Abstract
Background
As aging is associated with physiological changes, patients in methadone maintenance treatment (MMT) may require an adequate methadone dose adjustment. We aimed to study the relationship between aging and methadone dose and plasma level.
Methods
Patients with two methadone plasma level results, above one year apart, were included. Methadone dose and plasma levels, as well as their changes over time, were studied by age group.
Results
318 patients, 36.5% aged <50 years, 53.5% 50–64, and 10.1% aged ≥65 years, were compared. Methadone dose did not differ between groups (120.8±38.6 mg/day); however, methadone plasma levels were lowest in the <50y group (580.9±270.9 ng/ml), followed by the 50–64y group (715.4±345.1 ng/ml), and highest in the ≥65y group (893.1±379 ng/ml, p<0.001). This was also reflected in the proportion of patients with (≥1000 ng/ml methadone plasma levels): 6.9%, 18.8%, and 37.5%, respectively (p<0.001). Groups also differed in BMI, which was lowest in the ≥65 years group (24.8±3.9), compared to 26.0±5.5 in the <50 and 26.9±5.1 in the 50–64.9 age group (p=0.053). Methadone plasma levels still significantly differed by age group (p<0.001) after controlling for methadone dose (p<0.001) and BMI (p=0.02) (ANOVA, corrected model p<0.001, F=37.8). Following 4.6±1 years, at the latest evaluation, both methadone doses (Repeated Measures p(Time)=0.004) and plasma levels (p(Time)=0.002) were reduced, with no interaction by age group (p(Time*Group)=0.4 and 0.5, respectively), but only methadone plasma levels differed by age groups (p(Group)<0.001). The proportion of ≥1000 ng/ml methadone plasma levels remained significantly higher among the older age group.
Conclusions
Although the dose of methadone does not require elevation over the years, due to aging, methadone plasma level evaluation should be considered to avoid excessively high methadone plasma levels. However, as the older group represented a small subgroup, additional larger cohort studies and future follow-up are needed to confirm our preliminary findings.
Keywords: Methadone dose, Methadone plasma level, Aging, Change
Introduction
Methadone maintenance treatment (MMT) is considered the safest and most effective treatment for opioid use disorder (OUD), a chronic, relapsing brain disorder [1, 2]. It is associated with reduced illicit opioid use, decreased criminal behaviors, improved mental and physical well-being, reduced mortality, and fewer other complications [2].
While most attention within MMT is given to patients who continue to abuse substances and/or complain of an inadequate methadone dose, less attention is given to patients on a stable dose. These patients who have minimal treatment-related complaints often require little physician intervention, and methadone plasma levels are infrequently monitored. Moreover, as treatment is chronic and patients become older during treatment, methadone dose adjustment may be required, as several normal physiological changes occur with age and, in turn, lead to notable alterations in opioid pharmacokinetics [3–5].
Specifically, renal clearance declines by approximately 1% per year after the age of 50 [6], which reduces the clearance of most opioids and can lead to the build-up of metabolites, which are often active and/or neurotoxic [3]. Regarding hepatic function, the metabolic activity of the liver is reduced due to a decrease in liver size and hepatic blood flow. Moreover, there is an associated decrease in first-pass metabolism that can increase the bioavailability of certain orally administered opioids (e.g., morphine) [7]. Further, aging is associated with an increase in the percentage of body fat, thereby delaying the elimination of methadone, which is a lipophilic agent that accumulates in this tissue. Conversely, there is a decrease in total body water, leading to a reduced volume of distribution and increased concentrations of water-soluble metabolites [6]. The appropriately treated methadone dose for an individual is determined by a physician, based mainly on clinical signs and symptoms of opioid withdrawal or intoxication, together with evidence of opioids in urine analyses, and to a lesser extent, patients’ subjective reports of craving. Methadone plasma levels are not routinely determined in MMT clinics, although a few studies have shown that they contribute to determining an adequate therapeutic dose [8–9]. In our clinic, guidelines include a strict timeline for methadone plasma level evaluations, which enabled us to identify excessively high or low methadone plasma levels and provided the opportunity to study, over time, the relationship between methadone dose and plasma level. Accordingly, although aging is well understood, we found it important to retrospectively analyze the relationship between methadone dose and plasma level by age group, and how it changes over time.
Methods
The study analyses were approved by the Helsinki Committee (IRB) 07-111 of the Tel Aviv Sourasky Medical Center.
