Clinical trial NCT07022782: MEDiterranean Diet-driven Detoxification of OPioid Addicted patiEnts (MED-DOPE)
Official title: A Nutritional Intervention Based on the Principles of Mediterranean Diet as a Putative Regulator of Craving and Redox Status of Patients Under Medication-assisted Treatment With Methadone and Buprenorphine: The Study Protocol of a Randomized Controlled Trial (the MED-DOPE Study)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Opioid Addiction
Keywords: Mediterranean diet
Opioid use disorders
Methadone
Buprenorphine
Oxidative stress
Antioxidants
Nutrition
Craving
Lead sponsor: University of Thessaly
Sponsor class: OTHER
Collaborators: name: Organization Against Drugs (OKANA)
First posted: 2025-06-15
Enrollment: 40
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The MED-DOPE (MEDiterranean diet-driven Detoxification of OPioid addicted patiEnts) study is a randomized controlled trial that aims to investigate the role of a nutritional intervention based on the principles of Mediterranean diet on craving, which is the primary outcome, and blood redox status of opioid-addicted patients under medication-assisted treatment with buprenorphine and methadone. In detail, the patients of the intervention group will consume three meals per day (i.e., breakfast, lunch and dinner) based on the principles of Mediterranean diet for 90 days. The patients of the control group will follow their normal nutritional habits. Craving as the primary outcome, quality of sleep and biochemical parameters such as blood redox status will be evaluated. It is hypothesized that the applied nutritional intervention will reduce craving, probably through the improvement of blood redox status, of the patients of the intervention group compared to the patients of the control group.

Detailed description: Background: Methadone and buprenorphine are considered as the "gold standard" medication-assisted treatment (MAT) for patients with opioid use disorders (OUDs). Patients that suffer from OUDs usually experience serious health consequences in the psychosocial and the biochemical level. Specifically, they are at 10-fold higher mortality risk than that of the general population (Coffa and Snyder 2019). Moreover, there are inconsistencies related to the efficacy of MAT (i.e., methadone and buprenorphine) on retention to treatment and opioid craving, that is a major psychosocial parameter to be improved towards successful rehabilitation (Shulman et al. 2019). Craving is a central psychosocial component for addiction characterized by a strong urge to use an illicit substance. It appears that although MAT partially normalizes this parameter, patients with OUDs continue to experience craving for opioids leading to drug-seeking behavior and relapse (Kakko et al. 2008). Furthermore, opioids such as heroine induce oxidative stress, a common toxic biochemical outcome. However, this is the case also for methadone and buprenorphine, although in a lower extent compared to heroine (Leventelis et al. 2019; Arezoomandan et al. 2022). Therefore, opioid-addiction induced oxidative stress seems to be rather neglected and needs further attention. Oxidative stress is a result of excessive reactive oxygen species generation, which may cause protein and lipid oxidation and oxidative modification of DNA (Leventelis et al. 2023; Veskoukis et al. 2019; Tsai et al. 2017). To that end, the use of plant-derived compounds as auxiliary therapeutic approaches, in combination with methadone and buprenorphine could be a promising approach towards enhancement of the effectiveness of MAT. The biological plausibility for the adoption of such a nutritional practice relies on the fact that plant components namely polyphenols exert potent antioxidant properties against oxidative stress (Abu Bakar et al. 2015; Ibrahim et al. 2018). It has been clearly shown that pomegranate juice is such a physical product (Leventelis et al. 2025). A nutritional approach on the basis of Mediterranean diet could also be considered as an alternative approach towards rehabilitation from opioid addiction. Indeed, Mediterranean diet has been associated with better health outcomes (Estruch et al. 2018). Its beneficial effects on human health have largely been attributed to the antioxidant properties of its components, mainly polyphenols (Veskoukis et al. 2012; Billingsley et al. 2018; Alexandrova et al. 2021).

Objectives: The MED-DOPE (MEDiterranean diet-driven Detoxification of OPioid addicted patiEnts) study aims to investigate the role of a nutritional intervention based on the principles of Mediterranean diet on craving and blood redox status of patients with OUDs under buprenorphine and methadone. This diet scheme is rich in antioxidant compounds that, along with medication (i.e., methadone and buprenorphine), could putatively act beneficially on several health parameters of the patients with OUDs.

Methods: Three meals (i.e., breakfast, lunch and dinner) will be administered daily for 90 days to patients with OUDs under methadone and buprenorphine. In three time points namely Days 1, 45 and 90 the patients will form the heroine craving questionnaire to assess craving, which is the primary outcome of MED-DOPE study. Blood samples will also be collected from the participants in order to measure redox biomarkers (i.e., glutathione concentration, total antioxidant capacity, protein carbonyls, glutathione reductase activity and glutathione peroxidase activity).

Anticipated Outcome: It is hypothesized that the applied nutritional intervention will reduce craving probably through the improvement of blood redox status.

Conclusion: MED-DOPE is a hypothesis-driven and evidence-based project that proposes a nutrition-based solution for craving amelioration in patients with OUDs under MAT, potentially assisting towards their successful rehabilitation and societal reintegration.

References Abu Bakar NH, Hashim SN, Mohamad N, Husain R, Adnan LHM, Shariff H. Role of oxidative stress in opiate withdrawal and dependence: exploring the potential use of honey. J Appl Pharmaceut Sci 2015;5(12):159e61. https://doi.org/10.7324/japs.2015.501228.

Aleksandrova K, Koelman L, Rodrigues CE. Dietary patterns and biomarkers of oxidative stress and inflammation: A systematic review of observational and intervention studies. Redox Biol. 2021 Jun;42:101869. doi: 10.1016/j.redox.2021.101869.

