SpringerLink
Log in

Chronic Administration of Lisdexamfetamine Induces Apoptosis and Inflammation and Reduces Sperm Quality in Adult Male Rats

  • Reproductive Biology: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Concerns have been raised about potentially irreversible brain damage and damage to the neuroendocrine system during development when treating attention-deficit/hyperactivity disorder with lisdexamfetamine (LDX), a norepinephrine dopamine reuptake inhibitor. This study aims to elucidate the potential adverse effects of LDX on the male reproductive system due to its widespread use and potential for abuse. In this study, adult male rats were randomized into control and LDX groups. Thirty milligrams per kilogram LDX was administered orally for 3 weeks. After isolation of epididymal spermatozoa, the rats were euthanized and testicular tissues were collected for stereological and molecular analyses. The LDX group showed a decrease in sperm motility and an increase in DNA fragmentation compared to the control group. There was also a dramatic decrease in testosterone in the LDX group. Testicular expression of caspase-3 and TNF-α was significantly increased in the LDX group. According to our findings, prolonged use of LDX leads to reduced sperm quality. It also induces apoptosis, inflammatory response, and pathological changes in the testicular tissue. What we have observed in this study is noteworthy but requires further investigation, particularly in people who use LDX over a longer period of time.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Subcommittee on Attention-Deficit/Hyperactivity Disorder SCoQI, Management. ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. IL, USA: American Academy of Pediatrics Elk Grove Village; 2011. p. 1007–22.

    Google Scholar 

  2. Jain U, Hechtman L, Quinn D, Turgay A, Yaremko J, Mutch C. Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines. Toronto, Canada: CADDRA; 2006.

    Google Scholar 

  3. Banaschewski T, Coghill D, Santosh P, Zuddas A, Asherson P, Buitelaar J, et al. Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry. 2006;15(8):476–95.

    PubMed  Google Scholar 

  4. Wolraich ML, Hagan JF Jr, Allan C, Chan E, Davison D, Earls M, et al. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019;144(4):e20192528.

  5. Kooij J, Bijlenga D, Salerno L, Jaeschke R, Bitter I, Balazs J, et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019;56(1):14–34.

    CAS  PubMed  Google Scholar 

  6. Hodgkins P, Shaw M, McCarthy S, Sallee FR. The pharmacology and clinical outcomes of amphetamines to treat ADHD. CNS drugs. 2012;26(3):245–68.

    CAS  PubMed  Google Scholar 

  7. Coghill DR, Caballero B, Sorooshian S, Civil R. A systematic review of the safety of lisdexamfetamine dimesylate. CNS drugs. 2014;28(6):497–511.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Goodman DW. Lisdexamfetamine dimesylate (vyvanse), a prodrug stimulant for attention-deficit/hyperactivity disorder. Pharm Ther. 2010;35(5):273.

    Google Scholar 

  9. Adler LA, Alperin S, Leon T, Faraone SV. Pharmacokinetic and pharmacodynamic properties of lisdexamfetamine in adults with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2017;27(2):196–9.

    CAS  PubMed  Google Scholar 

  10. Ermer JC, Pennick M, Frick G. Lisdexamfetamine dimesylate: Prodrug delivery, amphetamine exposure and duration of efficacy. Clin Drug Investig. 2016;36(5):341–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hutson PH, Pennick M, Secker R. Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: A novel d-amphetamine pro-drug. Neuropharmacology. 2014;87:41–50.

    CAS  PubMed  Google Scholar 

  12. Schneider E, Higgs S, Dourish CT. Lisdexamfetamine and binge-eating disorder: A systematic review and meta-analysis of the preclinical and clinical data with a focus on mechanism of drug action in treating the disorder. Eur Neuropsychopharmacol: J Eur College Neuropsychopharmacol. 2021;53:49–78.

    CAS  Google Scholar 

  13. Cantwell DP. Attention deficit disorder: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 1996;35(8):978–87.

    CAS  PubMed  Google Scholar 

  14. CDC. Data and statistics about ADHD. 2023. Available from: https://www.cdc.gov/ncbddd/adhd/data.html.

  15. Siffel C, Page M, Maxwell T, Thun B, Kolb N, Rosenlund M, et al. Patterns of lisdexamfetamine dimesylate use in children, adolescents, and adults with attention-deficit/hyperactivity disorder in Europe. J Child Adolesc Psychopharmacol. 2020;30(7):439–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Samplaski MK, Nangia AK. Adverse effects of common medications on male fertility. Nat Rev Urol. 2015;12(7):401–13.

    CAS  PubMed  Google Scholar 

  17. Pham MN, Hudnall MT, Fantus RJ, Lai JD, Ambulkar SS, Wren JM, et al. The adverse association between stimulant use for attention deficit hyperactivity disorder (ADHD) and semen parameters. Andrologia. 2022;54(2):e14315.

    CAS  PubMed  Google Scholar 

  18. Barr AM, Hofmann CE, Weinberg J, Phillips AG. Exposure to repeated, intermittent d-amphetamine induces sensitization of HPA axis to a subsequent stressor. Neuropsychopharmacology. 2002;26(3):286–94.

    CAS  PubMed  Google Scholar 

  19. Dickerson SM, Walker DM, Reveron ME, Duvauchelle CL, Gore AC. The recreational drug ecstasy disrupts the hypothalamic-pituitary-gonadal reproductive axis in adult male rats. Neuroendocrinology. 2008;88(2):95–102.

    CAS  PubMed  Google Scholar 

  20. Duca Y, Aversa A, Condorelli RA, Calogero AE, La Vignera S. Substance abuse and male hypogonadism. J Clin Med. 2019;8(5):732.

  21. Barenys M, Macia N, Camps L, de Lapuente J, Gomez-Catalan J, Gonzalez-Linares J, et al. Chronic exposure to MDMA (ecstasy) increases DNA damage in sperm and alters testes histopathology in male rats. Toxicol Lett. 2009;191(1):40–6.

    CAS  PubMed  Google Scholar 

  22. Garcia-Quevedo L, Blanco J, Sarrate Z, Català V, Bassas L, Vidal F. Hidden mosaicism in patients with Klinefelter's syndrome: Implications for genetic reproductive counselling. Hum Reprod. 2011;26(12):3486–93.

    CAS  PubMed  Google Scholar 

  23. Malekasgar AM, Mombaini H. Screening of ‘Y’chromosome microdeletions in Iranian infertile males. J Hum Reprod Sci. 2008;1(1):2.

    PubMed  PubMed Central  Google Scholar 

  24. Patel B, Johnstone E, Presson A, Zhang C, Jenkins T, Aston K, et al. The effect of ADHD medications on semen analysis in sub-fertile couples. Fertil Steril. 2016;106(3):e234.

    Google Scholar 

  25.  Lacroix B, Citovsky V. A mutation in negative regulator of basal resistance WRKY17 of Arabidopsis increases susceptibility to Agrobacterium-mediated genetic transformation. F1000Res. 2013;2:33.

  26. Shalev H, Mizrakli Y, Zeadna A, Harlev A, Levitas E, Ifergane G, et al. Does methylphenidate use affect sperm parameters in patients undergoing infertility investigation? A retrospective analysis of 9769 semen samples. Arch Gynecol Obstet. 2021;304(2):539–46.

    CAS  PubMed  Google Scholar 

  27. Adriani W, Leo D, Guarino M, Natoli A, Di Consiglio E, De Angelis G, et al. Short-term effects of adolescent methylphenidate exposure on brain striatal gene expression and sexual/endocrine parameters in male rats. Ann N Y Acad Sci. 2006;1074(1):52–73.

    CAS  PubMed  Google Scholar 

  28. Manjanatha MG, Shelton SD, Dobrovolsky VN, Shaddock JG, McGarrity LG, Doerge DR, et al. Pharmacokinetics, dose-range, and mutagenicity studies of methylphenidate hydrochloride in B6C3F1 mice. Environ Mol Mutagen. 2008;49(8):585–93.

    CAS  PubMed  Google Scholar 

  29. Cansu A, Ekinci O, Ekinci O, Serdaroglu A, Erdogan D, Coskun ZK, Gürgen SG. Methylphenidate has dose-dependent negative effects on rat spermatogenesis: Decreased round spermatids and testicular weight and increased p53 expression and apoptosis. Hum Exp Toxicol. 2011;30(10):1592–600.

    CAS  PubMed  Google Scholar 

  30. Harlev A, Henkel R, Samanta L, Agarwal A. Ritalinic acid stimulates human sperm motility and maintains vitality in vitro. World J Mens Health. 2020;38(1):61–7.

    PubMed  Google Scholar 

  31. Da B, Schneider M, Youreneff M, Tse FL. Developmental toxicity assessment of d, l-Methylphenidate and d-Methylphenidate in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2008;83(5):489–501.

    Google Scholar 

  32. Wang Y. Epididymal sperm count. Curr Protoc Toxicol. 2002;14(1):16.6.1-.6. 5.

    Google Scholar 

  33. Ghaffari Novin M, Sabbagh Alvani M, Mafi Balani M, Aliaghaei A, Afshar A, Aghajanpour F, et al. Therapeutic effects of edaravone on azoospermia: Free radical scavenging and autophagy modulation in testicular tissue of mice. J Reprod Infertil. 2022;23(2):73–83.

    PubMed  PubMed Central  Google Scholar 

  34. Raee P, Shams Mofarahe Z, Nazarian H, Abdollahifar M-A, Ghaffari Novin M, Aghamiri S, Ghaffari NM. Male obesity is associated with sperm telomere shortening and aberrant mRNA expression of autophagy-related genes. Basic Clin Androl. 2023;33(1):13.

    PubMed  PubMed Central  Google Scholar 

  35. Nudmamud-Thanoi S, Thanoi S. Methamphetamine induces abnormal sperm morphology, low sperm concentration and apoptosis in the testis of male rats. Andrologia. 2011;43(4):278–82.

    CAS  PubMed  Google Scholar 

  36. Fazelipour S, Jahromy MH, Tootian Z, Kiaei SB, Sheibani MT, Talaee N. The effect of chronic administration of methylphenidate on morphometric parameters of testes and fertility in male mice. J Reprod Infertil. 2012;13(4):232.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Johnsen SG. Testicular biopsy score count—a method for registration of spermatogenesis in human testes: Normal values and results in 335 hypogonadal males. Hormones. 1970;1(1):2–25.

    CAS  PubMed  Google Scholar 

  38. Thanh TN, Van PD, Cong TD, Le Minh T, Vu QHN. Assessment of testis histopathological changes and spermatogenesis in male mice exposed to chronic scrotal heat stress. J Anim Behav Biometeorol. 2020;8(3):174–80.

    Google Scholar 

  39. Zarei L, Sadrkhanlou R, Shahrooz R, Malekinejad H, Eilkhanizadeh B, Ahmadi A. Protective effects of vitamin E and Cornus mas fruit extract on methotrexate-induced cytotoxicity in sperms of adult mice. Vet Res Forum. 2014;5(1):21–7.

  40. Sabour M, Khoradmehr A, Kalantar SM, Danafar AH, Omidi M, Halvaei I, et al. Administration of high dose of methamphetamine has detrimental effects on sperm parameters and DNA integrity in mice. Int J Reprod Biomed. 2017;15(3):161–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Panahi S, Karamian A, Sajadi E, Aliaghaei A, Nazarian H, Abdi S, et al. Sertoli cell–conditioned medium restores spermatogenesis in azoospermic mouse testis. Cell and Tissue Res. 2020;379(3):577–87.

    CAS  Google Scholar 

  42. Ziaeipour S, Ahrabi B, Naserzadeh P, Aliaghaei A, Sajadi E, Abbaszadeh H-A, et al. Effects of Sertoli cell transplantation on spermatogenesis in azoospermic mice. Cell Physiol Biochem. 2019;52:421–34.

    CAS  PubMed  Google Scholar 

  43.  Eskandarian Boroujeni M, Peirouvi T, Shaerzadeh F, Ahmadiani A, Abdollahifar MA, Aliaghaei A. Differential gene expression and stereological analyses of the cerebellum following methamphetamine exposure. Addict Biol. 2020;25(1):e12707.

  44. Alavi SH, Taghavi MM, Moallem SA. Evaluation of effects of methamphetamine repeated dosing on proliferation and apoptosis of rat germ cells. Syst Biol Reprod Med. 2008;54(2):85–91.

    CAS  PubMed  Google Scholar 

  45. Yamamoto Y, Yamamoto K, Hayase T. Effect of methamphetamine on male mice fertility. J Obstet Gynaecol. 1999;25(5):353–8.

    CAS  Google Scholar 

  46. Tsai S-C, Chiao Y-C, Lu C-C, Doong M-L, Chen YH, Shih HC, et al. Inhibition by amphetamine of testosterone secretion through a mechanism involving an increase of cyclic AMP production in rat testes. Br J Pharmacol. 1996;118(4):984.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hall P. Testicular steroid synthesis: Organization and regulation. Biol Reprod. 1994;2:1335–62.

  48. Rodriguez-Menchaca AA, Solis E Jr, Cameron K, De Felice LJ. S(+)amphetamine induces a persistent leak in the human dopamine transporter: Molecular stent hypothesis. Br J Pharmacol. 2012;165(8):2749–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Carvelli L, McDonald PW, Blakely RD, DeFelice LJ. Dopamine transporters depolarize neurons by a channel mechanism. Proc Natl Acad Sci U S A. 2004;101(45):16046–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. DeFelice LJ, Goswami T. Transporters as channels. Annu Rev Physiol. 2007;69:87–112.

    CAS  PubMed  Google Scholar 

  51. Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP, Amara SG. Multiple ionic conductances of the human dopamine transporter: The actions of dopamine and psychostimulants. J Neurosci. 1997;17(3):960–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cameron KN, Solis E Jr, Ruchala I, De Felice LJ, Eltit JM. Amphetamine activates calcium channels through dopamine transporter-mediated depolarization. Cell Calcium. 2015;58(5):457–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ruchala I, Cabra V, Solis E Jr, Glennon RA, De Felice LJ, Eltit JM. Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels. Cell Calcium. 2014;56(1):25–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. van Loo G, Bertrand MJM. Death by TNF: A road to inflammation. Nat Rev Immunol. 2023;23(5):289–303.

    PubMed  Google Scholar 

  55. Valvassori SS, Resende WR, Varela RB, Arent CO, Gava FF, Peterle BR, et al. The effects of histone deacetylase inhibition on the levels of cerebral cytokines in an animal model of mania induced by dextroamphetamine. Mol Neurobiol. 2018;55(2):1430–9.

    CAS  PubMed  Google Scholar 

  56. Quintero J, Gutiérrez-Casares JR, Álamo C. Molecular characterisation of the mechanism of action of stimulant drugs lisdexamfetamine and methylphenidate on ADHD neurobiology: A review. Neurol Ther. 2022;11(4):1489–517.

    PubMed  PubMed Central  Google Scholar 

  57. Theas MS, Rival C, Dietrich SJ, Guazzone VA, Lustig L. Death receptor and mitochondrial pathways are involved in germ cell apoptosis in an experimental model of autoimmune orchitis. Human Reprod. 2006;21(7):1734–42.

    CAS  Google Scholar 

  58. Theas S, Rival C, Lustig L. Germ cell apoptosis in autoimmune orchitis: Involvement of the Fas-FasL system. Am J Reprod Immunol. 2003;50(2):166–76.

