Olfactory Training for Substance Use Disorders

(EDITOR Trial)

Recruiting at 2 trial locations

Overseen By Opeyemi M Awofeso, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Evon Medics LLC

Must be taking: Buprenorphine, Naltrexone

Disqualifiers: Neurological disease, Serious mental illness, Unstable medical condition, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

300 Participants Needed

Trial Summary

What is the purpose of this trial?

The overarching goal of this study phase, Phase II component is to implement Enhanced Digital-Chemosensory-Based Olfactory Training for Remote Management of Substance Use Disorders (EDITOR) device in substance use disorder (SUD) clinics to demonstrate pilot effectiveness for SUD outcomes compared to treatment as usual (TAU) and Computerized Chemosensory-Based Orbitofrontal Networks Training (CBOT) device as active control. The investigators will conduct a multi-site study of 300 adult patients with opiate use disorder (OUD), stimulant (i.e., cocaine, methamphetamine) and/or alcohol use disorder (AUD) from community and clinics to evaluate whether EDITOR is associated with better patient treatment outcomes (e.g., retention in treatment and abstinence). The pilot study will provide preliminary data needed for design of a Phase III trial, including estimates of effect size. The investigators will also explore development of machine learning/AI algorithms integrating clinical and physiological data into treatment decision guides for providers.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must be willing to receive buprenorphine (for opioid use disorder) or naltrexone (for alcohol use disorder) during the study.

What data supports the effectiveness of the treatment Enhanced Digital-Chemosensory-Based Olfactory Training (EDITOR) for substance use disorders?

There is no direct evidence provided in the research articles about the effectiveness of Enhanced Digital-Chemosensory-Based Olfactory Training (EDITOR) for substance use disorders. However, the research highlights the role of brain circuits and neural responses in addiction, suggesting that treatments targeting these areas, like olfactory training, could potentially influence addiction-related behaviors. ^{1 2 3 4 5}

How is the treatment EDITOR different from other treatments for substance use disorders?

EDITOR is unique because it uses olfactory training, which involves the sense of smell, to help treat substance use disorders. This approach is novel as it targets the brain's olfactory circuits, potentially influencing behavior and cognitive processes related to addiction, unlike traditional treatments that focus on chemical or behavioral interventions. ^{3 4 6 7 8}

Research Team

Marc Fishman, MD

Principal Investigator

Maryland Treatment Center

Charles Nwaokobia

Principal Investigator

Evon Medics LLC

Tanya Alim, MD

Principal Investigator

Howard University

Evaristus Nwulia, MD

Principal Investigator

Evon Medics LLC

Edwin Chapman, MD

Principal Investigator

Clinics of Dr. Edwin Chapman at MHDG

Eligibility Criteria

This trial is for adults with substance use disorders, including opioid, methamphetamine, cocaine, and alcohol addiction. Participants will be recruited from community clinics and must be currently receiving treatment.

Inclusion Criteria

Have a stable place to stay and retain the EDITOR devices in a secure condition when receiving the intervention and during the entire duration of the study participation

Diagnosis of current moderate or severe substance use disorders, opioid use disorders, stimulant (cocaine and methamphetamine) use, and alcohol use disorders in the past three months, including the past month

Does not meet criteria for other current SUDs outside of the 3 above, except for mild or moderate use of cannabis

Exclusion Criteria

Known allergies or intolerance to aromas from plant essential oils. E.g., orange and lemon

Breastfeeding or pregnancy test positive or plans to get pregnant in the 6 months following enrollment

Individuals who are on parole or probation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily EDITOR therapy alongside treatment-as-usual (TAU) for three months, involving olfactory stimulation and training tasks.

12 weeks

Daily remote sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including retention and relapse rates.

4 weeks

Treatment Details

Interventions

• Enhanced Digital-Chemosensory-Based Olfactory Training

Trial Overview The study tests the EDITOR device—a digital-chemosensory olfactory training tool—against standard treatments and a control CBOT device. It aims to see if EDITOR can improve patient outcomes like staying in treatment longer and maintaining abstinence.

Participant Groups

Group I: Enhanced Digital-Chemosensory-Based Olfactory Training (EDITOR) Experimental Treatment 1 Intervention

The EDITOR device is designed to stimulate intensive neural activity in OFC over long periods of time. It consists of 40 daily cycles of intervention with a combination of olfactory stimulation and training tasks, lasting \~45 minutes, delivered once daily over three months. The device also includes 60% beta-caryophyllene chemosensory stimulation to target AUD and stimulant use disorder and 10 digital enhancements for the purpose of remote treatment, remote acquisition of behavioral and physiological data, and seamless data transmission to providers, through a HIPAA-compliant clinic end portal. Participants assigned to this arm will receive their treatment-as-usual (TAU) alongside daily EDITOR therapy for three months. TAU will depend on the drug abused \[Buprenorphine with a median dose of 24 mg (range 16 - 32 mg) for Opioid use disorder and naltrexone (50-100 mg daily for Alcohol use disorder (AUD).

Group II: Chemosensory-Based Olfactory Training (CBOT) Active Control 1 Intervention

CBOT with olfactory stimulants \& orbitofrontal (OFC) tasks TAU same as above + CBOT (Chemosensory-Based Olfactory Training) therapy (40 cycles of olfactory stimulation and OFC training tasks, lasting \~45 minutes, once daily over three months) + use of their smartphone to communicate with their clinic provider/staff

Group III: Chemosensory-Based Olfactory Training (CBOT) Sham Placebo Group 1 Intervention

Control Device (Sham) is CBOT device without olfactory stimulants and orbitofrontal tasks. TAU same as above + CBOT sham + use of their smartphone to communicate with their clinic provider/staff. This CBOT device uses compressed room air scented with phenylethylamine (rose scent) instead of olfactory stimulants and has shape pattern matching tasks instead of cognitive tasks in order to blind users to their treatment assignment. Similar to the active arm, sham COT will be used daily for 45 minutes.

