Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The why behind the high: determinants of neurocognition during acute cannabis exposure

Abstract

Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis‐related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Mesocorticolimbic circuit and salience network activity during THC intoxication.
Fig. 2: Dissociation between the impact of THC on the neurocognitive state and THC blood concentration.
Fig. 3: Moderators of the cannabis-induced neurocognitive state.

References

  1. 1.

    United Nations Office on Drugs and Crime. World Drug Report 2020 https://wdr.unodc.org/wdr2020/index.html (2020).

  2. 2.

    Hall, W. & Lynskey, M. Evaluating the public health impacts of legalizing recreational cannabis use in the United States. Addiction 111, 1764–1773 (2016).

    Google Scholar 

  3. 3.

    Hasin, D. S., Shmulewitz, D. & Sarvet, A. L. Time trends in US cannabis use and cannabis use disorders overall and by sociodemographic subgroups: a narrative review and new findings. Am. J. Drug Alcohol. Abuse 45, 623–643 (2019).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Abrams, D. I. The therapeutic effects of cannabis and cannabinoids: an update from the national academies of sciences, engineering and medicine report. Eur. J. Intern. Med. 49, 7–11 (2018).

    CAS  Google Scholar 

  5. 5.

    Kilmer, B. & Pacula, R. L. Understanding and learning from the diversification of cannabis supply laws. Addiction 112, 1128–1135 (2017).

    Google Scholar 

  6. 6.

    ElSohly, M. A. et al. Changes in cannabis potency over the last 2 decades (1995–2014): analysis of current data in the United States. Biol. Psychiatry 79, 613–619 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Spindle, T. R., Bonn-Miller, M. O. & Vandrey, R. Changing landscape of cannabis: novel products, formulations, and methods of administration. Curr. Opin. Psychol. 30, 98–102 (2019).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cash, M. C., Cunnane, K., Fan, C. & Romero-Sandoval, E. A. Mapping cannabis potency in medical and recreational programs in the United States. PLoS ONE 15, e0230167 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Freeman, T. P. et al. Increasing potency and price of cannabis in Europe, 2006–16. Addiction 114, 1015–1023 (2019).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Swift, W., Wong, A., Li, K. M., Arnold, J. C. & McGregor, I. S. Analysis of cannabis seizures in NSW, Australia: cannabis potency and cannabinoid profile. PLoS ONE 8, e70052 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Ramaekers, J. G. et al. High-potency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology 31, 2296–2303 (2006).

    CAS  Google Scholar 

  12. 12.

    Ramaekers, J. G., Kauert, G., Theunissen, E. L., Toennes, S. W. & Moeller, M. R. Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J. Psychopharmacol. 23, 266–277 (2009).

    CAS  Google Scholar 

  13. 13.

    Gonzalez, R. Acute and non-acute effects of cannabis on brain functioning and neuropsychological performance. Neuropsychol. Rev. 17, 347–361 (2007).

    Google Scholar 

  14. 14.

    Bossong, M. G., Jager, G., Bhattacharyya, S. & Allen, P. Acute and non-acute effects of cannabis on human memory function: a critical review of neuroimaging studies. Curr. Pharm. Des. 20, 2114–2125 (2014).

    CAS  Google Scholar 

  15. 15.

    Crane, N. A., Schuster, R. M., Fusar-Poli, P. & Gonzalez, R. Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences. Neuropsychol. Rev. 23, 117–137 (2013).

    Google Scholar 

  16. 16.

    Crean, R. D., Crane, N. A. & Mason, B. J. An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. J. Addict. Med. 5, 1–8 (2011).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Desrosiers, N. A., Ramaekers, J. G., Chauchard, E., Gorelick, D. A. & Huestis, M. A. Smoked cannabis’ psychomotor and neurocognitive effects in occasional and frequent smokers. J. Anal. Toxicol. 39, 251–261 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Newmeyer, M. N. et al. Free and glucuronide whole blood cannabinoids’ pharmacokinetics after controlled smoked, vaporized, and oral cannabis administration in frequent and occasional cannabis users: identification of recent cannabis intake. Clin. Chem. 62, 1579–1592 (2016).

    CAS  Google Scholar 

  19. 19.

    Broyd, S. J., van Hell, H. H., Beale, C., Yucel, M. & Solowij, N. Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol. Psychiatry 79, 557–567 (2016).

    CAS  Google Scholar 

  20. 20.

    Curran, H. V. et al. Keep off the grass? Cannabis, cognition and addiction. Nat. Rev. Neurosci. 17, 293–306 (2016).

    CAS  Google Scholar 

  21. 21.

    Arkell, T. R. et al. Effect of cannabidiol and Δ9-tetrahydrocannabinol on driving performance: a randomized clinical trial. JAMA 324, 2177–2186 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Curran, H. V., Brignell, C., Fletcher, S., Middleton, P. & Henry, J. Cognitive and subjective dose–response effects of acute oral Δ9-tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology 164, 61–70 (2002).

    CAS  Google Scholar 

  23. 23.

    Ranganathan, M. & D’Souza, D. C. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology 188, 425–444 (2006).

    CAS  Google Scholar 

  24. 24.

    Miller, L., Cornett, T. & McFarland, D. Marijuana: an analysis of storage and retrieval deficits in memory with the technique of restricted remiding. Pharmacol. Biochem. Behav. 8, 327–332 (1978).

    CAS  Google Scholar 

  25. 25.

    Doss, M. K., Weafer, J., Gallo, D. A. & de Wit, H. Δ9-Tetrahydrocannabinol at retrieval drives false recollection of neutral and emotional memories. Biol. Psychiatry 84, 743–750 (2018).

    CAS  Google Scholar 

  26. 26.

