SHEET Precautionary Statements: P201 - Obtain special instructions before use. P202 - Do not handle until all safety precautions have been read and understood.

7. labeling.pfizer.com labeling.pfizer.com/showlabeling.aspx?id=641

SOLU-CORTEF® (hydrocortisone sodium succinate ... Corticosteroids, including SOLU-CORTEF, may exacerbate systemic fungal infections; therefore, avoid SOLU-CORTEF use in the presence of such infections unless ...

8. drugs.com drugs.com/mtm/solu-cortef-injection.html

Solu-CORTEF injection Uses, Side Effects & Warnings Solu-CORTEF is a steroid medicine that is used in the treatment of many different conditions, including allergic disorders, skin conditions, ulcerative colitis ...

9. rxlist.com rxlist.com/solu-cortef-drug.htm

Solu Cortef (Hydrocortisone Sodium Succinate) Solu Cortef (Hydrocortisone Sodium Succinate) may treat, side effects, dosage, drug interactions, warnings, patient labeling, reviews, ...

10. webmd.com webmd.com/drugs/2/drug-6731-581/hydrocortisone-oral/hydrocortisone-oral/details

Hydrocortisone: Uses, Side Effects, Interactions, Pictures, ... Hydrocortisone is used to treat a variety of inflammatory, autoimmune, and hormonal conditions. It works by suppressing the body's immune response and reducing ...