Who Is Running the Clinical Trial?

Evon Medics LLC

Lead Sponsor

Trials

5

Recruited

1,000+

Howard University

Collaborator

Trials

44

Recruited

15,200+

Maryland Treatment Center

Collaborator

Trials

1

Recruited

300+

Clinics of Dr. Edwin Chapman, MD, PC @ MHDG

Collaborator

Trials

2

Recruited

490+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

The study of 156 individuals aged 18-25 revealed that olfactory abnormalities are linked to substance addiction, showing that these changes can predict earlier substance use and are associated with immune system issues.

Episodic users of substances exhibited reduced aversive reactions to certain odors, which correlated with signs of immune deficiency and increased cortisol levels, suggesting that olfactory testing could be a useful tool in understanding and predicting addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Association between pathological olfaction, immunological abnormalities and predisposition to substance use]. Nevidimova, TI., Batukhtina, EI., Savochkina, DN., et al.[2018]

The study developed a neuroimaging-guided approach to noninvasive brain stimulation (NIBS) targeting the cerebellar cortex and prefrontal cortex, showing that cerebellar tDCS can induce significant gamma oscillations in the cerebral cortex, which may help in addressing cue-reactivity in cannabis use disorder.

A preliminary study with 10 healthy participants demonstrated that cerebellar tDCS effectively increased oxyhemoglobin levels in both the cerebellum and prefrontal cortex, indicating the potential for NIBS to enhance cognitive functions related to substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Portable Neuroimaging-Guided Noninvasive Brain Stimulation of the Cortico-Cerebello-Thalamo-Cortical Loop-Hypothesis and Theory in Cannabis Use Disorder. Walia, P., Ghosh, A., Singh, S., et al.[2022]

Addiction is a chronic disease characterized by compulsive drug-seeking behavior, which can lead to long-lasting changes in the brain's structure and function, particularly in the mesolimbic dopamine system.

Current research is focused on understanding the specific neural pathways involved in addiction and how alterations in brain regions and synaptic connections contribute to the disease, which is essential for developing effective medical treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological substrates of addiction. Joffe, ME., Grueter, CA., Grueter, BA.[2021]

Rodent models of addiction have provided valuable insights into the mechanisms of drug-related behaviors, particularly highlighting the role of glutamatergic synaptic transmission and mesolimbic dopamine activation in addiction.

Using advanced techniques like optogenetics, researchers can manipulate specific brain circuits to reverse drug-induced changes, paving the way for new treatment options such as deep brain stimulation for addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Emergence of a Circuit Model for Addiction. Lüscher, C.[2018]

In a study involving 24 short-term abstinent heroin-dependent patients and 20 drug-naïve individuals, exposure to heroin-related cues significantly increased craving levels in the heroin-dependent group.

Neuroimaging revealed that this craving was associated with heightened activation in key brain areas related to reward and decision-making, such as the nucleus accumbens and prefrontal cortex, indicating a strong neural basis for the vulnerability to relapse in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Craving correlates with mesolimbic responses to heroin-related cues in short-term abstinence from heroin: an event-related fMRI study. Li, Q., Wang, Y., Zhang, Y., et al.[2021]

The cannabinoid type-1 (CB1) receptor is present in various olfactory brain areas and plays a significant role in how olfactory information is processed and influences behavior.

Recent research has begun to uncover the specific cellular mechanisms by which cannabinoid signaling affects olfactory processing, highlighting the importance of the endocannabinoid system in regulating olfactory circuits and related behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabinoid Control of Olfactory Processes: The Where Matters. Terral, G., Marsicano, G., Grandes, P., et al.[2021]

The vertebrate olfactory system uses a diverse set of G protein-coupled receptors, which make up about 1% of vertebrate genes, to recognize and differentiate a wide range of odors.

Recent studies have shown that odorant receptors can recognize multiple related odorants and that odor discrimination relies on a combinatorial code, where different receptors work together to identify specific smells, with this coding changing based on odor concentration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Odor discrimination by G protein-coupled olfactory receptors. Touhara, K.[2016]

Olfactory dysfunction can be an early indicator of various neurodegenerative and neuropsychiatric disorders, highlighting the importance of the olfactory system in understanding neuromodulation.

The endocannabinoid system interacts with olfactory processing, and recent advances in understanding its receptor dynamics may lead to new therapeutic drugs for conditions like neuroinflammation and neurodegeneration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endocannabinoid-mediated neuromodulation in the main olfactory bulb at the interface of environmental stimuli and central neural processing. Heinbockel, T., Bhatia-Dey, N., Shields, VDC.[2022]

References

1. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Association between pathological olfaction, immunological abnormalities and predisposition to substance use]. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Portable Neuroimaging-Guided Noninvasive Brain Stimulation of the Cortico-Cerebello-Thalamo-Cortical Loop-Hypothesis and Theory in Cannabis Use Disorder. [2022]

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

Biological substrates of addiction. [2021]

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

The Emergence of a Circuit Model for Addiction. [2018]

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

Craving correlates with mesolimbic responses to heroin-related cues in short-term abstinence from heroin: an event-related fMRI study. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Cannabinoid Control of Olfactory Processes: The Where Matters. [2021]

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

Odor discrimination by G protein-coupled olfactory receptors. [2016]

8. France pubmed.ncbi.nlm.nih.gov

Endocannabinoid-mediated neuromodulation in the main olfactory bulb at the interface of environmental stimuli and central neural processing. [2022]