Arezoomandan M, Zhiani R, Mehrzad J, Motavalizadehkakhky A, Eshrati S, Arezoomandan R. Inflammatory, oxidative stress and cognitive functions in patients under maintenance treatment with methadone or buprenorphine and healthy subjects. J Clin Neurosci 2022;101:57e62. https://doi.org/10.1016/j.jocn.2022.04.018.

Billingsley, H.E., Carbone, S. The antioxidant potential of the Mediterranean diet in patients at high cardiovascular risk: an in-depth review of the PREDIMED. Nutr \& Diabetes 8, 13 (2018). https://doi.org/10.1038/s41387-018-0025-1

Coffa D, Snyder H. Opioid use disorder: medical treatment options. Am Fam Physician 2019;100(7):416e25.

Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA, Fitó M, Gea A, Hernán MA, Martínez-González MA; PREDIMED Study Investigators. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. 2018 Jun 21;378(25):e34. doi: 10.1056/NEJMoa1800389.

Ibrahim HS, Ibrahim S, Iliyasu Z, Umar SA, Mohd KRA. Antioxidant potential of Phoenix dactylifera Linn extract and its effects on calcium channel antagonist in the treatment of withdrawal syndrome in morphine dependent rats. Trop J Nat Prod Res 2018;2(7):309e13. https://doi.org/10.26538/tjnpr.

Kakko J, von Wachenfeldt J, Svanborg KD, Lidstr€om J, Barr CS, Heilig M. Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence. Biol Psychiatr 2008;63(2): 172e7. https://doi.org/10.1016/j.biopsych.2007.05.001.

Leventelis C, Goutzourelas N, Kortsinidou A, Spanidis Y, Toulia G, Kampitsi A, Tsitsimpikou C, Stagos D, Veskoukis AS, Kouretas D. Buprenorphine and Methadone as Opioid Maintenance Treatments for Heroin-Addicted Patients Induce Oxidative Stress in Blood. Oxid Med Cell Longev. 2019 Apr 9;2019:9417048. doi: 10.1155/2019/9417048.

Leventelis C, Makri S, Ververi A, Papageorgiou K, Tentolouri A, Mountzouridi E, Tekos F, Barmpas PT, Tasoulis S, Metsios GS, Kouretas D, Veskoukis AS. Pomegranate juice ameliorates craving and oxidative stress on patients under medication for opioid addiction treatment with methadone and buprenorphine: A ranzomised controlled trial. Clin Nutr ESPEN. 2025 Apr;66:34-45. doi: 10.1016/j.clnesp.2025.01.025.

Leventelis C, Tasoulis S, Kouretas D, Metsios SG, Veskoukis SA. Pomegranate juice consumption by patients under medication for addiction treatment as regulator of craving and blood redox status: the study protocol of a randomized control trial (the NUTRIDOPE study). Int J Clin Skills 2023;17(7): 133e43. https://doi.org/10.37532/1753-0431.2023.17(7).316.

Shulman M, Wai JM, Nunes EV. Buprenorphine treatment for opioid use disorder: an overview. CNS Drugs 2019;33(6):567e80. https://doi.org/10.1007/s40263-019-00637-z.

Tsai MC, Huang TL. Brain-derived neurotrophic factor (BDNF) and oxidative stress in heroin-dependent male patients undergoing methadone maintenance treatment. Psychiatr Res 2017;249:46e50.

Veskoukis AS, Kerasioti E, Priftis A, Kouka P, Spanidis Y, Makri S, et al. A battery of translational biomarkers for the assessment of the in vitro and in vivo antioxidant action of plant polyphenolic compounds: the biomarker issue. Curr Opin Toxicol 2019;13:99e109. https://doi.org/10.1016/j.cotox.2018.10.001.

Veskoukis AS, Tsatsakis AM, Kouretas D. Dietary oxidative stress and antioxidant defense with an emphasis on plant extract administration. Cell Stress Chaperones. 2012 Jan;17(1):11-21. doi: 10.1007/s12192-011-0293-3.

Eligibility criteria: Inclusion Criteria:

* Over 20 years of age
* Long-term heroine or other opioid drug use
* Suffering from physical and mental dependence due to chronic opioid use

Exclusion Criteria:

* Serious medical problems, such as infection by human immunodeficiency virus or hepatitis B virus
* Current use of anti-inflammatory medication
* Relapse to other addictive substances (i.e., opioids, methamphetamine, benzodiazepines, cannabis, tetrahydrocannabinol, amphetamine) - To rule out the use of such substances, all participants will weekly undergo urine tests during the three-month period of the trial

Primary outcomes:
measure: Craving
timeFrame: Changes between Day 1 (baseline) and Days 45 and 90 will be assessed.
Secondary outcomes:
measure: Quality of Sleep
timeFrame: Changes between Day 1 (baseline) and Days 45 and 90 will be assessed.
measure: Blood GSH concentration
timeFrame: Changes in GSH concentration will be compared between Day 1 (baseline) and Days 45 and 90.
measure: Concentration of protein carbonyls in blood
timeFrame: Changes in protein carbonyl concentration will be compared between Day 1 (baseline) and Days 45 and 90.
measure: Total antioxidant capacity of blood
timeFrame: Changes in TAC will be compared between Day 1 (baseline) and Days 45 and 90.
measure: Activity of glutathione reductase
timeFrame: Changes in glutathione reductase activity will be compared between Day 1 (baseline) and Days 45 and 90.
measure: Activity of glutathione peroxidase
timeFrame: Changes in glutathione peroxidase activity will be compared between Day 1 (baseline) and Days 45 and 90.
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Organization Against Drugs (OKANA)
Study officials:
affiliation: Organization Against Drugs (OKANA)
name: Christonikos Leventelis
role: PRINCIPAL_INVESTIGATOR
References: