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| Name | Class |
|---|---|
| University of Thessaly | OTHER |
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The NUTRIDOPE (NUTRItion-driven Detoxification of OPioid addicted patiEnts) study is a clinical trial that aims to investigate the role of pomegranate juice consumption by opioid-addicted patients under buprenorphine and methadone on craving, which is the primary outcome, and other parameters. In detail, fresh pomegranate juice will be administered for 120 days (250 ml, 7 days/week) to the patients and craving as well as other psychosocial (e.g., depression, mood state, quality of life) and biochemical (i.e., blood redox status and inflammation) parameters will be evaluated. It is hypothesized that pomegranate juice will reduce craving probably through the improvement of blood redox and inflammation status.
Pomegranate juice, which is the examined nutritional intervention, will be administered to the participants of the experimental group, whereas their counterparts in the control group will not consume any similar beverage as a placebo due to the objective difficulties of making one that will be identical and not separable with the fresh pomegranate juice.
Background: Buprenorphine and methadone are considered the "gold standard" medication for addiction treatment (MAT) for patients with opioid use disorders (OUDs). However, they may cause side effects promoting craving (i.e., opioid use relapse). Therefore, the concurrent administration of natural products could be an adjunct intervention to back up opioid MAT. Pomegranate is a natural substance that contains antioxidant polyphenolic compounds, which have been associated with craving reduction. Moreover, pomegranate positively affects psychosocial parameters, such as depression and anxiety that are common feelings for patients with OUDs, probably due to its potent antioxidant and anti-inflammatory properties.
Objectives: The NUTRIDOPE (NUTRItion-driven Detoxification of OPioid addicted patiEnts) study aims to investigate the role of pomegranate juice consumption by patients with OUDs under buprenorphine and methadone on craving.
Methods: Fresh pomegranate juice will be administered for 120 days (250 ml, 7 days/week) and craving, as the primary outcome, as well as other psychosocial (e.g., depression, mood state, quality of life) and biochemical (i.e., blood redox status and inflammation) parameters will be evaluated.
Anticipated Results: It is hypothesized that pomegranate juice will reduce craving probably through the improvement of blood redox and inflammation status.
Conclusions: NUTRIDOPE is a hypothesis-driven, evidence-based, multifactorial project that proposes a nutrition-based solution towards craving reduction for patients with OUDs under MAT, potentially assisting towards their successful rehab and societal reintegration.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental group | Experimental | Patients under medication for addiction treatment (MAT) that are active members of the Greek Organization Against Drugs (OKANA) therapeutic units will be recruited for this investigation. The participants will be stratified into two subgroups, i.e., methadone maintenance treatment (MMT) and buprenorphine maintenance treatment (BMT), according to the maintenance treatment program they attend. Pomegranate juice, which is the examined nutritional intervention, will be administered to the participants of both MMT and BMT subgroups of the experimental group. The juice will be administered to the patients at the following dosage: 250 ml/day, seven days/week, for four months. |
|
| Control group | No Intervention | Patients under medication for addiction treatment (MAT) that are active members of the Greek Organization Against Drugs (OKANA) therapeutic units under methadone or buprenorphine treatment. The participants will be stratified into two subgroups, i.e., methadone maintenance treatment (MMT) and buprenorphine maintenance treatment (BMT), according to the maintenance treatment program they attend. The patients of the control group (both MMT and BMT subgroups) will not consume any similar beverage as a placebo due to the objective difficulties of making one that will be identical to the fresh pomegranate juice. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pomegranate juice | Dietary Supplement | The pomegranate juice that will be used in the experiment is a 100% natural product without conservatives. It will kindly be donated from the company Rodi Hellas SA, Pella, Greece. The product is in line with the quality assurance certificates by the International Organization for Standardization (ISO 22000:2005), Global Gap, Grasp and Kosher. |
| Measure | Description | Time Frame |
|---|---|---|
| Craving | Heroin Craving Questionnaire (HCQ), which is a validated instrument, will be used for the assessment of the effects of pomegranate juice on craving. It is consisted of 45 questions divided in 5 dimensions, namely desire to use heroin, intentions and planning to use heroin, anticipation of positive outcome, relief from withdrawal or dysphoria, and lack of control overuse. HCQ will be completed by the volunteers of both the experimental and control groups at four timepoints in order to assess the change on craving as follows: Before the start of the experiment (i.e., day 1 or baseline), in the middle of the experiment (i.e., day 60), at the end of the experiment (i.e., day 120), and 6 months after the end of the experiment (i.e., follow-up measurement). | Changes between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement) will be assessed. |
| Measure | Description | Time Frame |
|---|---|---|
| Quality of Life (QoL) | The Nottingham Health Profile (NHP) questionnaire will be used for the assessment of the pomegranate juice effects on the QoL of the patients. The questionnaire consists of two parts; the first part assesses parameters such as activity, pain, emotional reaction, sleep, social isolation, and mobility, whereas the second part evaluates the effects of health or disease on the activities of daily living. |
| Measure | Description | Time Frame |
|---|---|---|
| Sleep evaluation | Pittsburgh Sleep Quality Index (PSQI) self-reported questionnaire assesses through a Likert scale from 0-3 sleep quality and quantity, sleep habits related to quality and occurrence of sleep disturbances in adults consisting of seven components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. A score is calculated by the sum of the 7 components ranging between 0 and 21. The quality of sleep will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christonikos Leventelis, Dr | Organization against Drugs | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Organization Against Drugs | Athens | Attica | 14233 | Greece |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34418746 | Background | Abu-Taweel GM, Al-Mutary MG. Pomegranate juice moderates anxiety- and depression-like behaviors in AlCl3-treated male mice. J Trace Elem Med Biol. 2021 Dec;68:126842. doi: 10.1016/j.jtemb.2021.126842. Epub 2021 Aug 17. | |
| 16448212 | Background | Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D. Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem. 2006 Feb 8;54(3):980-5. doi: 10.1021/jf052005r. |
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Data obtained through this investigation will be provided to qualified researchers with related academic interest.
Data requests can be submitted starting one year after article publication and the data will be made accessible for up to 24 months.
Access to trial data can be requested by qualified researchers and will be provided following review and approval research approval.
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| ID | Term |
|---|---|
| D009293 | Opioid-Related Disorders |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D000079524 | Narcotic-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Determination of antioxidant enzyme Catalase (CAT) | Spectrophotometric evaluation of the activity of the antioxidant enzyme CAT expressed in U/gr Hb (haemoglobin) in red blood cell lysate (RBCL). The enzyme activity will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the total antioxidant capacity (TAC) of plasma | TAC will be evaluated spectrophotometrically in plasma expressed as mmol DPPH•/ml. TAC levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| In vitro evaluation of antioxidant and reducing properties of the administered pomegranate juice | The antioxidant and reducing properties of pomegranate juice will be evaluated using specific in vitro tests: 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), hydroxyl radical, superoxide radical, Fe+3 to Fe2+ reduction) expressed in half maximal inhibitory concentration (IC50) (μl). | Day 1 |
| Measurement of the concentration of protein carbonyls | Protein carbonyls, as a biomarker of protein oxidation, will be evaluated in plasma spectrophotometrically expressed in nmol/mg protein. The levels of protein carbonyls will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of thiobarbituric acid reactive substances (TBARS) | TBARS, a biomarker of lipid peroxidation, will be evaluated in plasma spectrophotometrically expressed in μmol/l. The levels of TBARS will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the capacity of plasma to reduce hydroxyl radical (OH•) | Spectrophotometric evaluation of the ability of plasma to reduce hydroxyl radical expressed in mmol deoxyribose/ml. The reducing capacity of plasma will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the capacity of plasma to reduce superoxide radical (O2•-) | Spectrophotometric evaluation of the ability of plasma to reduce superoxide radical expressed in % scavenging capacity. The reducing capacity of plasma will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the reducing power | Spectrophotometric evaluation of the ability of plasma to reduce Fe+3 to Fe+2 expressed in mmol potassium ferricyanide/ml. The reducing capacity of plasma will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of GSH concentration | The reduced form of glutathione (GSH) as a crucial antioxidant molecule will be measured spectrophotometrically and its levels will be expressed in μmol/g Hb. GSH levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the activity of the antioxidant enzyme superoxide dismutase (SOD) | The activity of the antioxidant enzyme SOD expressed in U/gr Hb (haemoglobin) will be measured in red blood cell lysate (RBCL). SOD activity levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the activity of the antioxidant enzyme glutathione peroxidase (GPx) | The activity of the antioxidant enzyme GPx expressed in U/gr Hb (haemoglobin) will be