Thymoquinone: From Nigella sativa to a protective pharmacological compound in managing opioid dependence and amphetamine type stimulant issues

Document Type : Mini Review


Faculty of Medicine, University Sultan Zainal Abidin, City Campus, 20400 Kuala Terengganu, Malaysia


Opioids, amphetamines, and other types of substances have been widely abused around the world. Opioid dependence and tolerance are two distinct phenomena that have been associated with substance abuse issues. The management of its adverse consequences is becoming more challenging. More and more people are treated in Methadone Maintenance Therapy (MMT) program yet the issues are still unresolved. Researchers are continuing to study the best formulation in treating opioid dependent people starting with modern and alternative drug therapies.  Since 2008 , thymoquinone (TQ) has been extensively studied by researchers around the world and has emerged to be a new potential drug candidate in managing substance abuse issues. Thus, the aim of this article is to review the effects that TQ may have on opioid dependent subjects and other abused substances such as amphetamine may have been studied. All of the articles from 2008 until 2019 involving the effects of TQ on substance abuse from Google Scholar®, Scopus®, and Pubmed® databases have been searched and reviewed. The keywords used were thymoquinone, opioid dependence, amphetamine, and Nigella sativa. The research results also have  been discussed in this article. Based on the research conducted, TQ was effective in reducing the adverse health consequences associated with substance abuse such as withdrawal symptoms, tolerance, and cell damages. It is concluded that TQ could be a potential drug that can be complemented with the currently available drugs in substance abuse therapies.


