Hab-o Shefa,a Persian Medicine Compound for Maintenance Treatment of Opioid Dependence: Randomized Placebo-Controlled Clinical Trial

Abstract

Objectives:

The major problem in maintenance treatment of opioid use disorder is craving and relapse. The utilization of herbal compounds and complementary therapy for treatment of disease and addiction has been widely expanding. Considering the significant effect of Hab-o Shefa in detoxification phase, this clinical trial has explored the influence of this compound on maintenance treatment of opioid-dependent patients. This product is made of four herbs, including Datura stramonium L., Rheum palmatum L., Zingiber officinale Roscoe, and Acacia senegal L.

Design:

The authors conducted a two-group parallel randomized double-blind clinical trial on 81 opioid-dependent patients within 12 weeks. After medically assisted detoxification, participants were assigned randomly to Hab-o Shefa (n = 41) and placebo (n = 40). Outcome measures included craving assessed by craving beliefs questionnaire, self-reported opioid use, and lapse (any opioid-positive urine test) according to urinalysis and addiction severity index-lite questionnaire, retention in treatment, and depression and anxiety scores on the Hamilton's anxiety and depression scales.

Results:

Forty-one participants completed the study for 12 weeks, 21 subjects in the drug group and 20 subjects in the placebo group. The rates of opioid-positive urine tests and self-reported opioid use were significantly lower in Hab-o Shefa group (f = 8.41, p = 0.001). Hab-o Shefa also indicated a significant superiority over placebo in the effect of treatment by time interaction for craving (f = 5.91, p = 0.001), depression (f = 3.40, p = 0.01), and anxiety (f = 2.58, p = 0.035). The retention time was 66.6 days for drug group and 59.6 days for placebo one. Although the causes for dropping out in two groups were different, there was no significant difference (p = 0.623). The side effects of the two groups were not significantly different.

Conclusion:

Results indicated that Hab-o Shefa could be useful for opioid maintenance treatment, and it can also be considered as a new promising drug for prevention of craving and relapse.

Introduction

Opioid dependence is one of the major health concerns and social issues in most societies.¹ Opioids are among the three most commonly used substances in the world and they have also been the most problematic abused substances in Iran.² Generally, for addiction treatment, there are four main goals: reducing the symptoms of withdrawal, managing and controlling craving, stopping the rewarding effects of drugs, and treating comorbidities such as depression and anxiety.³

Although various methods have been suggested to attenuate withdrawal symptoms, a long-term treatment for at least 1 year or even more after detoxification phase is required.⁴ The main problem of treatment is relapse, which is defined as two or more consecutive lapses. Craving, described as a strong desire for substance use, is one of the main reasons for relapse.⁵ Based on several studies, some drugs have been found to reduce craving such as naltrexone and baclofen, but no drug has been specifically approved by the Food and Drug Administration as anticraving drug.^4,6

Moreover, the comorbidities are estimated to be up to 65% among opioid-dependent patients, which play an important role in relapse.⁷ Maintenance treatments for opioids have little effect on comorbidities.⁸ Finally, despite the existing therapeutic approaches and their positive effects, there is a treatment gap difference between prevalence of disease and the number of patients under treatment in the treatment of addiction.^2,9

Most recently, the utilization of traditional medicine for the treatment of addiction has been widespread in many countries. In the history, Persian medicine (PM) dates back to 10,000 years ago, which was one of the burgeoning schools of medicine.¹⁰ PM with several thousands of articles, famous scientists, and verbal sources in different languages can be helpful in the treatment of various diseases and in the development of new drugs by using modern technology.^11

–14 Some of the physicians in PM were the pioneers of neurology, psychiatry, and psychology.^15,16 Some of the first psychiatric hospitals were established by them.¹⁷ Imad al-Din Mahmud, a famous PM physician, has penned the first comprehensive book in history on the topic of opium and its pertinent issues.¹⁸ In the mentioned book and other PM literature, various methods such as replacement therapy with single product and herbal compounds for the treatment of opiate addiction were expressed. One of them is a herbal remedy called Hab-o Shefa.¹⁹ This product is made of four herbs, including Datura stramonium L., Rheum palmatum L., Zingiber officinale Roscoe, and Acacia senegal L. Herbal remedies can be an appropriate solution to this problem due to their high acceptance by the public and society, little side effects, high influence, availability, and affordability.^20,21