Study population
The Adelson MMT Clinic in Tel Aviv, Israel, is accredited by the Commission on Accreditation of Rehabilitation Facilities (CARF International) and is part of a large, tertiary, university-affiliated medical center. It treats up to 330 patients who, upon admission, met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR or DSM-5) criteria for opioid use disorder and, in accordance with Israeli Ministry of Health regulations, had experienced at least two unsuccessful institutional detoxification attempts. Patient characterization, demographic data, and clinical effectiveness have been reported elsewhere [10–11].
Study participants
Patients are routinely evaluated for plasma methadone levels annually if the daily methadone dose is ≥ 150 mg/day, or biennially if the dose is < 150 mg/day. Plasma methadone levels are also evaluated before granting the first methadone take-home dose (THD) privilege for patients who have a steady methadone dose and have had no opiate, cocaine, cannabis, or benzodiazepine detected in urinalysis for at least three months.
When the methadone dose is stabilized (defined as a minimum of 14 days with no dose change), a methadone blood test is taken on the fifth day, after four consecutive days of observed methadone administration in the clinic. The blood test is performed on the fifth day, in the morning, before the methadone dose is administered, to assess trough plasma levels [12]. Whenever a blood test is performed, an electrocardiogram (ECG) is also performed to measure the corrected QT interval (QTc) [13]. Automated ECG measurements were based on Bazett’s formula (Nihon Kohden, ECG-9620) and accompanied by a urine toxicological substance screen, as well as weight and height measurements to calculate body mass index (BMI).
Methadone plasma levels were determined using enzyme immunoassay (DRI® Thermo Scientific, CA, USA) between 2017 and June 2025, and the gas chromatography-mass spectroscopy (GC-MS) method (Clinical Science Laboratory, Mansfield, MA, USA) was used from 2003 to 2024. The current study participants included 318 patients who had two methadone plasma level measurements obtained at least one year apart (mean duration was 4.6 ± 1 y, ranged 1-7.6y), between July 2017 and June 2025. The proportion of change in weight and methadone dose was calculated (latest value minus first value) divided by the latest value.
Age groups were categorized as < 50, 50–64, and ≥ 65 years. The rationale for these cut points was that renal clearance declines by approximately 1% per year after the age of 50 [6], and ≥ 65 years is commonly used by the WHO to define older age. Additional variables included sex, infectious disease (hepatitis C antibody and PCR results, hepatitis B antigen, and HIV antibody). Variables collected at the time of methadone plasma level testing included urine toxicology, weight and height (BMI), blood pressure (BP), and QTc.
Additional analyses included 522 patients who had two methadone plasma level measurements detected by GC-MS, with a mean interval of 9.7 ± 6.2 years between measurements (range, 1.0-20.7 years). This analysis was conducted to specifically examine sex differences and long-term changes over an extended follow-up period.
Urine toxicology
Observed urine samples for the detection of opiates, cocaine metabolite (benzoylecgonine), benzodiazepine, and cannabis were analyzed using the enzyme immunoassay systems (DRI® and CEDIA®) [14].
Statistical analyses
Statistical analyses were performed using the SPSS-29 package. The chi-square test was used for categorical variables, and one-way analysis of variance (ANOVA) was used for continuous variables to compare the three patient age groups. For multivariate analysis, ANCOVA was performed to control for potential confounding covariates. Changes between the two time points were analyzed using repeated-measures multivariate analyses to compare methadone dose, plasma level, QTc, and BMI. Additional repeated-measures multivariate analyses were conducted to examine change in methadone dose and plasma levels by selected variables (age group and sex). Pearson’s correlation coefficients were used to examine linear associations between continuous variables.
Results
Patient characteristics
A total of 318 patients − 36.5% aged < 50 years, 53.5% aged 50–64 years, and 10.1% aged ≥ 65 years, were compared. The three age groups are compared in Table 1. The older patients (aged ≥ 65 years) were admitted to treatment at an older age (p < 0.001), had fewer females (p < 0.001), and fewer tested positive for HIV (p = 0.009) and hepatitis C (p = 0.03). Hypertension was more prevalent among them (p = 0.03), and they had lower BMI (P = 0.05). Methadone dose did not differ between groups (120.8 ± 38.6 mg/day); however, methadone plasma levels were lowest in the < 50y group (580.9 ± 270.9 ng/ml), followed by the 50–64y group (715.4 ± 345.1 ng/ml), and highest in the ≥ 65y group (893.1 ± 379 ng/ml; p < 0.001). The proportion of patients with ≥ 1000 ng/ml methadone plasma levels also increased with age: 6.9%, 18.8%, and 37.5%, respectively (p < 0.001). Fewer older patients tested positive for opioids (p = 0.004) and cocaine (p = 0.02).
Table 1.
Comparison between age group characteristics
| < 50y 116(100%) |
50–64 170(100%) |
≥ 65 32(100%) |
||
|---|---|---|---|---|
| p value (F) | ||||
| Age admitted MMT*, y | 35.7 ± 7.3 | 45.8 ± 8.9 | 57.3 ± 9.1 | <0.001(100.3) |
| Female gender (%) | 42(36.2) | 21(12.4) | 2(6.3) | < 0.001 |
| HIV antibody (%) | 12(10.3) | 7(4.1) | 0(0.0) | 0.02(8.3) #0.009(6.8) |
| Hepatitis C antibody (%) | 70(60.3) | 85(50.6) | 13(40.6) | #0.03 (4.9) |
| Hepatitis C PCR (%) | 55(47.0) | 65(38.7) | 8(25.0) | #0.02(5.5) |
| Hepatitis B antigen (%) | 4(3.4) | 3(1.8) | 0(0.0) | 0.3 |
| Hypertension≠ (%) | 27(30.0) | 50(35.2) | 14(58.3) | 0.04(6.4), #0.03(4.9) |
| BMI*, kg/m2 | 26.0 ± 5.5 | 26.9 ± 5.1 | 24.8 ± 3.9 | 0.05(3.0) |
| Methadone dose*, mg/d | 121.9 ± 38.7 | 120.7 ± 39.2 | 117.8 ± 35.6 | 0.9 |
| Methadone plasma level*, ng/ml | 580.9 ± 270.9 | 715.4 ± 345.1 | 893.1 ± 379 | < 0.001(13.4) |
| Methadone plasma ≥ 1000ng/ml (%) | 8(6.9) | 32(18.8) | 12(37.5) | < 0.001 |
| QTc interval*, ms | 423.2 ± 31.3 | 430.7 ± 27.8 | 426.7 ± 29.5 | 0.1 |
| Substance abuse | ||||
| Opioids (%) | 18(15.7) | 8(4.7) | 1(3.2) | 0.004 |
| Cocaine (%) | 24(20.9) | 22(13.0) | 2(6.5) | 0.02# |
| Benzodiazepine (%) | 29(25.2) | 43(25.4) | 6(19.4) | 0.8 |
| Cannabis (%) | 14(12.2) | 16(9.5) | 2(6.5) | 0.6 |
Percentages are compared with Chi-square # Chi square Linear by linear association *Continuous variables are presented as mean ± S.D and compared with ANOVA, ≠information was available in 77.5%, 83.5%, and 75% of the groups, respectively
Multivariate analysis
Methadone plasma levels were still significantly different between age group (p < 0.001) in a model that included methadone dose (p < 0.001) and BMI (p = 0.02) (corrected model p < 0.001, F = 37.8). Methadone plasma level did not differ by all variables that differed between age groups: gender, hypertension, HIV, hepatitis C, opioids, and cocaine testing positive (data not shown).
Follow-up
Following 4.6 ± 1 years (range: 1 to 7.6 years), at the latest evaluation, the dose was reduced in 43.8% of patients, remained unchanged in 28.6%, and was increased in 15.6%. The reduction was most prevalent among the elderly group (39.5% in < 50y, 44.4% in 50–64.9y, and 56.3% in ≥ 65y; linear association, p = 0.016).
Table 2 present change in methadone dose and plasma level of age groups by selected variables. Specifically, the methadone dose was reduced significantly (Repeated Measures p(Time) = 0.004), with no interaction by age group (p(Time*Group) = 0.5) and no age groups difference (p(Group) = 0.6). Methadone plasma level was reduced significantly (p(Time) = 0.002), with no age group interaction (p(Time*Group) = 0.4), and a significant methadone plasma level difference between age groups (p(Group) < 0.001). QTc interval was reduced between the two evaluations (p(Time) < 0.001) and differed between age groups (p(Group) = 0.01). BMI was lower among the older group (p(Group) = 0.05), and also was reduced between the two evaluations (p(Time) = 0.046), specifically in the older group.