1. Stotts AL, Dodrill CL, Kosten TR. Opioid dependence treatment: options in pharmacotherapy. Expert Opin Pharmacother 2009; 10:1727-1740.
2. Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, Tagliamonte A. QTc interval prolongation in patients on long-term methadone maintenance therapy. Eur Addict Res 2004; 11:44-49.
3. Ghayur MN, Gilani AH, Janssen LJ. Intestinal, airway, and cardiovascular relaxant activities of thymoquinone. Evid Based Complement Alternat Med 2012; 2012:1-13.
4. Nutten S, Philippe D, Mercenier A, Duncker. Opioid receptors stimulating compounds (thymoquinone, nigella sativa) and food allergy: United states patent application no. 13/321,060.
5. Ahmad NZ, Mat KC, Mohamad N, Husain RB, Bakar NH, Zakaria NH, et al. A review on opioid dependence, mechanism and treatments used: option of treatments: modern versus alternative medicine. Bangladesh J Med Sci 2019; 18:171-177.
6. Shahraki S, Khajavirad A, Shafei MN, Mahmoudi M, Tabasi NS. Effect of total hydroalcholic extract of Nigella sativa and its n-hexane and ethyl acetate fractions on ACHN and GP-293 cell lines. J Tradit Complement Med 2015; 6:89-96.
7. Mehri S, Shahi M, Razavi BM, Hassani FV, Hosseinzadeh H. Neuroprotective effect of thymoquinone in acrylamide-induced neurotoxicity in Wistar rats. Iran J Basic Med Sci 2014; 17:1007-1011.
8. Sangi S, Ahmed SP, Channa MA, Ashfaq M, Mastoi SM. A new and novel treatment of opioid dependence: Nigella sativa 500 mg. J Ayub Med Coll Abbottabad 2008; 20:118-124.
9. Linjawi SA, Khalil WK, Hassanane MM, Ahmed ES. Evaluation of the protective effect of Nigella sativa extract and its primary active component thymoquinone against DMBA-induced breast cancer in female rats. Arch Med Sci 2015; 11:220-229.
10. Hosseinzadeh H, Parvardeh S, Nassiri-Asl M, Mansouri MT. Intracerebroventricular administration of thymoquinone, the major constituent of Nigella sativa seeds, suppresses epileptic seizures in rats. Med Sci Monit 2005; 11: 106-110.
11. Javidi S, Razavi BM, Hosseinzadeh H. A review of neuropharmacology effects of Nigella sativa and its main component, thymoquinone. Phytother Res 2016; 30:1219-1229.
12. Abdel-Zaher AO, Mostafa MG, Farghly HM, Hamdy MM, Omran GA, Al-Shaibani NK. Inhibition of brain oxidative stress and inducible nitric oxide synthase expression by thymoquinone attenuates the development of morphine tolerance and dependence in mice. Eur J Pharmacol 2013; 702:62-70.
13. Tabatabai SM, Dashti S, Doosti F, Hosseinzadeh H. Phytotherapy of opioid dependence and withdrawal syndrome: a review. Phytother Res 2014; 28:811-830.
14. Mohamad N, Bakar N, Musa N, Talib N, Ismail R. Better retention of Malaysian opiate dependents treated with high dose methadone in methadone maintenance therapy. Harm Reduct J 2010; 7:30-38.
15. Zhang L, Chow EP, Zhuang X, Liang Y, Wang Y, Tang C, et al. Methadone maintenance treatment participant retention and behavioural effectiveness in China: a systematic review and meta-analysis. Plos One 2013; 8:68906-68916.
16. Yang F, Lin P, Li Y, He Q, Long Q, Fu X, et al. Predictors of retention in community-based methadone maintenance treatment program in Pearl River Delta, China. Harm Reduct J 2013;10:3-10.
17. Adnan LMA, Mohamad N, Bakar NHA. Opioid dependent and substitution therapy: thymoquinone as potential novel supplement therapy for better outcome for mmt substitution therapy. Iran J Basic Med Sci 2014; 17:926-928.
18. Hosseinzadeh H, Parvardeh S, Masoudi A, Moghimi M, Mahboobifard F. Attenuation of morphine tolerance and dependence by thymoquinone in mice. Avicenna J Phytomed 2016; 6:55-66.
19. Adnan LHM, Mohamad N, Mat KC, Yeo CC, Bakar NH, Ismail R. Thymoquinone regulates gene expression levels in morphine addiction pathways in opioid receptor expressing cells (U87 MG). Electronic J Biol 2017; 13:166-173.
20. Liyana HMA, Nasir M, Khairi CM, Nor Hidayah AB, Siti NH, Mohd HM et al. Attenuation of morphine-induced cAMP overshoot by thymoquinone in opioid receptor expressing cells (u87 mg) mediated by chronic morphine treatment. J Eng Appl Sci 2018; 13:8906-8911.
21. Nestler EJ. Molecular mechanisms of drug addiction. Neuropharmacology 2004; 47:24-32.
22. Jalili C, Sohrabi M, Jalili F, Salahshoor MR. Assessment of thymoquinone effects on apoptotic and oxidative damage induced by morphine in mice heart. Cell Mol Biol 2018; 64:33-38.
23. Jalili C, Salahshoor MR, Hoseini M, Roshankhah S, Sohrabi M, Shabanizadeh A. Protective effect of thymoquinone against morphine injuries to kidneys of mice. Iran J Kidney Dis 2017; 11:142-150.
24. Md Fauzi NF, Bakar NH, Mohamad N, Mat KC, Omar SH, Othman M, et al. Potential therapeutic effects of thymoquinone on treatment of amphetamine abuse. Asian Pac J Trop Biomed 2018; 8:187-188.
25. Schrantee A, Vaclav L, Heijtel DF, Caan MWA, Gsell W, Lucassen PJ, et al. Dopaminergic system dysfunction in recreational dexamphetamine users. Neuropsychopharmacol 2015; 40:1172-1180.  
26. Ciccarone D. Stimulant abuse: Pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy. Prim Care 2011; 38:41-58.  
27. Norliza C, Norni A, Anandjit S, Mohd FM. A review of substance abuse research in Malaysia. Med Journal Malays 2014; 69:55-58.  
28. Ashok AH, Mizuno Y, Volkow ND, Howes OD. Association of stimulant use with dopaminergic alterations in users of cocaine, amphetamine, or methamphetamine: A systematic review and meta-analysis. JAMA Psychiatry 2017; 74:511-519.  
29. Mustafa NS, Bakar NH, Adnan LH, Fauzi NF, Thoarlim A, Omar SH, et al. Protective effects of thymoquinone on the MDMA-induced cerebrospinal fluid serotonin depletion in rats. Transylv Rev 2018; 1:1.