In recent investigations, Hab-o Shefa's effects on opioid withdrawal symptoms and pain were studied.^19,22
–24 The toxic consideration of Hab-o Shefa in the study of animal toxicology did not exhibit any toxicity sign, also in another randomized clinical trial (RCT), no significant side effect was observed.^19,22 In the double-blind clinical trial performed in the authors' research center on the effect of Hab-o Shefa on detoxification treatment of 90 opiates addicts, Hab-o Shefa was more effective than clonidine in controlling subjective opioid withdrawal symptom, clinical opioid withdrawal symptom, depression, and anxiety.²²

Considering the results of this product in detoxification phase, the aim of this study was to investigate the preliminary effect of this product on the rates of lapse, craving, anxiety, and depression in maintenance treatment for those with opioid use disorder.

Materials and Methods

Study overview

This study was registered in the Iranian Registry of Clinical Trial (RCT No. RCT2015101024446N1) and was licensed by Shahed University Research Ethics Committee (No. 1233/4) on March 9, 2015.

At the beginning of the study, the objectives, advantages, and the probable disadvantages of the process were comprehensively explained to the participants.

It was also mentioned that their cooperation is voluntary and in case of rejection, they can resume their routine treatment. Moreover, it was elaborated that they could quit their cooperation at any time they would like to. The first participant was enrolled on July 2015 and the last participant was discharged on March 2017. All subjects enrolled voluntarily and signed the informed consent.

Study design

This was a semiexperimental randomized parallel group and double-blind clinical trial. After detoxification, the subjects were treated for 12 weeks and evaluated for outcomes in four times: before the onset of the medication (pretest), 4 weeks (post-test 1), 8 weeks (post-test 2), and 12 weeks (post-test 3) after the onset of treatment. The participants of negative naloxone challenge test (NCT) were asked to complete the demographic information form, addiction severity index-lite (ASI-Lite) questionnaire, craving beliefs questionnaire (CBQ), and Hamilton's anxiety and depression scale. Patients were allowed to take acetaminophen and antihistamine if needed, but they were excluded from the study if continuous medication was necessary (for instance, in the case of remaining the symptoms of the disease or being afflicted to a disease that requires continuous treatment).

Detoxification and intervention

To initiate the study, first a complete description of research and its purpose was provided for the selected subjects. After consents of patients, they underwent detoxification by administration of clonidine, nonsteroid anti-inflammatory drugs such as diclofenac sodium, chlordiazepoxide, hyoscine, and acetaminophen over a period of 10–14 days. Then the drugs were gradually quitted within a week. At the end of detoxification, morphine urine test was performed and then, if negative, to determine the opioid dependence, the NCT was performed by intravenous administration of naloxone (0.8 mg). This test was indicative of opioid dependency, drug interferences that cause the morphine test result to be positive or false-negative have no effect on the result.

Subjects and location

The participants were selected for this trial from a residential center of addiction treatment in Isfahan, Iran (Its name was Navide Zendegi). The addiction therapist visited subjects and performed physical and psychologic examination. The number of patients in this period was 164. Subjects were selected using purposive sampling, a method that is selected for opting participants of the study with specific characteristics based on the inclusion and exclusion criteria.

Inclusion and exclusion criteria

In this study, the inclusion criteria were as follows: Diagnostic and Statistical Manual of Mental Disorders-IV criteria for addiction, age between 18 and 65 years, desire to participate in the study, healthy condition, and signed informed consent. The following exclusion criteria were considered: addiction to alcohol, positive history of other psychiatric disorders, taking psychiatric drugs such as sodium valproate and lithium, pregnancy and breast feeding, serious medical diseases such as glaucoma, urinary retention, epilepsy, Parkinson, brain disease, heart and renal disease, allergic reaction to medical herbs, and incidence of side effect.

Plant material

The combination of Hab-o Shefa includes Datura stramonium L. seed at a rate of 43.3%, root of Rheum palmatum L. at a rate of 27.9%, Zingiber officinale Roscoe rhizome at a rate of 14.4%, and Acacia senegal L. at a rate of 14.4%. D. stramonium is the main ingredient of this compound. Dry plant was purchased from Vazir Nezam Company in Tehran, Iran, and was identified in the Herbarium Center of School of Pharmacy, Tehran University of Medicinal Sciences, under the voucher numbers PMP-779 for Datura stramonium L. (solanaceae), PMP-250 for Rheum palmatum L. (polygonaceae), PMP-251 for Zingiber officinale Roscoe (zingiberaceae), and PMP-842 for Acacia Senegal L. (leguminosae). The products were completely floured and mixed according to the ratio mentioned earlier and prepared by the third person who was blind to the composition of drug as 500 mg capsules in the pharmaceutical laboratories of traditional medicine in Shahed University of Tehran, Iran. For placebo, powdered sugar was selected and prepared in capsules of the same shape and weight. The initial dose was 500 mg per day, with a daily increase of 500 mg to three capsules per day (eventually after 3 days).

Randomization

The selected patients randomly allocated to the study groups and the desired drugs (Hab-o Shefa or placebo) by using random number table that were encoded by computerized random numbers without any mention of names. They were distributed by a third person who had no direct contact with the patients and the investigator. The allocation ratio was 1:1, with 41 patients in the intervention group and 40 patients in the control group. The duration of the drug consumption was 12 weeks. Patients and prescribing doctor were not aware of the contents of capsules.

Assessments

The outcome measures in this study were the number of opioid negative urine test, craving, depression, anxiety, and retention in treatment. Craving measures beliefs about the craving substances and it has been assessed with CBQ, which is a self-report scale. The questionnaire contains 20 questions each of which is scored on a scale of 1–7 degrees (from strongly disagree to strongly agree).^25,26 Hamilton Rating Scale for Depression was employed to assess depression²⁷ and Hamilton Anxiety Scale was applied for assessment of anxiety.²⁸ Treatment retention is the number of days that the participant remains in the study from the beginning of the medication until the last day of the study.²⁹ The validity and reliability of all tools employed to fulfill this study have been evaluated and verified in Persian.^30

–33

Participants were examined each month and rated for symptoms typically pertinent to pharmacologic side effects of Hab-o Shefa by a score sheet, including headache, weakness, blurred vision, dyspnea, palpitation, dysuria, urinary retention, tremor, vertigo, and nausea. Each item was rated as present (1) or absent (0). Vital signs, including blood pressure, temperature, pulse rate, and respiration rate, were also recorded monthly.

Statistical analysis

Craving, anxiety, and depression were analyzed using SPSS version 16. For this purpose, repeated measures analysis of variance (ANOVA) was applied. Before performing repeated measures ANOVA, the normal distribution of the dependent variables was evaluated by the Kolmogorov–Smirnov test. Furthermore, so as to evaluate the assumption of sphericity matrix-dependent variables, Mauchly's test sphericity was utilized. The results revealed that the assumption of sphericity for anxiety, depression, and craving was established. All statistical tests were two-sided and were considered significant at p < 0.05.

Results

Characteristics of the participants, recruitment, retention in treatment, and follow-up

Figure 1 illustrates recruitment, enrollment, and follow-up of participants in this study. Out of 164 participants who were initially examined, 107 eligible patients were enrolled and detoxified. Among them, 26 failed to successfully complete the detoxification process. The 81 remained subjects were randomly allocated to two groups and received either drug or placebo. Finally, a total of 41 participants completed the study for 12 weeks: 21subjects in the drug group and 20 subjects in the placebo group.

FIG. 1.

Participant flow (Consolidated Standards of Reporting Trials diagram).

Demographic and clinical characteristics of participants are demonstrated in Table 1. There is no significant difference between the two groups in these parameters.