Table 2.
Change in methadone dose and plasma level of age groups by selected variables
| < 50y N = 116 |
50-64y N = 170 |
≥ 65y N = 32 |
p(T) (F) | p (T*G)(F) | P(G) (F) | |
|---|---|---|---|---|---|---|
| Methadone dose, mg/d | 0.004 (8.4) | 0.5 | 0.6 | |||
| 1st | 121.9 ± 38.7 | 120.7 ± 39.2 | 117.8 ± 35.6 | |||
| 2nd | 118.4 ± 44.1 | 116.9 ± 41.4 | 108.0 ± 31.6 | |||
| Methadone level, ng/ml | 0.002 (9.4) | 0.4 | < 0.001 (14.9) | |||
| 1st | 580.9 ± 270.9 | 715.4 ± 345.1 | 893.1 ± 379 | |||
| 2nd | 543.5 ± 285.7 | 626.8 ± 332.4 | 797.0 ± 329.1 | |||
| QTc interval, ms | < 0.001 (22.5) | 0.9 | 0.01 (4.3) | |||
| 1st | 423.2 ± 31.3 | 430.7 ± 27.8 | 426.7 ± 29.5 | |||
| 2nd | 411.4 ± 29.7 | 420.5 ± 26.5 | 414.4 ± 34.8 | |||
| BMI, kg/m2 | 0.046 (4.0) | 0.3 | 0.05 (3.0) | |||
| 1st | 26.0 ± 5.5 | 26.9 ± 5.1 | 24.8 ± 3.9 | |||
| 2nd | 26.0 ± 5.7 | 26.3 ± 5.3 | 23.9 ± 4.8 |
p(T) = p(Time); p(G) = p(Group); p(T*G) = p(Tima*Group)
Proportion of patients with methadone plasma levels ≥ 1000 ng/ml at each time point, by age group
Methadone plasma levels ≥ 1000 ng/ml at the first evaluation were among 14.8% (40 patients) of the 282 patients aged < 65 years, and in 9.2% (26 patients) at the second evaluation (10 in both evaluations). Of the 32 aged ≥ 65 years, the proportion was almost three times higher (37.5%, 12 patients) at the first evaluation and 28.1% at the second evaluation (9 patients, 7 from the first evaluation).
Comparison between patients by changes in methadone plasma levels and age groups
A decrease in methadone plasma levels was observed in 51.4% of patients aged < 65 years and 43.8% of those aged ≥ 65 years. No change was observed in 20.6% of patients aged < 65 years and 18.8% of those aged ≥ 65 years, while an increase in plasma levels was observed in 28.0% of patients aged < 65 years and 37.5% of those aged ≥ 65 years. No significant differences were found between the age groups (p = 0.5). When examining methadone dose changes by methadone plasma level change groups and age groups, a significant time effect and group differences were observed (Repeated measures: p(Time) = 0.046, p(Time*age group) = 0.053, p(Time*plasma level groups) < 0.001; p(Group: age group*plasma level group) = 0.016) (Figs. 1 and 2). Specifically, among patients aged < 65 years, the methadone dose increased in those whose plasma levels were elevated, decreased in those whose plasma levels were reduced, and remained stable in those with no change in plasma levels (Fig. 1). In contrast, among the elderly group (≥ 65 years), the methadone dose did not change in those with elevated plasma levels (see details of each patient in the appendix) and was reduced in patients whose plasma levels remained stable. The group whose plasma levels decreased showed a substantial reduction in methadone dose (Fig. 2).
Fig. 1.
Methadone dose at first and latest evaluation by methadone plasma level change groups, among the age < 65 y group
Fig. 2.
Methadone dose at first and latest evaluation by methadone plasma level change groups, among the age 65 + y group
Linear correlation
Methadone plasma levels linearly correlated with age of admission (R = 0.14, p = 0.013), age at evaluation (R = 0.27, p < 0.001), and BMI (R = 0.13, p = 0.02). Proportional changes in methadone dose linearly correlated with methadone plasma level change (R = 0.51, p < 0.001). The proportion change in weight linearly correlated with methadone level change (R = 0.19, p < 0.001), but not with proportion change of methadone dose (p = 0.2).
Methadone dose and plasma levels by age and sex groups (Table 3)
Table 3.