    PubMed  Google Scholar 

  59. Suescun MO, Rival C, Theas MS, Calandra RS, Lustig L. Involvement of tumor necrosis factor-alpha in the pathogenesis of autoimmune orchitis in rats. Biol Reprod. 2003;68(6):2114–21.

    CAS  PubMed  Google Scholar 

  60. Yao PL, Lin YC, Richburg JH. TNF alpha-mediated disruption of spermatogenesis in response to Sertoli cell injury in rodents is partially regulated by MMP2. Biol Reprod. 2009;80(3):581–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang M, Su P. The role of the Fas/FasL signaling pathway in environmental toxicant-induced testicular cell apoptosis: An update. Syst Biol Reprod Med. 2018;64(2):93–102.

    CAS  PubMed  Google Scholar 

  62. Metukuri MR, Reddy CM, Reddy PR, Reddanna P. Bacterial LPS-mediated acute inflammation-induced spermatogenic failure in rats: Role of stress response proteins and mitochondrial dysfunction. Inflammation. 2010;33(4):235–43.

    CAS  PubMed  Google Scholar 

  63. Eger GA, Ferreira VV, Batista CR, Bonde H, de Lima DD, Wyse AT, et al. Antioxidant effect of simvastatin throught oxidative imbalance caused by lisdexamfetamine dimesylate. Anais da Academia Brasileira de Ciencias. 2016;88(1):335–48.

    CAS  PubMed  Google Scholar 

  64. Themmen A, Hoogerbrugge J, Rommerts F, Van der Molen H. Effects of LH and an LH-releasing hormone agonist on different second messenger systems in the regulation of steroidogenesis in isolated rat Leydig cells. J Endocrinol. 1986;108(3):431–40.

    CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Author information

Authors and Affiliations

  1. Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Susan Roustaee, Abbas Aliaghaei & Hamid Nazarian

  2. Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Susan Roustaee, Pourya Raee, Reza Bahar, Seyedeh Naghmeh Nourirad, Mohammad-Jasim Golzarian, Amirreza Beirami, Hosein Jafary, Mohammad amin Aalipour, Mohammad Taghizadeh, Mohammad-Amin Abdollahifar, Mohammad Hossain Heidari, Hojjat-Allah Abbaszadeh, Abbas Aliaghaei & Hamid Nazarian

  3. Department of Educational Neuroscience, Aras International Campus, University of Tabriz, Tabriz, Iran

    Mojtaba Sani

  4. Department of Genetics, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran

    Maryam Mehranpour

  5. Department of Anatomical Sciences, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran

    Meysam Hassani Moghaddam

  6. Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Kimia Vakili & Mobina Fathi

  7. Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hojjat-Allah Abbaszadeh

Authors
  1. Susan Roustaee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mojtaba Sani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maryam Mehranpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pourya Raee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meysam Hassani Moghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reza Bahar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seyedeh Naghmeh Nourirad
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohammad-Jasim Golzarian
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Amirreza Beirami
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hosein Jafary
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mohammad amin Aalipour
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mohammad Taghizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mohammad-Amin Abdollahifar
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kimia Vakili
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mobina Fathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mohammad Hossain Heidari
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hojjat-Allah Abbaszadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Abbas Aliaghaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Hamid Nazarian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AA and HN conceived and designed the study. SR, MM, MS, RB, SNN, MJG, PR, HA, and MHH performed the experiments. AB, HJ, MAA, MT, KV, and MF analyzed the data. MAA and MHM prepared the manuscript.

Corresponding authors

Correspondence to Abbas Aliaghaei or Hamid Nazarian.

Ethics declarations

Ethics Approval

The research was approved by the Animal Care and Use Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.AEC.1401.082).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roustaee, S., Sani, M., Mehranpour, M. et al. Chronic Administration of Lisdexamfetamine Induces Apoptosis and Inflammation and Reduces Sperm Quality in Adult Male Rats. Reprod. Sci. 31, 1278–1289 (2024). https://doi.org/10.1007/s43032-023-01449-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-023-01449-9

Keywords

Search

Navigation