Table 1.

Baseline Demographic and Clinical Characteristics of Participants

	Hab-o Shefa	Placebo	p^*
Age, mean (SD)	33.9 (6.32)	35.85 (7.54)	0.375
Married, n (%)	13 (62)	10 (50)	0.443
Unemployed, n (%)	2 (9.6)	1 (5)	0.679
High-school education or less, n (%)	16 (76.2)	15 (75)	0.91
Years of opioid use, mean (SD)	10.76 (5.7)	10 (3.7)	0.623
Lifetime IDU, n (%)	6 (28.6)	7 (33.3)	0.83

By independent t test.

IDU, intravenous drug use; SD, standard deviation.

The mean retention time in the Hab-o Shefa group for 84 days of study was 66.6 ± 30.28 days and it was 59.60 ± 34.80 in the placebo group. Independent t test analysis indicated that there was no meaningful difference between the two groups (p = 0.623). The reasons for dropping out differed in two groups (Table 2). In the drug group, ineffectiveness of the drug was not the reason for dropping out and in case of a person (5%) interruption was due to relapse. In the placebo group, 30% of dropping out was due to insufficient efficacy (which was reported by participant) and in three persons (15%) interruption was due to relapse.

Table 2.

Reasons for Dropout in Hab-o Shefa and Placebo

	Hab-o Shefa (N = 41), n (%)	Placebo (N = 40), n (%)	Total (N = 81), n (%)
Left the residential center	17 (85)	11 (55)	28 (70)
Drug side effect	2 (10)	—	2 (5)
Relapse	1 (5)	3 (15)	4 (10)
Insufficient efficacy	—	6 (30)	6 (15)
Total	20 (48.8)	20 (50)	40 (49.4)

Effects on substance use

The results of morphine tests and self-reported opioid use are demonstrated in Table 3. The analysis by Mann–Whitney U test indicated that in the 8th and 12th weeks, the frequency of lapse rates in the placebo group was significantly higher than that of the Hab-o Shefa group. The self-reported opioid use also confirmed these findings so that with the passage of time, the self-reported opioid use in the Hab-o Shefa group was 0. However, it increased in the control group over time (f = 8.41, p = 0.001).

Table 3.

Results of Morphine Urine Test and Self-Reported Opioid Use

Time	Positive morphine urine test			Self-reported days of opioids use
Time	Hab-o Shefa	Placebo, n (%)	p	Hab-o Shefa	Placebo	p
4th Week	0	1 (5)	0.306	0	0.25 ± 1.12	0.312
8th Week	0	7 (35)	0.003	0	3.55 ± 7.41	0.017
12th Week	0	14 (70)	0.001	0	7.15 ± 9.05	0.001

The effects on craving, depression, and anxiety

To evaluate the efficacy of Hab-o Shefa on craving, anxiety, and depression in subjects, repeated measure ANOVA was employed. The results are presented in Table 4. The results demonstrated that all dependent variables in four stages of evaluation followed normal distribution. The results were considered for a selection of the test effects among the subjects.

Table 4.

Effects of Treatment-Group Assignment on Craving, Depression, and Anxiety

	Pretest (mean ± SD)	4th Week (mean ± SD)	8th Week (mean ± SD)	12th Week (mean ± SD)	Main effect of time	Main effect of time × treatment
Craving
Hab-o Shefa	71.55 ± 20.27	61.40 ± 11.38	59.05 ± 13.68	50.60 ± 9.89	F = 4.1^, p ^* = 0.002	F = 5.91^, p ^* = 0.001
Placebo	68.65 ± 19.48	58.01 ± 21.81	64.25 ± 19.17	71.50 ± 22.21
p-Value^***	0.647	0.338	0.63	0.003
Depression
Hab-o Shefa	10.45 ± 7.82	6.3 ± 3.9	6.55 ± 5.55	6.35 ± 4.48	F = 2.96^, p ^* = 0.021	F = 3.4^, p ^* = 0.01
Placebo	9.1 ± 4.45	7.35 ± 4.42	8.45 ± 5.15	12.3 ± 5.77
p-Value^***	0.253	0.217	0.126	0.001
Anxiety
Hab-o Shefa	11.8 ± 8.96	10.7 ± 4.93	12.1 ± 7.28	11.75 ± 5.63	F = 2.4^, p ^* = 0.042	F = 2.58^, p ^* = 0.035
Placebo	9.9 ± 5.01	11.8 ± 5.4	10.4 ± 5.12	16 ± 9.28
p-Value^***	0.413	0.5	0.388	0.04

The effects of the test subjects with the assumption of sphericity.