Change in methadone dose and plasma levels by age groups and by age and sex groups. (Data from 522 patients with methadone plasma levels measured by GC-MS)
| < 50y N = 358 |
≥ 50y N = 164 |
pT (F) |
p(T*G) (F) |
pG (F) | |
|---|---|---|---|---|---|
| Dose, mg/d | < 0.001 (55.9) | 0.005(8.1) | 0.004(8.4) | ||
| 1st | 145.0 ± 44.3 | 128.9 ± 40.0 | |||
| 2nd | 124.2 ± 45.0 | 119.6 ± 37.9 | |||
| Level, ng/ml | 0.5 | 0.025(5.0) | 0.3 | ||
| 1st | 569.9 ± 326.9 | 547.6 ± 253.1 | |||
| 2nd | 539.3 ± 406.6 | 607.7 ± 259.6 | |||
| Dose (Male) | n = 256 | n = 153 | < 0.001 | 0.031(4.6) Age | 0.06 Sex |
| 1st | 142.9 ± 42.1 | 127.7 ± 40.1 | |||
| 2nd | 125.3 ± 42.3 | 118.0 ± 37.6 | |||
| Dose (Female) | n = 102 | n = 11 | |||
| 1st | 150.2 ± 49.0 | 148.0 ± 34.6 | |||
| 2nd | 121.6 ± 57.0 | 143.5 ± 35.1 | |||
| Level (Male) | 0.7 | 0.09 Age | 0.06 Age | ||
| 1st | 567.8 ± 325.4 | 540.8 ± 256.1 | |||
| 2nd | 556.4 ± 452.2 | 598.4 ± 258.0 | |||
| Level (Female) | |||||
| 1st | 575.0 ± 332.0 | 642.7 ± 192.5 | |||
| 2nd | 496.3 ± 255.5 | 738.2 ± 258.0 |
p(T) = p(Time); p(G) = p(Group); p(T*G) = p(Tima*Group). The significant or trend for significant (p < 0.1) for Age and or Sex groups are reported
Based on data of 522 patients with methadone plasma levels detected by GC-MS:
The < 50 y age group presented a higher dose (Repeated measure, p(Group) = 0.004) that significantly decreased over time (p(Time) < 0.001), with an interaction between age groups (p(T*G) = 0.005) showing a stable low dose among the older > 50 y group. The methadone plasma level did not change over time (p(Time) = 0.5), but there was an interaction between age groups (p(T*G) = 0.025). Specifically, the level was elevated among the older group and decreased among the younger group. When stratified by age and sex groups, a similar pattern was observed (significant for the dose and as a trend toward significance for the plasma levels).
Discussion
This is the first study specifically evaluating the relationship between methadone dose and plasma level by age group, and how it changes over time. As would be expected, younger individuals showed a reduction in methadone plasma levels when the dose was reduced or maintained stable levels when the methadone dose remained unchanged. However, in elderly patients, methadone plasma levels were increased, although the methadone dose was stable, and even when the dose was reduced. These findings were independent of sex and observed in both males and females.
Interestingly, age and BMI did not relate in either the first or the latest evaluation; however, both BMI and age were inversely correlated with weight proportion change. The weight proportion change was positively linearly correlated with the methadone plasma level change. Therefore, weight reduction, particularly of older individuals, may be associated with the need for methadone dose reduction to adjust and reduce methadone to achieve an adequate plasma level.
The older group differs from the youngest patients in their lower rate of hepatitis C and HIV, as well as a lower proportion of substance abuse, which together describe a stable, maintained individual. On the other hand, the elderly group presents a higher prevalence of hypertension, a condition that has already been reported in the elderly receiving MMT [15].
We found that none of the above-mentioned variables that characterized the older subjects were significantly related to the higher methadone plasma levels that characterized the older patients. Therefore, as is already known, both the hepatic system and the kidney function normally decrease with age, and both systems are involved in methadone metabolism and clearance [5]. This most likely relates to the current findings of higher methadone plasma levels in the elderly. In addition, several medications that may be taken due to a medical condition, as well as prescribed or non-prescribed medications that are used, may affect the methadone dose. We recently reported that pregabalin, which is highly abused among our patients [16], is associated with a high methadone plasma level [17], but independent of age.
Another intriguing question regards the possible effects of the life-long use of drugs before initiation of the maintenance treatment (and rehabilitation) on the normal aging process: does it (and if it does, to what extent) accelerate the normal (age-associated) gradual decline in the liver and kidney functions, as well as in other body organs and mechanisms. It would be interesting to study differences between men and women, and to compare them to both smokers (tobacco) and non-smokers. This would be challenging to study in our population, as patients here tend to start MMT a decade later than in the USA [10].