    Kloft, L. et al. False memory formation in cannabis users: a field study. Psychopharmacology 236, 3439–3450 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kloft, L. et al. Cannabis increases susceptibility to false memory. Proc. Natl Acad. Sci. USA 117, 4585–4589 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    D’Souza, D. C. et al. Blunted psychotomimetic and amnestic effects of Δ9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology 33, 2505–2516 (2008).

    Google Scholar 

  29. 29.

    Ballard, M. E., Bedi, G. & de Wit, H. Effects of Δ9-tetrahydrocannabinol on evaluation of emotional images. J. Psychopharmacol. 26, 1289–1298 (2012).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Zuurman, L. et al. Effect of intrapulmonary tetrahydrocannabinol administration in humans. J. Psychopharmacol. 22, 707–716 (2008).

    CAS  Google Scholar 

  31. 31.

    van Wel, J. et al. Psychedelic symptoms of cannabis and cocaine use as a function of trait impulsivity. J. Psychopharmacol. 29, 324–334 (2015).

    Google Scholar 

  32. 32.

    Bhattacharyya, S. et al. Induction of psychosis by Δ9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch. Gen. Psychiatry 69, 27–36 (2012).

    CAS  Google Scholar 

  33. 33.

    Bhattacharyya, S. et al. Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis. Eur. Neuropsychopharmacol. 25, 26–37 (2015).

    CAS  Google Scholar 

  34. 34.

    Colizzi, M. et al. Modulation of acute effects of Δ9-tetrahydrocannabinol on psychotomimetic effects, cognition and brain function by previous cannabis exposure. Eur. Neuropsychopharmacol. 28, 850–862 (2018).

    CAS  Google Scholar 

  35. 35.

    Stokes, P. R., Mehta, M. A., Curran, H. V., Breen, G. & Grasby, P. M. Can recreational doses of THC produce significant dopamine release in the human striatum? Neuroimage 48, 186–190 (2009).

    Google Scholar 

  36. 36.

    Colizzi, M., Weltens, N., McGuire, P., Van Oudenhove, L. & Bhattacharyya, S. Descriptive psychopathology of the acute effects of intravenous Δ9-tetrahydrocannabinol administration in humans. Brain Sci. 9, 93 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Favrat, B. et al. Two cases of “cannabis acute psychosis” following the administration of oral cannabis. BMC Psychiatry 5, 17 (2005).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Barrett, F. S., Schlienz, N. J., Lembeck, N., Waqas, M. & Vandrey, R. “Hallucinations” following acute cannabis dosing: a case report and comparison to other hallucinogenic drugs. Cannabis Cannabinoid Res. 3, 85–93 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Hall, W. What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? Addiction 110, 19–35 (2015).

    Google Scholar 

  40. 40.

    Horwood, L. J. et al. Cannabis use and educational achievement: findings from three Australasian cohort studies. Drug Alcohol. Depend. 110, 247–253 (2010).

    Google Scholar 

  41. 41.

    Silins, E. et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatry 1, 286–293 (2014).

    Google Scholar 

  42. 42.

    Macdonald, S. et al. Testing for cannabis in the work-place: a review of the evidence. Addiction 105, 408–416 (2010).

    Google Scholar 

  43. 43.

    Ramaekers, J. G., Berghaus, G., van Laar, M. & Drummer, O. H. Dose related risk of motor vehicle crashes after cannabis use. Drug Alcohol. Depend. 73, 109–119 (2004).

    CAS  Google Scholar 

  44. 44.

    Hartman, R. L. & Huestis, M. A. Cannabis effects on driving skills. Clin. Chem. 59, 478–492 (2013).

    CAS  Google Scholar 

  45. 45.

    Bondallaz, P. et al. Cannabis and its effects on driving skills. Forensic Sci. Int. 268, 92–102 (2016).

    CAS  Google Scholar 

  46. 46.

    Asbridge, M., Hayden, J. A. & Cartwright, J. L. Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ 344, e536 (2012).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Li, M. C. et al. Marijuana use and motor vehicle crashes. Epidemiol. Rev. 34, 65–72 (2012).

    CAS  Google Scholar 

  48. 48.

    Rogeberg, O. & Elvik, R. The effects of cannabis intoxication on motor vehicle collision revisited and revised. Addiction 111, 1348–1359 (2016).

    Google Scholar 

  49. 49.

    Colizzi, M. & Bhattacharyya, S. Cannabis use and the development of tolerance: a systematic review of human evidence. Neurosci. Biobehav. Rev. 93, 1–25 (2018).

    CAS  Google Scholar 

  50. 50.

    Ramaekers, J. G., Mason, N. L. & Theunissen, E. L. Blunted highs: pharmacodynamic and behavioral models of cannabis tolerance. Eur. Neuropsychopharmacol. 36, 191–205 (2020).

    CAS  Google Scholar 

  51. 51.

    Volkow, N. D. et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry 73, 292–297 (2016).

    Google Scholar 

  52. 52.

    Ferland, J. N. & Hurd, Y. L. Deconstructing the neurobiology of cannabis use disorder. Nat. Neurosci. 23, 600–610 (2020).

    CAS  Google Scholar 

  53. 53.

    Hashimotodani, Y., Ohno-Shosaku, T. & Kano, M. Endocannabinoids and synaptic function in the CNS. Neuroscientist 13, 127–137 (2007).

    CAS  Google Scholar 

  54. 54.

    Mackie, K. Cannabinoid receptors: where they are and what they do. J. Neuroendocrinol. 20 (Suppl. 1), 10–14 (2008).

    CAS  Google Scholar 

  55. 55.

    Freund, T. F., Katona, I. & Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83, 1017–1066 (2003).

    CAS  Google Scholar 

  56. 56.

    Zou, S. & Kumar, U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int. J. Mol. Sci. 19, 833 (2018).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Iversen, L. Cannabis and the brain. Brain 126, 1252–1270 (2003).

    Google Scholar 

  58. 58.

    Goonawardena, A. V., Robinson, L., Hampson, R. E. & Riedel, G. Cannabinoid and cholinergic systems interact during performance of a short-term memory task in the rat. Learn. Mem. 17, 502–511 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Prini, P. et al. Neurobiological mechanisms underlying cannabis-induced memory impairment. Eur. Neuropsychopharmacol. 36, 181–190 (2020).

    CAS  Google Scholar 

  60. 60.

    Van Waes, V., Beverley, J. A., Siman, H., Tseng, K. Y. & Steiner, H. CB1 cannabinoid receptor expression in the striatum: association with corticostriatal circuits and developmental regulation. Front. Pharmacol. 3, 21 (2012).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381 (1986).

    CAS  Google Scholar 

  62. 62.

    Bonelli, R. M. & Cummings, J. L. Frontal-subcortical circuitry and behavior. Dialogues Clin. Neurosci. 9, 141–151 (2007).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Silveira, M. M. et al. Seeing through the smoke: human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks. Neurosci. Biobehav. Rev. 76, 380–395 (2017).

    CAS  Google Scholar 

  64. 64.

    Bloomfield, M. A. P. et al. The neuropsychopharmacology of cannabis: a review of human imaging studies. Pharmacol. Ther. 195, 132–161 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Mathew, R. J., Wilson, W. H., Humphreys, D. F., Lowe, J. V. & Wiethe, K. E. Regional cerebral blood flow after marijuana smoking. J. Cereb. Blood Flow. Metab. 12, 750–758 (1992).

    CAS  Google Scholar 

  66. 66.

    Klumpers, L. E. et al. Manipulating brain connectivity with Δ9-tetrahydrocannabinol: a pharmacological resting state FMRI study. Neuroimage 63, 1701–1711 (2012).

    CAS  Google Scholar 

  67. 67.

    Wall, M. B. et al. Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity. J. Psychopharmacol. 33, 822–830 (2019).

    CAS  Google Scholar 

  68. 68.

    Zaytseva, Y. et al. Cannabis-induced altered states of consciousness are associated with specific dynamic brain connectivity states. J. Psychopharmacol. 33, 811–821 (2019).

    CAS  Google Scholar 

  69. 69.

    Pierce, R. C. & Kumaresan, V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci. Biobehav. Rev. 30, 215–238 (2006).

    CAS  Google Scholar 

  70. 70.

    Volkow, N. D., Wang, G. J., Fowler, J. S., Tomasi, D. & Telang, F. Addiction: beyond dopamine reward circuitry. Proc. Natl Acad. Sci. USA 108, 15037–15042 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Bossong, M. G. et al. Δ9-Tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 34, 759–766 (2009).

    CAS  Google Scholar 

  72. 72.

    Kuepper, R. et al. Δ9-Tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study. PLoS ONE 8, e70378 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Bossong, M. G. et al. Further human evidence for striatal dopamine release induced by administration of 9-tetrahydrocannabinol (THC): selectivity to limbic striatum. Psychopharmacology 232, 2723–2729 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Ramaekers, J. G. et al. Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit. Psychopharmacology 229, 219–226 (2013).

    CAS  Google Scholar 

  75. 75.

    Ramaekers, J. G. et al. Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes. Brain Imaging Behav. 10, 1254–1263 (2016).

    CAS  Google Scholar 

  76. 76.

    Mason, N. L. et al. Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity. Eur. Neuropsychopharmacol. 29, 247–256 (2019).

    CAS  Google Scholar 

  77. 77.

    Mason, N. L. et al. Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users. Addict. Biol. 26, e12870 (2021).

    CAS  Google Scholar 

  78. 78.

    Bloomfield, M. A., Ashok, A. H., Volkow, N. D. & Howes, O. D. The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature 539, 369–377 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Colizzi, M. et al. Δ9-Tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis. Mol. Psychiatry 25, 3231–3240 (2019).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    McCutcheon, R. A. et al. Mesolimbic dopamine function is related to salience network connectivity: an integrative positron emission tomography and magnetic resonance study. Biol. Psychiatry 85, 368–378 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Seeley, W. W. et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J. Neurosci. 27, 2349–2356 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Kucyi, A., Hodaie, M. & Davis, K. D. Lateralization in intrinsic functional connectivity of the temporoparietal junction with salience- and attention-related brain networks. J. Neurophysiol. 108, 3382–3392 (2012).

    Google Scholar 

  83. 83.

    Hermans, E. J., Henckens, M. J., Joels, M. & Fernandez, G. Dynamic adaptation of large-scale brain networks in response to acute stressors. Trends Neurosci. 37, 304–314 (2014).

    CAS  Google Scholar 

  84. 84.

    Menon, V. in Brain Mapping: An Encyclopedic Reference Vol. 2 (ed. Toga, A. W.) 597–611 (Academic Press: Elsevier, 2015).

  85. 85.

    Friston, K. J. Functional and effective connectivity: a review. Brain Connect. 1, 13–36 (2011).

    Google Scholar 

  86. 86.

    Hermans, E. J. et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science 334, 1151–1153 (2011).

    CAS  Google Scholar 

  87. 87.

    Shafiei, G. et al. Dopamine signaling modulates the stability and integration of intrinsic brain networks. Cereb. Cortex 29, 397–409 (2019).

    Google Scholar 

  88. 88.

    Seeley, W. W. The salience network: a neural system for perceiving and responding to homeostatic demands. J. Neurosci. 39, 9878–9882 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Dosenbach, N. U. et al. Distinct brain networks for adaptive and stable task control in humans. Proc. Natl Acad. Sci. USA 104, 11073–11078 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Menon, V. & Uddin, L. Q. Saliency, switching, attention and control: a network model of insula function. Brain Struct. Funct. 214, 655–667 (2010).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    van Hell, H. H. et al. Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study. Int. J. Neuropsychopharmacol. 14, 1377–1388 (2011).

    Google Scholar 

  92. 92.

    Bossong, M. G. et al. Acute effects of 9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype. Eur. Neuropsychopharmacol. 29, 766–776 (2019).

    CAS  Google Scholar 

  93. 93.

    Jansma, J. M. et al. THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine addiction. Transl. Psychiatry 3, e234 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    de Sousa Fernandes Perna, E. B. et al. Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication. Addict. Biol. 22, 823–832 (2017).

    Google Scholar 

  95. 95.

    Freeman, T. P. et al. Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. Int. J. Neuropsychopharmacol. 21, 21–32 (2018).

    CAS  Google Scholar 

  96. 96.

    Bhattacharyya, S. et al. Cannabinoid modulation of functional connectivity within regions processing attentional salience. Neuropsychopharmacology 40, 1343–1352 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Battistella, G. et al. Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving. PLoS ONE 8, e52545 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Weinstein, A. et al. Brain imaging study of the acute effects of Δ9-tetrahydrocannabinol (THC) on attention and motor coordination in regular users of marijuana. Psychopharmacology 196, 119–131 (2008).

    CAS  Google Scholar 

  99. 99.

    Raichle, M. E. The brain’s default mode network. Annu. Rev. Neurosci. 38, 433–447 (2015).

    CAS  Google Scholar 

  100. 100.

    Bossong, M. G. et al. Default mode network in the effects of Δ9-tetrahydrocannabinol (THC) on human executive function. PLoS ONE 8, e70074 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Borgwardt, S. J. et al. Neural basis of Δ9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol. Psychiatry 64, 966–973 (2008).

    CAS  Google Scholar 

  102. 102.

    Bhattacharyya, S. et al. Opposite effects of Δ9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35, 764–774 (2010).

    CAS  Google Scholar 

  103. 103.

    Theunissen, E. L. et al. Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans. Psychopharmacology 232, 343–353 (2015).

    CAS  Google Scholar 

  104. 104.

    Adam, K. C. S., Doss, M. K., Pabon, E., Vogel, E. K. & de Wit, H. Δ9-Tetrahydrocannabinol (THC) impairs visual working memory performance: a randomized crossover trial. Neuropsychopharmacology 45, 1807–1816 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Doss, M. K., Weafer, J., Gallo, D. A. & de Wit, H. Δ9-Tetrahydrocannabinol during encoding impairs perceptual details yet spares context effects on episodic memory. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 5, 110–118 (2020).

    Google Scholar 

  106. 106.

    Tzavara, E. T., Wade, M. & Nomikos, G. G. Biphasic effects of cannabinoids on acetylcholine release in the hippocampus: site and mechanism of action. J. Neurosci. 23, 9374–9384 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Bossong, M. G. et al. Effects of Δ9-tetrahydrocannabinol administration on human encoding and recall memory function: a pharmacological FMRI study. J. Cogn. Neurosci. 24, 588–599 (2012).

    Google Scholar 

  108. 108.

    Bhattacharyya, S. et al. Modulation of mediotemporal and ventrostriatal function in humans by Δ9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Arch. Gen. Psychiatry 66, 442–451 (2009).

    CAS  Google Scholar 

  109. 109.

    Bhattacharyya, S. et al. Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of Δ-9-THC. Psychol. Med. 48, 2748–2756 (2018).

    Google Scholar 

  110. 110.

    Bossong, M. G. et al. Effects of Δ9-tetrahydrocannabinol on human working memory function. Biol. Psychiatry 71, 693–699 (2012).

    CAS  Google Scholar 

  111. 111.

    Sherif, M., Radhakrishnan, R., D’Souza, D. C. & Ranganathan, M. Human laboratory studies on cannabinoids and psychosis. Biol. Psychiatry 79, 526–538 (2016).

    CAS  Google Scholar 

  112. 112.

    Radhakrishnan, R. et al. GABA deficits enhance the psychotomimetic effects of Δ9-THC. Neuropsychopharmacology 40, 2047–2056 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Kreek, M. J., Nielsen, D. A., Butelman, E. R. & LaForge, K. S. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat. Neurosci. 8, 1450–1457 (2005).

    CAS  Google Scholar 

  114. 114.

    Hess, C. et al. A functional dopamine-beta-hydroxylase gene promoter polymorphism is associated with impulsive personality styles, but not with affective disorders. J. Neural Transm. 116, 121–130 (2009).

    CAS  Google Scholar 

  115. 115.

    Kohnke, M. D. et al. A genotype-controlled analysis of plasma dopamine β-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function. Biol. Psychiatry 52, 1151–1158 (2002).

    CAS  Google Scholar 

  116. 116.

    Brody, A. L. et al. Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens. Arch. Gen. Psychiatry 63, 808–816 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Yavich, L., Forsberg, M. M., Karayiorgou, M., Gogos, J. A. & Mannisto, P. T. Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum. J. Neurosci. 27, 10196–10209 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Henquet, C. et al. An experimental study of catechol-O-methyltransferase Val158Met moderation of Δ-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 31, 2748–2757 (2006).

    CAS  Google Scholar 

  119. 119.

    Tunbridge, E. M. et al. Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences. J. Psychopharmacol. 29, 1146–1151 (2015).

    CAS  Google Scholar 

  120. 120.

    Ranganathan, M. et al. Highs and lows of cannabinoid–dopamine interactions: effects of genetic variability and pharmacological modulation of catechol-O-methyl transferase on the acute response to Δ-9-tetrahydrocannabinol in humans. Psychopharmacology 236, 3209–3219 (2019).

    CAS  Google Scholar 

  121. 121.

    Bhattacharyya, S. et al. Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of Δ-9-tetrahydrocannabinol on midbrain and striatal function. Mol. Psychiatry 17, 1152–1155 (2012).

    CAS  Google Scholar 

  122. 122.

    Shumay, E. et al. New repeat polymorphism in the AKT1 gene predicts striatal dopamine D2/D3 receptor availability and stimulant-induced dopamine release in the healthy human brain. J. Neurosci. 37, 4982–4991 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Nordstrom, B. R. & Hart, C. L. Assessing cognitive functioning in cannabis users: cannabis use history an important consideration. Neuropsychopharmacology 31, 2798–2799 (2006).

    CAS  Google Scholar 

  124. 124.

    Ramaekers, J. G. et al. Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users. Psychopharmacology 214, 391–401 (2011).

    CAS  Google Scholar 

  125. 125.

    Foltin, R. W. in Encyclopedia of Psychopharmacology (eds Price L. & Stolerman, I.) https://doi.org/10.1007/978-3-642-27772-6_58-2 (Springer, 2013).

  126. 126.

    Breivogel, C. S. et al. Chronic Δ9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J. Neurochem. 73, 2447–2459 (1999).

    CAS  Google Scholar 

  127. 127.

    McKinney, D. L. et al. Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to Δ9-tetrahydrocannabinol. J. Pharmacol. Exp. Ther. 324, 664–673 (2008).

    CAS  Google Scholar 

  128. 128.

    Hirvonen, J. et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol. Psychiatry 17, 642–649 (2012).

    CAS  Google Scholar 

  129. 129.

    Ceccarini, J. et al. [18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users. Addict. Biol. 20, 357–367 (2015).

    CAS  Google Scholar 

  130. 130.

    D’Souza, D. C. et al. Rapid changes in CB1 receptor availability in cannabis dependent males after abstinence from cannabis. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 1, 60–67 (2016).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Cadoni, C., Valentini, V. & Di Chiara, G. Behavioral sensitization to Δ9-tetrahydrocannabinol and cross-sensitization with morphine: differential changes in accumbal shell and core dopamine transmission. J. Neurochem. 106, 1586–1593 (2008).

    CAS  Google Scholar 

  132. 132.

    Zhou, X. et al. Cue reactivity in the ventral striatum characterizes heavy cannabis use, whereas reactivity in the dorsal striatum mediates dependent use. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 4, 751–762 (2019).

    Google Scholar 

  133. 133.

    Pope, H. G. Jr, Gruber, A. J., Hudson, J. I., Huestis, M. A. & Yurgelun-Todd, D. Neuropsychological performance in long-term cannabis users. Arch. Gen. Psychiatry 58, 909–915 (2001).

    Google Scholar 

  134. 134.

    Bosker, W. M. et al. Psychomotor function in chronic daily cannabis smokers during sustained abstinence. PLoS ONE 8, e53127 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Lorenzetti, V., Solowij, N. & Yucel, M. The role of cannabinoids in neuroanatomic alterations in cannabis users. Biol. Psychiatry 79, e17–e31 (2016).

    CAS  Google Scholar 

  136. 136.

    Schreiner, A. M. & Dunn, M. E. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp. Clin. Psychopharmacol. 20, 420–429 (2012).

    Google Scholar 

  137. 137.

    Cha, Y. M., White, A. M., Kuhn, C. M., Wilson, W. A. & Swartzwelder, H. S. Differential effects of Δ9-THC on learning in adolescent and adult rats. Pharmacol. Biochem. Behav. 83, 448–455 (2006).

    CAS  Google Scholar 

  138. 138.

    Schneider, M., Schomig, E. & Leweke, F. M. Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats. Addict. Biol. 13, 345–357 (2008).

    CAS  Google Scholar 

  139. 139.

    Carvalho, A. F., Reyes, B. A., Ramalhosa, F., Sousa, N. & Van Bockstaele, E. J. Repeated administration of a synthetic cannabinoid receptor agonist differentially affects cortical and accumbal neuronal morphology in adolescent and adult rats. Brain Struct. Funct. 221, 407–419 (2016).

    CAS  Google Scholar 

  140. 140.

    Mokrysz, C., Freeman, T. P., Korkki, S., Griffiths, K. & Curran, H. V. Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males. Transl. Psychiatry 6, e961 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Matheson, J. et al. Sex differences in the acute effects of smoked cannabis: evidence from a human laboratory study of young adults. Psychopharmacology 237, 305–316 (2020).

    CAS  Google Scholar 

  142. 142.

    Spindle, T. R. et al. Acute pharmacokinetic profile of smoked and vaporized cannabis in human blood and oral fluid. J. Anal. Toxicol. 43, 233–258 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Sholler, D. J., Strickland, J. C., Spindle, T. R., Weerts, E. M. & Vandrey, R. Sex differences in the acute effects of oral and vaporized cannabis among healthy adults. Addict. Biol. https://doi.org/10.1111/adb.12968 (2020).

    Article  Google Scholar 

  144. 144.

    Munro, C. A. et al. Sex differences in striatal dopamine release in healthy adults. Biol. Psychiatry 59, 966–974 (2006).

    CAS  Google Scholar 

  145. 145.

    Evans, S. M. & Foltin, R. W. Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men. Neuropsychopharmacology 31, 659–674 (2006).

    CAS  Google Scholar 

  146. 146.

    Evans, S. M., Haney, M. & Foltin, R. W. The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology 159, 397–406 (2002).

    CAS  Google Scholar 

  147. 147.

    Cooper, Z. D. & Craft, R. M. Sex-dependent effects of cannabis and cannabinoids: a translational perspective. Neuropsychopharmacology 43, 34–51 (2018).

    CAS  Google Scholar 

  148. 148.

    Hunault, C. C. et al. Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg Δ-9-tetrahydrocannabinol (THC). Psychopharmacology 204, 85–94 (2009).

    CAS  Google Scholar 

  149. 149.

    Vandrey, R. et al. Pharmacokinetic profile of oral cannabis in humans: blood and oral fluid disposition and relation to pharmacodynamic outcomes. J. Anal. Toxicol. 41, 83–99 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Oleson, E. B. & Cheer, J. F. A brain on cannabinoids: the role of dopamine release in reward seeking. Cold Spring Harb. Perspect. Med. 2, a012229 (2012).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Ramaekers, J. G. et al. Cognition and motor control as a function of Δ9-THC concentration in serum and oral fluid: limits of impairment. Drug Alcohol. Depend. 85, 114–122 (2006).

    CAS  Google Scholar 

  152. 152.

    Spindle, T. R. et al. Acute effects of smoked and vaporized cannabis in healthy adults who infrequently use cannabis: a crossover trial. JAMA Netw. Open 1, e184841 (2018).

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Grotenhermen, F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin. Pharmacokinet. 42, 327–360 (2003).

    CAS  Google Scholar 

  154. 154.

    Huestis, M. A. Human cannabinoid pharmacokinetics. Chem. Biodivers. 4, 1770–1804 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Hunault, C. C. et al. Acute subjective effects after smoking joints containing up to 69 mg Δ9-tetrahydrocannabinol in recreational users: a randomized, crossover clinical trial. Psychopharmacology 231, 4723–4733 (2014).

    CAS  Google Scholar 

  156. 156.

    McCartney, D., Arkell, T. R., Irwin, C. & McGregor, I. S. Determining the magnitude and duration of acute Δ9-tetrahydrocannabinol (Δ9-THC)-induced driving and cognitive impairment: a systematic and meta-analytic review. Neurosci. Biobehav. Rev. 126, 175–193 (2021).

    CAS  Google Scholar 

  157. 157.

    Newmeyer, M. N., Swortwood, M. J., Abulseoud, O. A. & Huestis, M. A. Subjective and physiological effects, and expired carbon monoxide concentrations in frequent and occasional cannabis smokers following smoked, vaporized, and oral cannabis administration. Drug Alcohol. Depend. 175, 67–76 (2017).

    CAS  Google Scholar 

  158. 158.

    Hollister, L. E. Structure–activity relationships in man of cannabis constituents, and homologs and metabolites of Δ9-tetrahydrocannabinol. Pharmacology 11, 3–11 (1974).

    CAS  Google Scholar 

  159. 159.

    Poyatos, L. et al. Oral administration of cannabis and Δ-9-tetrahydrocannabinol (THC) preparations: a systematic review. Medicina 56, 309 (2020).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Englund, A., Freeman, T. P., Murray, R. M. & McGuire, P. Can we make cannabis safer? Lancet Psychiatry 4, 643–648 (2017).

    Google Scholar 

  161. 161.

    Jikomes, N. & Zoorob, M. The cannabinoid content of legal cannabis in washington state varies systematically across testing facilities and popular consumer products. Sci. Rep. 8, 4519 (2018).

    PubMed  PubMed Central  Google Scholar 

  162. 162.

    Arkell, T. R. et al. Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition. Psychopharmacology 263, 2713–2723 d (2019).

    Google Scholar 

  163. 163.

    Cinnamon Bidwell, L., YorkWilliams, S. L., Mueller, R. L., Bryan, A. D. & Hutchison, K. E. Exploring cannabis concentrates on the legal market: user profiles, product strength, and health-related outcomes. Addict. Behav. Rep. 8, 102–106 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Bidwell, L. C. et al. Association of naturalistic administration of cannabis flower and concentrates with intoxication and impairment. JAMA Psychiatry 77, 787–796 (2020).

    Google Scholar 

  165. 165.

    Alzghari, S. K., Fung, V., Rickner, S. S., Chacko, L. & Fleming, S. W. To dab or not to dab: rising concerns regarding the toxicity of cannabis concentrates. Cureus 9, e1676 (2017).

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    EMCDDA. European Drug Report 2017. Trends and Developments (EMCDDA, 2017).

  167. 167.

    Adams, A. J. et al. “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N. Engl. J. Med. 376, 235–242 (2017).

    CAS  Google Scholar 

  168. 168.

    Alves, V. L., Goncalves, J. L., Aguiar, J., Teixeira, H. M. & Camara, J. S. The synthetic cannabinoids phenomenon: from structure to toxicological properties. A review. Crit. Rev. Toxicol. 50, 359–382 (2020).

    CAS  Google Scholar 

  169. 169.

    Ossato, A. et al. Psychostimulant effect of the synthetic cannabinoid JWH-018 and AKB48: behavioral, neurochemical, and dopamine transporter scan imaging studies in mice. Front. Psychiatry 8, 130 (2017).

    PubMed  PubMed Central  Google Scholar 

  170. 170.

    Basavarajappa, B. S. & Subbanna, S. Potential mechanisms underlying the deleterious effects of synthetic cannabinoids found in Spice/K2 products. Brain Sci. 9, 14 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Auwarter, V. et al. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs? JMS 44, 832–837 (2009).

    Google Scholar 

  172. 172.

    Spaderna, M., Addy, P. H. & D’Souza, D. C. Spicing things up: synthetic cannabinoids. Psychopharmacology 228, 525–540 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Theunissen, E. L. et al. Neurocognition and subjective experience following acute doses of the synthetic cannabinoid JWH-018: a phase 1, placebo-controlled, pilot study. Br. J. Pharmacol. 175, 18–28 (2018).

    CAS  Google Scholar 

  174. 174.

    Theunissen, E. L. et al. Neurocognition and subjective experience following acute doses of the synthetic cannabinoid JWH-018: responders versus nonresponders. Cannabis Cannabinoid Res. 4, 51–61 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Theunissen, E. L. et al. Psychotomimetic symptoms after a moderate dose of a synthetic cannabinoid (JWH-018): implications for psychosis. Psychopharmacology https://doi.org/10.1007/s00213-021-05768-0 (2021).

    Article  Google Scholar 

  176. 176.

    Theunissen, E. L. et al. Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users. Pharmacol. Biochem. Behav. 202, 173118 (2021).

    CAS  Google Scholar 

  177. 177.

    Toennes, S. W. et al. Pharmacokinetic properties of the synthetic cannabinoid JWH-018 and of its metabolites in serum after inhalation. J. Pharm. Biomed. Anal. 140, 215–222 (2017).

    CAS  Google Scholar 

  178. 178.

    Olla, P. et al. Short-term effects of cannabis consumption on cognitive performance in medical cannabis patients. Appl. Neuropsychol. Adult https://doi.org/10.1080/23279095.2019.1681424 (2019).

    Article  Google Scholar 

  179. 179.

    Gruber, S. A. et al. Splendor in the grass? A pilot study assessing the impact of medical marijuana on executive function. Front. Pharmacol. 7, 355 (2016).

    PubMed  PubMed Central  Google Scholar 

  180. 180.

    Gruber, S. A. et al. The grass might be greener: medical marijuana patients exhibit altered brain activity and improved executive function after 3 months of treatment. Front. Pharmacol. 8, 983 (2017).

    Google Scholar 

  181. 181.

    Muller-Vahl, K. R. et al. Treatment of Tourette syndrome with Δ-9-tetrahydrocannabinol (Δ9-THC): no influence on neuropsychological performance. Neuropsychopharmacology 28, 384–388 (2003).

    Google Scholar 

  182. 182.

    Honarmand, K., Tierney, M. C., O’Connor, P. & Feinstein, A. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology 76, 1153–1160 (2011).

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Banister, S. D., Krishna Kumar, K., Kumar, V., Kobilka, B. K. & Malhotra, S. V. Selective modulation of the cannabinoid type 1 (CB1) receptor as an emerging platform for the treatment of neuropathic pain. Medchemcomm 10, 647–659 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Kim, K. H., Seo, H. J., Abdi, S. & Huh, B. All about pain pharmacology: what pain physicians should know. Korean J. Pain 33, 108–120 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Moriarty, O., McGuire, B. E. & Finn, D. P. The effect of pain on cognitive function: a review of clinical and preclinical research. Prog. Neurobiol. 93, 385–404 (2011).

    Google Scholar 

  186. 186.

    Deleens, R., Pickering, G. & Hadjiat, Y. Pain in the elderly and cognition: state of play. Geriatr. Psychol. Neuropsychiatr. Vieil. 15, 345–356 (2017).

    Google Scholar 

  187. 187.

    Veldhuijzen, D. S. et al. Effect of chronic nonmalignant pain on highway driving performance. Pain 122, 28–35 (2006).

    CAS  Google Scholar 

  188. 188.

    Veldhuijzen, D. S. et al. Acute and subchronic effects of amitriptyline 25 mg on actual driving in chronic neuropathic pain patients. J. Psychopharmacol. 20, 782–788 (2006).

    CAS  Google Scholar 

  189. 189.

    Sabatowski, R., Scharnagel, R., Gyllensvard, A. & Steigerwald, I. Driving ability in patients with severe chronic low back or osteoarthritis knee pain on stable treatment with tapentadol prolonged release: a multicenter, open-label, phase 3b trial. Pain. Ther. 3, 17–29 (2014).

    PubMed  PubMed Central  Google Scholar 

  190. 190.

    Bonar, E. E. et al. Driving under the influence of cannabis among medical cannabis patients with chronic pain. Drug Alcohol. Depend. 195, 193–197 (2019).

    PubMed  PubMed Central  Google Scholar 

  191. 191.

    de la Fuente-Sandoval, C. et al. Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a longitudinal proton magnetic resonance spectroscopy study. JAMA Psychiatry 70, 1057–1066 (2013).

    PubMed  PubMed Central  Google Scholar 

  192. 192.

    Jelen, L. A., King, S., Mullins, P. G. & Stone, J. M. Beyond static measures: a review of functional magnetic resonance spectroscopy and its potential to investigate dynamic glutamatergic abnormalities in schizophrenia. J. Psychopharmacol. 32, 497–508 (2018).

    CAS  Google Scholar 

  193. 193.

    McCutcheon, R. A., Krystal, J. H. & Howes, O. D. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry 19, 15–33 (2020).

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    Jauhar, S. et al. The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study. Lancet Psychiatry 5, 816–823 (2018).

    PubMed  PubMed Central  Google Scholar 

  195. 195.

    Radhakrishnan, R., Wilkinson, S. T. & D’Souza, D. C. Gone to pot—a review of the association between cannabis and psychosis. Front. Psychiatry 5, 54 (2014).

    PubMed  PubMed Central  Google Scholar 

  196. 196.

    Rentero Martin, D., Arias, F., Sanchez-Romero, S., Rubio, G. & Rodriguez-Jimenez, R. Cannabis-induced psychosis: clinical characteristics and its differentiation from schizophrenia with and without cannabis use. Adicciones 33, 95–108 (2020).

    Google Scholar 

  197. 197.

    Singer, H. S. Motor control, habits, complex motor stereotypies, and Tourette syndrome. Ann. NY Acad. Sci. 1304, 22–31 (2013).

    CAS  Google Scholar 

  198. 198.

    Kanaan, A. S. et al. Pathological glutamatergic neurotransmission in Gilles de la Tourette syndrome. Brain 140, 218–234 (2017).

    Google Scholar 

  199. 199.

    Brunnauer, A. et al. Cannabinoids improve driving ability in a Tourette’s patient. Psychiatry Res. 190, 382 (2011).

    Google Scholar 

  200. 200.

    Karschner, E. L., Swortwood-Gates, M. J. & Huestis, M. A. Identifying and quantifying cannabinoids in biological matrices in the medical and legal cannabis era. Clin. Chem. 66, 888–914 (2020).

    Google Scholar 

  201. 201.

    Rogeberg, O. A meta-analysis of the crash risk of cannabis-positive drivers in culpability studies — avoiding interpretational bias. Accid. Anal. Prev. 123, 69–78 (2019).