By repeated measure analysis of variance.

***

By independent t test.

ES, effect size.

Craving

The results of the test of pairwise comparisons with Bonferroni's correction indicated that the craving rate decreased significantly only in the Hab-o Shefa group. These results revealed that the Hab-o Shefa caused the reduction of craving over time (f = 4.10, p = 0.002). Also, the effect of treatment by time interaction indicated that the changing trend in craving over time in the Hab-o Shefa group was different from that of the placebo group (f = 5.91, p = 0.001). Thus, the craving score decreased in the Hab-o Shefa group, whereas in the placebo group it decreased in 4th week but increased in the 8th and 12th weeks.

Depression

There was a significant effect of time on depression (f = 2.96, p = 0.021). With this regard, the results of the test of pairwise comparisons with Bonferroni's correction demonstrated that the depression rate in placebo group increased significantly in 4th and 8th weeks compared with that of the 12th week. In contrast, the level of depression in the Hab-o Shefa group has not changed over time. Also, the effect of treatment by time interaction indicated that the trend of change in depression over time in the Hab-o Shefa group was different from that of placebo group (f = 3.40, p = 0.010).

Anxiety

The results of the test of pairwise comparisons with Bonferroni's correction displayed that the anxiety rate changed only in the placebo group. In contrast, the level of anxiety in the Hab-o Shefa group did not change over time. So, there was a significant categorical effect of time (f = 2.40, p = 0.021). Also, the effect of treatment by time interaction disclosed that the trend of change in anxiety over time in the Hab-o Shefa group was different from that of placebo group (f = 2.58, p = 0.035). On the contrary, although the change in anxiety level in the placebo group until week 8 was almost constant, it increased significantly in week 12.

Discussion

The objective of this study was to investigate the effect of Hab-o Shefa on the rates of lapse, retention in treatment, craving, anxiety, and depression in maintenance treatment of people with opioid use disorder. This is the first time that this study has been conducted for evaluation of this component in maintenance treatment. The results showed that this compound has reduced the rates of lapse, self-reported opioid use, craving, depression, and anxiety.

The index of lapse rates in this study has suggested that the rate of lapses in the placebo group is significantly higher than the Hab-o Shefa group. Also, the results of the ASI-Lite questionnaire have unraveled that the Hab-o Shefa group did not have any history of self-reported opioid use during the study, whereas in the placebo group an increase in the number of days of consumption was evident. Although there has not been any similar study on Hab-o Shefa, studies on the effect of other drugs in opioid maintenance therapy such as baclofen, olanzapine, and extended-release naltrexone have disclosed similar results in terms of the positive morphine urine test and self-reported opioid use.^30,34,35 One of the fascinating points in this study was the significant difference of self-reported opioid use and rates of lapse between placebo and Hab-o Shefa after the first month. The two groups showed similar results in the first month. To explain such results, it can be inferred that one of the reasons for the negative morphine urine test and self-reported opioid use in the placebo group in the week 4 is the placebo effect that was eliminated after this period and consequently the rates of lapse were increased in the placebo group. Thus, the Hab-o Shefa despite lack of agonistic effects on opioid receptors led to significant reduction in the rates of lapse and self-reported opioid use.

Shih-ku Lin who reviewed the drugs for craving states that among naltrexone, acomprosate, topiramate, disulfiram, baclofen, n-acetyl cysteine and bupropion that were presented as anticraving drugs, only naltrexone and baclofen effectively reduced craving in opioid addicted patients.³⁶ The possible cause of anticraving effect of naltrexone may be lack of pleasure in the use of opioid. However, the mechanism of baclofen is unclear.⁴ The results also demonstrated that Hab-o Shefa significantly reduced craving scores compared with that of placebo (Table 4). The mechanism(s) of Hab-o Shefa in reduction of craving is not clear yet. However, the most important alkaloids of Datura stramonium L. (main ingredient of Hab-o Shefa) are scopolamine and hyoscyamine that have anticholinergic effect.³⁷ In this regard, Liu et al. have reported that administration of scopolamine in opioid addicts, not only did reduce physical symptoms in detoxification, but also had significant anticraving effect compared with the effect of methadone.³⁸

The results indicated that the depression and anxiety scores in the placebo group increased significantly during the week 12. On the contrary, these scores in the Hab-o Shefa group did not change over time. The mechanism(s) of Hab-o Shefa in reducing depression and anxiety are yet to be identified. In case of its main alkaloid, scopolamine, several studies on animals and human beings have displayed evidence of antidepressant effects of scopolamine.^39

–42 In tandem with these results, increasing cholinergic activity can induce depression-like behaviors in human beings and animals, consequently reducing cholinergic activity may be associated with alleviated depressive symptoms.^43

–47

Study limitations

This study had some limitations. One of the limitations was the high rate of dropping out during the study. Many patients were discharged from the center after treatment's period and had no access to the study. The next limitation was the small sample size. Failure to follow-up after termination of intervention to evaluate the efficacy or possible side effects was another limitation. Moreover, false-negative urine morphine test was a limitation, of course, for both groups.

Conclusions

The results of this study have provided the primary evidence to support the hypothesis that Hab-o Shefa is useful in opioid maintenance treatment and its associated parameters, particularly craving. In terms of relapse prevention, it can be a new promising drug. Further studies are required to elucidate the underlying mechanism(s) of Hab-o Shefa on craving. It is recommended for future studies to be conducted with larger participants and in outpatient centers. In addition, the patients could be followed up, for example, 6 months after completion of treatment to determine the product stability effects.

Footnotes

Acknowledgments

This article is inspired from a PhD student thesis (No. 24/90) of traditional Persian medicine (TPM) in the department of TPM, School of Medicine, Shahed University, Tehran, Iran.

Statement of Ethics

The Iranian Registry of Clinical Trial number and Ethics Committee license of this study was RCT2015101024446N1 and No. 1233/4 on March 9, 2015, respectively.

Authors' Contributions

Ab.M. performed experiments and cowrote the article; Az.M. and M.N. designed the experiments and cowrote the article; F.G., H.A., and R.J.H. cowrote the article; S.F. did the data analysis.

Author Disclosure Statement

The authors have declared that there is no conflict of interest.

Funding Information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

Mokri

, Chawarski

, Taherinakhost

, et al. Medical treatments for opioid use disorder in Iran: A randomized, double-blind placebo-controlled comparison of buprenorphine/naloxone and naltrexone maintenance treatment. Addiction, 2016; 111:874–882.

Fedotov

. World Drug Report. New York: United Nations Office on Drug and Crime, 2018.

Edens

, Massa

, Petrakis

. Novel pharmacological approaches to drug abuse treatment. Curr Top Behav Neurosci, 2010; 3:343–386.

O'Brien

. Anticraving medications for relapse prevention: A possible new class of psychoactive medications. Am J Psychiatry, 2005; 162:1423–1431.

Koob

, Volkow

. Neurobiology of addiction: A neurocircuitry analysis. Lancet Psychiatry, 2016; 3:760–773.

Fareed

, Vayalapalli

, Casarella

, et al. Heroin anticraving medications: A systematic review. Am J Drug Alcohol Abuse, 2010; 36:332–341.

McRae

, Sonne

, Brady

, et al. A randomized, placebo-controlled trial of buspirone for the treatment of anxiety in opioid-dependent individuals. Am J Addict, 2004; 13:53–63.

Teoh Bing Fei

, Yee

, Habil

MHB

. Psychiatric comorbidity among patients on methadone maintenance therapy and its influence on quality of life. Am J Addict, 2016; 25:49–55.

Kreek

, Vocci

. History and current status of opioid maintenance treatments: Blending conference session. J Subst Abuse Treat, 2002; 23:93–105.

10.

Ghaffari

, Naseri

, Jafari Hajati

, et al. Rhazes, a pioneer in contribution to trials in medical practice. Acta Med Hist Adriat, 2017; 15:261–270.

11.

Ahmadi

, Mohagheghi

, Karimi

, et al. Therapeutic effects of HESA-A in patients with end-stage metastatic cancers. Integr Cancer Ther, 2010; 9:32–35.

12.

Ghaffari

, Naseri

, Asghari

, et al. Abul-hasan al-tabari: A review of his views and works. Arch Iran Med, 2014; 17:299–301.

13.

Pasalar

, Lankarani

, Mehrabani

, et al. The effect of Descureania sophia L. and Prunus domestica L. in prevention of constipation among Iranian Hajj Pilgrims, Saudi Arabia. Res J Pharm Biol Chem Sci, 2013; 2:1195–1204.

14.

Soltanian

, Mehdibarzi

, Faghihzadeh

, et al. Mixture of Arnebia euchroma and Matricaria chamomilla (Marhame-Mafasel) for pain relief of osteoarthritis of the knee—A two-treatment, two-period crossover trial. Arch Med Sci 2010;6 950.

15.

Ghaffari

, Naseri

, Movahhed

, et al. Spinal traumas and their treatments according to Avicenna's Canon of Medicine. World Neurosurg, 2015; 85:173–177.

16.

Nozad

, Naseri

, Safari

, et al. Food reduction in Avicenna's view and related principles in classical. Iran Red Crescent Med J, 2016; 18:e25760.

17.

Najmabadi

. History of Medicine in Iran after Islam [In Persian]. Tehran: Tehran University, 1996.

18.

Moosavyzadeh

, Ghaffari

, Mosavat

, et al. The medieval Persian manuscript of Afyunieh: The first individual treatise on the opium and addiction in history. J Integr Med, 2018; 16:77–83.

19.

Nazari

, Naseri

, Mokri

, et al. Evaluation of the effect of oral administration of Hab-o Shefa on morphine withdrawal syndrome in rats: A behavioral study. J Basic Clin Pathophysiol, 2013; 1:45–49.

20.

Kerachian

, Alaee

, Gharavi-Naini

, et al. Effects of alcoholic extract of Avena sativa, Hypericum perforatum, Passiflora incarnata and Lavandula officinalis on symptoms of morphine withdrawal syndrome in rats [In Persian]. Physiol Pharmacol, 2007; 10:313–321.

21.

Rahimi-Movaghar

, Khastoo

, Fekri

, Sh

. Treatment of addiction by medicinal herbs sellers in Tehran. Hakim Syst Res J, 2008; 11:11–19.

22.

Nazari

, Naseri

, Mokri

, et al. Hab-o Shefa (an Iranian traditional medicine compound) in withdrawal syndrome and its effects in acute detoxification of opiates addict: A randomized, double blind, clinical trials. J Med Plant Res, 2013; 7:1628–1635.

23.

Ghayoorul

, Iqbal

, Ghufran

, et al. Efficacy of Habb-e-Shifa as pre-anaesthetic medication. Hamdard Med, 2009; 52:87–96.

24.

Tajuddin

, Khan

, Tajuddin Afzat

. Analgesic, anticonvulsant and antipyretic effects of a Unani compound formulation, Habb-e-Shifa. Indian J Traditional Knowl, 2007; 6:315–318.

25.

Beck

, Steer

, Brown

. Manual for the Beck Depression Inventory—II. San Antonio, TX: The Psychological Corporation. Harcourt Brace & Company San Antonio, 1996.

26.

Newman

. Cognitive Therapy of Substance Abuse. New York: Guilford Press, 2001.

27.

Hamilton

. A rating scale for depression. J Neurol Neurosurg Psychiatry, 1960; 23:5642.

28.

Maier

, Buller

, Philipp

, et al. The Hamilton anxiety scale: Reliability, validity and sensitivity to change in anxiety and depressive disorders. J Affect Disord, 1988; 14:61–68.

29.

Guo

, Manning

, Yang

, et al. Lofexidine versus diazepam for the treatment of opioid withdrawal syndrome: A double-blind randomized clinical trial in Singapore. J Subst Abuse Treat, 2018; 91:1–11.

30.

Mokri

, Shams

, Bagheri Valujerdi

, et al. The study of the effectiveness of olanzapine as a maintenance treatment in opioid dependents: A randomized clinical trial [In Persian]. Res Addict, 2009; 3:53–76.

31.

Gharaii

, Mehryar

, Mehrabi

. Attribution style in patients with anxiety and depression comorbidity. Iran J Psychiatry Clin Psychol, 2000; 5:37–43.

32.

Khaleghi

, Mohammadkhani

, Hasani

. Effectiveness of emotional schema therapy in reduction of Worry and Anxiety's signs and symptoms in patients with generalized anxiety disorder: Single-subject design. J Clin Psychol, 2016; 8:43–55.

33.

Rahmanian

, Mirjafari

, Hasani

. The relationship between craving and attentional bias in opioid dependent, relapsed and abstinent individuals. Iran J Psychiatry Clin Psychol, 2006; 12:216–222.

34.

Assadi

, Radgoodarzi

, Ahmadi-Abhari

. Baclofen for maintenance treatment of opioid dependence: A randomized double-blind placebo-controlled clinical trial [ISRCTN32121581]. BMC Psychiatry, 2003; 3:16.

35.

Krupitsky

, Nunes

, Ling

, et al. Injectable extended-release naltrexone for opioid dependence: A double-blind, placebo-controlled, multicentre randomised trial. Lancet, 2011; 377:1506–1513.

36.

Lin

. Pharmacological means of reducing human drug dependence: A selective and narrative review of the clinical literature. Br J Clin Pharmacol, 2014; 77:242–252.

37.

Miraldi

, Masti

, Ferri

, et al. Distribution of hyoscyamine and scopolamine in Datura stramonium . Fitoterapia, 2001; 72:644–648.

38.

Liu

, Li

, Shen

, et al. Scopolamine detoxification technique for heroin dependence: A randomized trial. CNS Drugs, 2013; 27:1093–1102.

39.

Drevets

, Furey

. Replication of scopolamine's antidepressant efficacy in major depressive disorder: A randomized, placebo-controlled clinical trial. Biol Psychiatry, 2010; 67:432–438.

40.

Furey

, Khanna

, Hoffman

, et al. Scopolamine produces larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology, 2010; 35:2479–2488.

41.

Khajavi

, Farokhnia

, Modabbernia

, et al. Oral scopolamine augmentation in moderate to severe major depressive disorder: A randomized, double-blind, placebo-controlled study. J Clin Psychiatry, 2012; 73:1428–1433.

42.

Witkin

, Overshiner

, Li

, et al. M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther, 2014; 351:448–456.

43.

Drevets

, Zarate

, Furey

. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: A review. Biol Psychiatry, 2013; 73:1156–1163.

44.

Janowsky

, Davis

, El-Yousef

, et al. A cholinergic-adrenergic hypothesis of mania and depression. Lancet, 1972; 300:632–635.

45.

Janowsky

, El-Yousef

, Davis

, et al. Cholinergic reversal of manic symptoms. Lancet, 1972; 299:1236–1237.

46.

Krystal

. N-methyl-D-aspartate glutamate receptor antagonists and the promise of rapid-acting antidepressants. Arch Gen Psychiatry, 2010; 67:1110–1111.

47.

Liu

, Zhou

, Xie

, et al. Muscarinic receptors modulate the mRNA expression of NMDA receptors in brainstem and the release of glutamate in periaqueductal grey during morphine withdrawal in rats [In Chinese]. Sheng Li Xue Bao, 2004; 56:95–100.