Background The study has the primary objective of assessing the efficacy/safety of rac-methadone, levomethadone, and buprenorphine in maintenance patients and naïve, in pharmacological polytherapy. The secondary objective of the study is to evaluate efficacy/safety of the treatments in subgroups of patients with comorbidity under psychological support. Methods The primary endpoint was the temporal reduction of urinary positivity to the substance of abuse evaluated every three months, expressed as a percentage of responders out of the total number of recruits. Secondary endpoints were: the safety assessment. Psychopathology was assessed by ASI, Scl90, and a novel COVID-19 questioner. Results To date, 211 patients have been recruited, made up of 81% by males with an average age of 44.41 +5.24 and 19% by females with an average age of 43.16 + 2.89, over 98% of patients recruited are of Italian Caucasian. At recruitment, 75% of patients were already on treatment, most of them from less than (> 80%) to 1 year. 20% + 1.3, 12% + 5.9, 7%+5, and 5% + 0.9 had psychiatric, infectious, cardiological, and metabolic comorbidity. At enrollment, 65% of female patients were treated with rac-methadone at a mean dose of 55 mg + 10 mg/day, 35% were treated with levomethadone at the dose of 45.11 mg + 6.5 mg/ day and the rest were treated with buprenorphine/naloxone at a dosage of 4 mg + 2.62 mg/day. In the male group, 50% of patients were treated with rac-methadone with a mean dosage of 57.21 mg +10.88 mg/day, 25% were treated with levomethadone with a mean dosage of 28.75 mg + 7.5 mg/day and the rest were treated with buprenorphine/naloxone at a mean dosage of 8 mg +3.62 mg/day. The starting Craving was respectively 32/100 in males and 31/100 in females, according to VAS. Out of 30% of patients who have completed their visits to date, 180 days after recruitment showed stability in urinary methadone positivity with a marked decrease in heroin positivity -53% + 4%, cannabinols -48% + 2% and cocaine -37% + 6%. The observed ADRs were: constipation, muscle fatigue, and one case of Stevens-Johnson syndrome. 60 patients at enrollment showed a mean QTc of 430.2 +12.4, mean BPM of 75.23 + 5.3, systolic and diastolic blood pressure of 122.5 + 2.14 and 81.4 + 3.3 mmHg respectively, which remained unchanged. Adverse events of any nature were: decreased willpower, job loss, increased alcohol use, changes in personality including dullness and depression. Conclusion The patients were stabilized after 180 days of observation in our SERDs with a marked decreased dosing of levomethadone in males but with minor dosing reduction in the female. Whether this is due to factors affecting PD/PK is under investigation.