measured in red blood cell lysate (RBCL). GPx activity levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the activity of the antioxidant enzyme glutathione reductase (GR) | The activity of the antioxidant enzyme GR expressed in U/gr Hb (haemoglobin) will be measured in red blood cell lysate (RBCL). GR activity levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of interferon gamma (IFN-γ) | IFN-γ, expressed in pg/ml, is a cytokine that recruits macrophages at the site of inflammation. Its concentration will be assessed through immunofluorescence. IFN-γ levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of interferon alpha-2 (IFN-a2) | IFN-a2, expressed in pg/ml, regulates the activation of the immune system and inhibits cell proliferation. Its concentration will be assessed through immunofluorescence. IFN-a2 levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of interleukin-1 betta (IL-1b) | IL-1b, expressed in pg/ml, is activated by macrophages and neutrophils and regulate immune response. Its concentration will be assessed through immunofluorescence. IL-1b levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of interleukin-8 (IL-8) | Chemokine IL-8, expressed in pg/ml, induces chemotaxis of neutrophils and other granulocytes in an inflammation site. Its concentration will be assessed through immunofluorescence. IL-8 levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of monocyte chemoattractant protein-1 (MCP-1) | MCP-1,expressed in pg/ml, recruits monocytes, lymphocytes, and neutrophils at the site of inflammation. Its concentration will be assessed through immunofluorescence. MCP-1 levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of interleukin-1 alpha (IL-1a) | IL-1a, expressed in pg/m, regulates immune response after its activation by macrophages and neutrophils. Its concentration will be assessed through immunofluorescence. IL-1a levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of tumor necrosis factor alpha (TNF-a) | TNF-a, expressed in pg/ml, is realised by macrophages for cell signaling as part of the immune response. Its concentration will be assessed through immunofluorescence. TNF-a levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of melatonin | Melatonin is involved in circadian regulation through sleep-wake timing. Saliva samples will be taken at 22.00 in dim light by patients themselves under oral and typed guidelines. Dim light melatonin onset (DLMO) concentration will be measured using enzyme-linked immunosorbent assay (ELISA) and will be expressed in pg/ml. Melatonin levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Measurement of the concentration of cortisol | Cortisol belongs to glycocorticoid class of hormones related with stress system and can weaken the activity of immune system through the releasing of cytokines in inflammation site. Plasma samples will be collected early in the morning and cortisol concentration will be expressed in pg/ml and be measured using enzyme-linked immunosorbent assay (ELISA). Cortisol levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Fatigue evaluation | Fatigue Severity Scale (FSS) is a 9-item, self-administered questionnaire which assesses the magnitude of fatigue that the patients have experienced throughout the past weeks. Fatigue levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Mood | Profile of Mood States (POMS-short version) questionnaire consists of 37 self-administered items and assesses current mood states in 6 dimensions, namely tension, depression, anger, vigour, fatigue, and confusion. Mood levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Evaluation of constipation | Patient Assessment of Constipation - Quality of Life (PAC-QOL) questionnaire consists of 28 self-reported items that assess the effects of constipation on the patient QOL during the last two weeks. It comprises four dimensions referring to physical discomfort, psychosocial discomfort, treatment satisfaction and worries discomfort. The responses are scored on a Likert scale ranging from 0 to 5. Higher score indicates increase of severity of the negative effects of the intervention in question on QOL. Constipation levels will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
| Faecal evaluation | Bristol Stool Form Scale (BSFS) will be used as a pictorial representation of each stool type ranging from the hardest (i.e., type 1) to the softest (i.e., type 7) related to specific bowel symptoms, such as constipation. Faecal evaluation will be compared between Day 1 (baseline) and the following time points: Day 60, Day 120, six months following the end of the experiment (follow-up measurement). | Day 1; Day 60; Day 120, six months following the end of the experiment (follow-up measurement) |
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| 40709794 | Derived | Leventelis C, Barmpas PT, Kampitsi A, Iliopoulou K, Toutouktsi N, Malakopoulos P, Tasoulis S, Veskoukis AS. Pomegranate Juice Consumption Improves Sleep Quality and Melatonin Concentration of Patients With Opioid Use Disorders Under Medication-Assisted Treatment With Methadone and Buprenorphine: A Randomized Controlled Trial. Subst Use Addctn J. 2025 Oct;46(4):981-993. doi: 10.1177/29767342251342666. Epub 2025 Jul 25. |
| 39798867 | Derived | 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. Epub 2025 Jan 10. |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |