, Volume 234, Issue 15, pp 2299–2309 | Cite as

Blunted stress reactivity in chronic cannabis users

  • Carrie CuttlerEmail author
  • Alexander Spradlin
  • Amy T. Nusbaum
  • Paul Whitney
  • John M. Hinson
  • Ryan J. McLaughlin
Original Investigation



One of the most commonly cited reasons for chronic cannabis use is to cope with stress. Consistent with this, cannabis users have shown reduced emotional arousal and dampened stress reactivity in response to negative imagery.


To our knowledge, the present study represents the first to examine the effects of an acute stress manipulation on subjective stress and salivary cortisol in chronic cannabis users compared to non-users.


Forty cannabis users and 42 non-users were randomly assigned to complete either the stress or no stress conditions of the Maastricht Acute Stress Test (MAST). The stress condition of the MAST manipulates both physiological (placing hand in ice bath) and psychosocial stress (performing math under conditions of social evaluation). Participants gave baseline subjective stress ratings before, during, and after the stress manipulation. Cortisol was measured from saliva samples obtained before and after the stress manipulation. Further, cannabis cravings and symptoms of withdrawal were measured.


Subjective stress ratings and cortisol levels were significantly higher in non-users in the stress condition relative to non-users in the no stress condition. In contrast, cannabis users demonstrated blunted stress reactivity; specifically, they showed no increase in cortisol and a significantly smaller increase in subjective stress ratings. The stress manipulation had no impact on cannabis users’ self-reported cravings or withdrawal symptoms.


Chronic cannabis use is associated with blunted stress reactivity. Future research is needed to determine whether this helps to confer resiliency or vulnerability to stress-related psychopathology as well as the mechanisms underlying this effect.


Cannabis Marijuana Stress Cortisol Craving Withdrawal 



Washington State University’s Dedicated Marijuana Account funded this study. We thank Anthony Berger for running the cortisol assays.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Block RI, Farinpour R, Schlechte JA (1991) Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend 28(2):121–128CrossRefPubMedGoogle Scholar
  2. Buckner JD, Silgado J, Schmidt NB (2011) Marijuana craving during a public speaking challenge: understanding marijuana use vulnerability among women and those with social anxiety disorder. J Behav Ther Exp Psychiatry 42(1):104–110. doi: 10.1016/j.jbtep.2010.07.005 CrossRefPubMedGoogle Scholar
  3. Buckner JD, Ecker AH, Vinci C (2013) Cannabis use vulnerability among socially anxious users: cannabis craving during a social interaction. Psychol Addict Behav 27(1):236–242. doi: 10.1037/a0029763 CrossRefPubMedGoogle Scholar
  4. Buckner JD, Zvolensky MJ, Ecker AH, Jeffries ER (2016) Cannabis craving in response to laboratory-induced social stress among racially diverse cannabis users: the impact of social anxiety disorder. J Psychopharmacol 30(4):363–369. doi: 10.1177/0269881116629115 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Budney AJ, Novy PL, Hughes JR (1999) Marijuana withdrawal among adults seeking treatment of marijuana dependence. Addiction 94:1311–1322. doi: 10.1046/j.13600443.1999.94913114.x CrossRefPubMedGoogle Scholar
  6. Budney AJ, Moore BA, Vandrey RG, Hughes JR (2003) The time course and significance of cannabis withdrawal. J Abnorm Psychol 112:393–402. doi: 10.1037/0021-843X.112.3.393 CrossRefPubMedGoogle Scholar
  7. Childs E, Lutz JA, de Wit H (2017) Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug Alcohol Depend (in press)Google Scholar
  8. Cleck JN, Blendy JA (2008) Making a bad thing worse: adverse effects of stress on drug addiction. J Clin Invest 118(2):454–461. doi: 10.1172/JCI33946 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cohen S, Williamson G (1988) Perceived stress in a probability sample of the United States. In: Spacapan S, Oskamp S (eds) The social psychology of health: Claremont symposium on applied social psychology. Newbury Park, CaliforniaGoogle Scholar
  10. Copeland J, Swift W, Rees V (2001) Clinical profile of participants in a brief intervention program for cannabis use disorder. J Subst Abus Treat 20(1):45–52CrossRefGoogle Scholar
  11. Cornelius JR, Aizenstein HJ, Hariri AR (2010) Amygdala reactivity is inversely related to level of cannabis use in individuals with comorbid cannabis dependence and major depression. Addict Behav 35(6):644–646. doi: 10.1016/j.addbeh.2010.02.004 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cuttler C, Spradlin A (2017) Measuring cannabis consumption. Psychometric properties of the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ-CU). PLOS ONE (in press)Google Scholar
  13. Di Marzo V, Berrendero F, Bisogno T, González S, Cavaliere P, Romero J, Cebeira M, Ramos JA, Fernández-Ruiz JJ (2000) Enhancement of anandamide formation in the limbic forebrain and reduction of endocannabinoid contents in the striatum of delta9-tetrahydrocannabinol-tolerant rats. J Neurochem 74(4):1627–1635CrossRefPubMedGoogle Scholar
  14. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23(12):4850–4857PubMedGoogle Scholar
  15. Elo AL, Leppänen A, Jahkola A (2003) Validity of a single-item measure of stress symptoms. Scand J Work Environ Health 29:444–451CrossRefPubMedGoogle Scholar
  16. Ginty AT, Jones A, Carroll D, Roseboom TJ, Phillips AC, Painter R, de Rooij SR (2014) Neuroendocrine and cardiovascular reactions to acute psychological stress are attenuated in smokers. Psychoneuroendocrinology 48:87–97. doi: 10.1016/j.psyneuen.2014.05.023 CrossRefPubMedGoogle Scholar
  17. Gold PW, Chrousos GP (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7(3):254–275. doi: 10.1038/ CrossRefPubMedGoogle Scholar
  18. González S, Fernández-Ruiz J, Di Marzo V, Hernández M, Arévalo C, Nicanor C, Cascio MG, Ambrosio E, Ramos JA (2004) Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence. Drug Alcohol Depend 74(2):159–170. doi: 10.1016/j.drugalcdep.2003.12.011 CrossRefPubMedGoogle Scholar
  19. Gorka SM, Fitzgerald DA, de Wit H, Phan KL (2015) Cannabinoid modulation of amygdala subregion functional connectivity to social signals of threat. Int J Neuropsychopharmacol 18(3):pyu104. doi: 10.1093/ijnp/pyu104 CrossRefPubMedCentralGoogle Scholar
  20. Gruber SA, Rogowska J, Yurgelun-Todd DA (2009) Altered affective response in marijuana smokers: an FMRI study. Drug Alcohol Depend 105(1–2):139–153. doi: 10.1016/j.drugalcdep.2009.06.019 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Heishman SJ, Singleton EG, Liguori A (2001) Marijuana Craving Questionnaire: development and initial validation of a self-report instrument. Addiction 97(7):1023–1034. doi: 10.1080/096552140120053084 CrossRefGoogle Scholar
  22. Herman JP (2013) Neural control of chronic stress adaptation. Front Behav Neurosci 7:61. doi: 10.3389/fnbeh.2013.00061 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, Scheimann J, Myers B (2016) Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol 6(2):603–621. doi: 10.1002/cphy.c150015 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hesse M, Thylstrup B (2013) Time-course of the DSM-5 cannabis withdrawal symptoms in poly-substance abusers. BMC Psychiatry 13:258. doi: 10.1186/1471-244X-13-258 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hill MN, Tasker JG (2012) Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience 204:5–16. doi: 10.1016/j.neuroscience.2011.12.030 CrossRefPubMedGoogle Scholar
  26. Hill MN, McLaughlin RJ, Pan B, Fitzgerald ML, Roberts CJ, Lee TT, Karatsoreos IN, Mackie K, Viau V, Pickel VM, McEwen BS, Liu QS, Gorzalka BB, Hillard CJ (2011) Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci 31(29):10506–10515. doi: 10.1523/JNEUROSCI.0496-11.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hyman SM, Sinha R (2009) Stress-related factors in cannabis use and misuse: implications for prevention and treatment. J Subst Abus Treat 36(4):400–413. doi: 10.1016/j.jsat.2008.08.005 CrossRefGoogle Scholar
  28. Kedzior KK, Laeber LT (2014) A positive association between anxiety disorders and cannabis use or cannabis use disorders in the general population—a meta-analysis of 31 studies. BMC Psychiatry 14:136. doi: 10.1186/1471-244X-14-136 CrossRefPubMedPubMedCentralGoogle Scholar
  29. King GR, Ernst T, Deng W, Stenger A, Gonzales RM, Nakama H, Chang L (2011) Altered brain activation during visuomotor integration in chronic active cannabis users: relationship to cortisol levels. J Neurosci 31(49):17923–17931. doi: 10.1523/JNEUROSCI.4148-11.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW (2013) Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry 18(6):692–699. doi: 10.1038/mp.2012.144 CrossRefPubMedGoogle Scholar
  31. Malcher-Lopes R, Di S, Marcheselli VS, Weng FJ, Stuart CT, Bazan NG, Tasker JG (2006) Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release. J Neurosci 26(24):6643–6650. doi: 10.1523/JNEUROSCI.5126-05.2006 CrossRefPubMedGoogle Scholar
  32. McEwen BS (1998) Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci 840:33–44CrossRefPubMedGoogle Scholar
  33. McEwen BS, Sapolsky RM (1995) Stress and cognitive function. Curr Opin Neurobiol 5(2):205–216CrossRefPubMedGoogle Scholar
  34. McEwen BS, Nasca C, Gray JD (2016) Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41(1):3–23. doi: 10.1038/npp.2015.171 CrossRefPubMedGoogle Scholar
  35. McLaughlin RJ, Hill MN, Gorzalka BB (2014) A critical role for prefrontocortical endocannabinoid signaling in the regulation of stress and emotional behavior. Neurosci Biobehav Rev 42:116–131. doi: 10.1016/j.neubiorev.2014.02.006 CrossRefPubMedGoogle Scholar
  36. Mizrahi R, Suridjan I, Kenk M, George TP, Wilson A, Houle S, Rusjan P (2013) Dopamine response to psychosocial stress in chronic cannabis users: a PET study with [11C]-+-PHNO. Neuropsychopharmacology 38(4):673–682. doi: 10.1038/npp.2012.232 CrossRefPubMedGoogle Scholar
  37. Monteleone P, Di Filippo C, Fabrazzo M, Milano W, Martiadis V, Corrivetti G, Monteleone AM, Maj M (2014) Flattened cortisol awakening response in chronic patients with schizophrenia onset after cannabis exposure. Psychiatry Res 215(2):263–267. doi: 10.1016/j.psychres.2013.12.016 CrossRefPubMedGoogle Scholar
  38. Morgan CJ, Page E, Schaefer C, Chatten K, Manocha A, Gulati S, Curran HV, Brandner B, Leweke FM (2013) Cerebrospinal fluid anandamide levels, cannabis use and psychotic-like symptoms. Br J Psychiatry 202(5):381–382. doi: 10.1192/bjp.bp.112.121178 CrossRefPubMedGoogle Scholar
  39. Okaneku J, Vearrier D, McKeever RG, LaSala GS, Greenberg MI (2015) Change in perceived risk associated with marijuana use in the United States from 2002 to 2012. Clin Toxicol (Phila) 53(3):151–155. doi: 10.3109/15563650.2015.1004581 CrossRefGoogle Scholar
  40. Phan KL, Fitzgerald DA, Nathan PJ, Moore GJ, Uhde TW, Tancer ME (2005) Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry 57(3):210–219. doi: 10.1016/j.biopsych.2004.10.030 CrossRefPubMedGoogle Scholar
  41. Phan KL, Angstadt M, Golden J, Onyewuenyi I, Popovska A, de Wit H (2008) Cannabinoid modulation of amygdala reactivity to social signals of threat in humans. J Neurosci 28(10):2313–2319CrossRefPubMedPubMedCentralGoogle Scholar
  42. Ranganathan M, Braley G, Pittman B, Cooper T, Perry E, Krystal J, D’Souza DC (2009) The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology 203(4):737–744. doi: 10.1007/s00213-008-1422-2 CrossRefPubMedGoogle Scholar
  43. Sami MB, Rabiner EA, Bhattacharyya S (2015) Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date. Eur Neuropsychopharmacol 25(8):1201–1224. doi: 10.1016/j.euroneuro.2015.03.011 CrossRefPubMedGoogle Scholar
  44. Schuermeyer J, Salomonsen-Sautel S, Price RK, Balan S, Thurstone C, Min SJ, Sakai JT (2014) Temporal trends in marijuana attitudes, availability and use in Colorado compared to non-medical marijuana states: 2003-11. Drug Alcohol Depend 140:145–155. doi: 10.1016/j.drugalcdep.2014.04.016 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Sexton M, Cuttler C, Finnell J, Mischley L (2016) A cross-sectional survey of medical cannabis users: patterns of use and perceived efficacy. Cannabis Cannabinoid Res 1:131–138. doi: 10.1089/can.2016.0007 CrossRefGoogle Scholar
  46. Smeets T, Cornelisse S, Quaedflieg CW, Meyer T, Jelicic M, Merckelbach H (2012) Introducing the Masstricht Acute Stress Test (MAST): a quick and non-invasive approach to elicit robust autonomic and glucocorticoid stress responses. Psychneuroendocrinology 37:1998–2008. doi: 10.1016/j.psyneuen.2012.04.012 CrossRefGoogle Scholar
  47. Somaini L, Manfredini M, Amore M, Zaimovic A, Raggi MA, Leonardi C, Gerra ML, Donnini C, Gerra G (2012) Psychobiological responses to unpleasant emotions in cannabis users. Eur Arch Psychiatry Clin Neurosci 262(1):47–57. doi: 10.1007/s00406-011-0223-5 CrossRefPubMedGoogle Scholar
  48. Sotnikov S, Wittmann A, Bunck M, Bauer S, Deussing J, Schmidt M, Touma C, Landgraf R, Czibere L (2014) Blunted HPA axis reactivity reveals glucocorticoid system dysbalance in a mouse model of high anxiety-related behavior. Psychoneuroendocrinology 48:41–51. doi: 10.1016/j.psyneuen.2014.06.006 CrossRefPubMedGoogle Scholar
  49. Stolzenberg L, D’Alessio SJ, Dariano D (2016) The effect of medical cannabis laws on juvenile cannabis use. Int J Drug Policy 27:82–88. doi: 10.1016/j.drugpo.2015.05.018 CrossRefPubMedGoogle Scholar
  50. Substance Abuse and Mental Health Services Administration (SAMHSA) (2014). Behavioral health trends in the United States: results from the 2014 National Survey on Drug Use and Health. Retrieved March 15th, from
  51. Tu MT, Lupien SJ, Walker CD (2006) Diurnal salivary cortisol levels in postpartum others as a function of infant feeding choice and parity. Psychneuroendocrinology 31(7):812–824. doi: 10.1016/j.psyneuen.2006.03.006 CrossRefGoogle Scholar
  52. United Nations Office on Drugs and Crime (2012) World drug report. United Nations, New YorkGoogle Scholar
  53. Urry HL, van Reekum CM, Johnstone T, Kalin NH, Thurow ME, Schaefer HS, Jackson CA, Frye CJ, Greischar LL, Alexander AL, Davidson RJ (2006) Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. J Neurosci 26(16):4415–4425. doi: 10.1523/JNEUROSCI.3215-05.2006 CrossRefPubMedGoogle Scholar
  54. Volkow ND, Wang GJ, Telang F, Fowler JS, Alexoff D, Logan J, Jayne M, Wong C, Tomasi D (2014) Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci U S A 111(30):E3149–E3156. doi: 10.1073/pnas.1411228111 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Webb CW, Webb SM (2014) Therapeutic benefits of cannabis: a patient survey. Hawaii J Med Public Health 73(4):109–111PubMedPubMedCentralGoogle Scholar
  56. Yehuda R (2009) Status of glucocorticoid alterations in post-traumatic stress disorder. Ann N Y Acad Sci 1179:56–69. doi: 10.1111/j.1749-6632.2009.04979.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Carrie Cuttler
    • 1
    • 2
    Email author
  • Alexander Spradlin
    • 1
  • Amy T. Nusbaum
    • 1
  • Paul Whitney
    • 1
  • John M. Hinson
    • 1
  • Ryan J. McLaughlin
    • 1
    • 2
    • 3
  1. 1.Department of PsychologyWashington State UniversityPullmanUSA
  2. 2.Translational Addiction Research CenterWashington State UniversityPullmanUSA
  3. 3.Department of Integrative Physiology and NeuroscienceWashington State UniversityPullmanUSA

Personalised recommendations