Generally, when patients have no complaints about their methadone dose and no drugs detected in their urine, physicians assume their dose is adequate. Such patients as they become older, may be at risk for elevated (above therapeutic) methadone plasma levels, especially if they have also succeeded in losing weight.
Notably, without plasma level evaluation, the risk of excessively high methadone levels may not be detected. It should be emphasized that although there has been ongoing interest and attempts to define a ‘threshold’ trough plasma level, which is adequate to achieve treatment aims, the therapeutic window varies among laboratories and studies, ranging from 200 to 400 ng/ml [18–19] to 1000 ng/ml [9].
As periodic plasma level evaluations are a burden and expense to the patient and healthcare system, future follow-up is needed before recommending these evaluations. Additional information is needed regarding adverse effects (i.e., cognitive impairment, and ADL and IADL activity, as well as morbidity and mortality). Additional follow-up studies are needed on periodic plasma level evaluations, particularly at an older age and/or in cases of significant physical changes, such as weight reduction or hepatitis C cure, and not necessarily only in the presence of illness.
Limitation
In the current study, participants were mostly from one geographical and catchment area. The older group represented a small subgroup, particularly among female subjects, which reduced the statistical power of our results, but the difference, together with the change over time, emphasized our findings. The lack of information on concomitant medications and the lack of correlation with adverse effects served as additional limitations.
Conclusion
We found that, unlike young patients, methadone plasma levels in elderly patients, both male and female, increase over the years even when the methadone dose is stable or has been reduced. Specifically, patients who have no drugs in their urine, are stable on their dose for years, are doing well in their lives, and never complain, may be at risk of elevated (above-therapeutic) methadone plasma levels, especially if they have also experienced weight loss.
Acknowledgements
Acknowledge to Miriam and Sheldon G. Adelson Foundation for the Biology of Addictive Diseases.
Appendix
Methadone plasma levels of patients aged ≥65 with no dose change
| # | Age, y | Sex | Hepatitis C Ab | Dose Mg/d |
level ng/ml | Drug in urine | BMI | Time past (years) | Level ng/ml | BMI | Drug in urine |
|---|---|---|---|---|---|---|---|---|---|---|---|
| First evaluation | Latest evaluation | ||||||||||
| 1 | 77 | male | Negative | 90 | 440 | No | 23.6 | 6.23 | 530 | 19.3 | No |
| 2 | 72 | male | Positive | 95 | 1150 | Yes | 22.3 | 2.05 | 1244 | 22.6 | yes |
| 3 | 74 | male | Negative | 100 | 900 | No | 23.7 | 3.38 | 1072 | 19.4 | No |
| 4 | 66 | male | Negative | 110 | 650 | No | 21.5 | 6.02 | 220 | 23.6 | No |
| 5 | 75 | male | Negative | 115 | 970 | Yes | 20.0 | 3.62 | 800 | 18.7 | No |
| 6* | 65 | female | Positive | 140 | 1398 | Yes | 19.5 | 4.26 | 920 | 17.5 | yes |
| 7 | 70 | male | Positive | 150 | 1100 | Yes | 19.2 | 1.02 | 1125 | 18.1 | yes |
| 8 | 66 | male | Negative | 175 | 700 | Yes | 25.1 | 2.13 | 1452 | 21.7 | yes |
| 9 | 67 | male | Negative | 180 | 690 | No | 25.8 | 6.12 | 740 | 23.5 | No |
*This patient was treated for hepatitis C and was cured at the second evaluation
Author contributions
E.P wrote the manuscript and did the statistical analyses, A.S collected the data and was responsible for its accuracy, S.S and M.A were involved in the manuscript writing. All authors approved the final version.
Funding
Dr. Miriam and Sheldon G. Adelson Foundation for the Biology of Addictive Diseases.
Data availability
Data will be provided for reasonable request.
Declarations
Ethical approval
The study analyses were approved by the Helsinki Committee (IRB) 07-111 of the Tel Aviv Sourasky Medical Center.
Consent to participate
All participants signed informed consent.
Consent to publication
Approved by the Helsinki Committee (IRB) 07-111 of the Tel Aviv Sourasky Medical Center.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
Data will be provided for reasonable request.