Stress-Mimicking Drugs for Cannabis Use Disorder

(COBRAS Trial)

Overseen By Julia Gorday, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Auburn 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

Trial Summary

What is the purpose of this trial?

The goal of this study is to test the impact of two drugs that produce temporary stress-like symptoms, both in isolation and together, on cannabis use motivation in individuals with Cannabis Use Disorder. The main questions it will answer are: 1. How do different forms of stress affect cannabis use motivation? 2. How do different forms of stress affect the body's natural cannabinoids? Researchers will compare a placebo to both drugs in isolation, as well as together, across four separate lab visits. Participants will: 1) Complete a clinical screening interview (by phone or in-person) and visit the lab for a medical screening, and if eligible: a) Visit the lab four times where they will: i). Take one of four drug combinations ii). Complete an interview, questionnaires, and computerized tasks iii). Have their brain activity recorded with an EEG cap iv). Provide three blood samples

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.

What data supports the effectiveness of the drug Hydrocortisone Oral and Yohimbine Hydrochloride for treating Cannabis Use Disorder?

The research does not provide direct evidence supporting the effectiveness of Hydrocortisone Oral and Yohimbine Hydrochloride for treating Cannabis Use Disorder. However, yohimbine has been shown to induce stress-related responses and increase drug-seeking behavior in animal studies, suggesting it may influence stress pathways involved in addiction. ^{1 2 3 4 5}

Is yohimbine hydrochloride safe for humans?

Yohimbine hydrochloride can increase blood pressure and cause stress-like responses in humans, which suggests it may have some safety concerns, especially for those with heart conditions or anxiety. ^{5 6 7 8 9}

How is the drug for Cannabis Use Disorder different from other treatments?

This treatment is unique because it uses stress-mimicking drugs, Hydrocortisone and Yohimbine, which are not typically used for Cannabis Use Disorder. Yohimbine is known to induce stress-related responses, which may help in understanding and managing stress-induced relapse, a common challenge in addiction treatment. ^{4 5 7 10 11}

Research Team

Richard J Macatee, PhD

Principal Investigator

Auburn University

Eligibility Criteria

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.

My urine test was positive for THC.

Timeline

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

Treatment Details

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.

Participant Groups

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?

Auburn University

Lead Sponsor

Trials

81

Recruited

14,600+

Wayne State University

Collaborator

Trials

318

Recruited

111,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

References

1. England 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. [2019]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Influence of tiagabine maintenance on cannabis effects and related behaviors in daily cannabis users. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. [2015]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats. [2014]

6. United States pubmed.ncbi.nlm.nih.gov

Intravenous yohimbine. Selective enhancer of norepinephrine and cortisol secretion and systolic blood pressure in humans. [2019]

7. Germany 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. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine. [2019]

9. England 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. [2021]

10. Germany 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. [2021]

11. France pubmed.ncbi.nlm.nih.gov

Pattern of neural activation following yohimbine-induced reinstatement of alcohol seeking in rats. [2021]