    Google Scholar 

  202. 202.

    Gjerde, H. & Morland, J. Risk for involvement in road traffic crash during acute cannabis intoxication. Addiction 111, 1492–1495 (2016).

    Google Scholar 

  203. 203.

    Peng, Y. W., Desapriya, E., Chan, H. & R Brubacher, J. Residual blood THC levels in frequent cannabis users after over four hours of abstinence: a systematic review. Drug Alcohol. Depend. 216, 108177 (2020).

    CAS  Google Scholar 

  204. 204.

    Arkell, T. R., Spindle, T. R., Kevin, R. C., Vandrey, R. & McGregor, I. S. The failings of per se limits to detect cannabis-induced driving impairment: results from a simulated driving study. Traffic Inj. Prev. 22, 102–107 (2021).

    Google Scholar 

  205. 205.

    Pabon, E. & de Wit, H. Developing a phone-based measure of impairment after acute oral Δ9-tetrahydrocannabinol. J. Psychopharmacol. 33, 1160–1169 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Ramaekers, J. G., Robbe, H. W. & O’Hanlon, J. F. Marijuana, alcohol and actual driving performance. Hum. Psychopharmacol. 15, 551–558 (2000).

    Google Scholar 

  207. 207.

    Bosker, W. M. et al. Medicinal Δ9-tetrahydrocannabinol (dronabinol) impairs on-the-road driving performance of occasional and heavy cannabis users but is not detected in standard field sobriety tests. Addiction 107, 1837–1844 (2012).

    Google Scholar 

  208. 208.

    Hartman, R. L. et al. Cannabis effects on driving lateral control with and without alcohol. Drug Alcohol. Depend. 154, 25–37 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Stuster, J. & Burns, M. Validation of the Standardized Field Sobriety Test Battery at BACs Below 0.10 Percent DOT-HS-808-839 (US Department of Transportation, National Highway Traffic Safety Administration, 1998).

  210. 210.

    Downey, L. A. et al. Detecting impairment associated with cannabis with and without alcohol on the standardized field sobriety tests. Psychopharmacology 224, 581–589 (2012).

    CAS  Google Scholar 

  211. 211.

    MacCallum, C. A. & Russo, E. B. Practical considerations in medical cannabis administration and dosing. Eur. J. Intern. Med. 49, 12–19 (2018).

    CAS  Google Scholar 

  212. 212.

    Patel, S., Khan, S., M, S. & Hamid, P. The association between cannabis use and schizophrenia: causative or curative? A systematic review. Cureus 12, e9309 (2020).

    PubMed  PubMed Central  Google Scholar 

  213. 213.

    Ortiz-Medina, M. B. et al. Cannabis consumption and psychosis or schizophrenia development. Int. J. Soc. Psychiatry 64, 690–704 (2018).

    Google Scholar 

  214. 214.

    Carliner, H., Brown, Q. L., Sarvet, A. L. & Hasin, D. S. Cannabis use, attitudes, and legal status in the U.S.: a review. Prev. Med. 104, 13–23 (2017).

    PubMed  PubMed Central  Google Scholar 

  215. 215.

    Menetrey, A. et al. Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Δ9-THC. J. Anal. Toxicol. 29, 327–338 (2005).

    CAS  Google Scholar 

  216. 216.

    Albayram, O. et al. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. Proc. Natl Acad. Sci. USA 108, 11256–11261 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217.

    Marsicano, G. & Lutz, B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur. J. Neurosci. 11, 4213–4225 (1999).

    CAS  Google Scholar 

  218. 218.

    Urfer, S., Morton, J., Beall, V., Feldmann, J. & Gunesch, J. Analysis of Δ9-tetrahydrocannabinol driving under the influence of drugs cases in Colorado from January 2011 to February 2014. J. Anal. Toxicol. 38, 575–581 (2014).

    CAS  Google Scholar 

  219. 219.

    Hall, W. & Lynskey, M. Assessing the public health impacts of legalizing recreational cannabis use: the US experience. World Psychiatry 19, 179–186 (2020).

    PubMed  PubMed Central  Google Scholar 

  220. 220.

    World Health Organization. ICD-11 International Classification of Diseases for Mortality and Morbidity Statistics, 11th Revision (WHO, 2019).

  221. 221.

    American Psychiatric Publishing. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Publishing, 2013).

  222. 222.

    Gabrys, R. Clearing the Smoke on Cannabis. Edible Cannabis Products, Cannabis Extracts and Cannabis Topicals Report No. ISBN 978-1-77178-639-3 1-16 (Canadian Center on Substance Abuse and Addiction, 2020).

  223. 223.

    EMCDDA. Perspectives on drugs: synthetic cannabinoids in Europe. (EMCDDA, 2013).

  224. 224.

    Tsang, C. C. & Giudice, M. G. Nabilone for the management of pain. Pharmacotherapy 36, 273–286 (2016).

    CAS  Google Scholar 

  225. 225.

    Badowski, M. E. & Perez, S. E. Clinical utility of dronabinol in the treatment of weight loss associated with HIV and AIDS. HIV AIDS 8, 37–45 (2016).

    CAS  Google Scholar 

  226. 226.

    Wade, D. T., Collin, C., Stott, C. & Duncombe, P. Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Mult. Scler. 16, 707–714 (2010).

    CAS  Google Scholar 

  227. 227.

    Podda, G. & Constantinescu, C. S. Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis. Expert Opin. Biol. Ther. 12, 1517–1531 (2012).

    CAS  Google Scholar 

  228. 228.

    Jaklevic, M. C. CBD drug is approved for a third form of epilepsy. JAMA 324, 1026 (2020).

    Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Johannes G. Ramaekers.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neuroscience thanks S. Bhattacharyya (who co-reviewed with C. Davies), Z. Cooper, W. Hall and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Glossary

Cannabinoids

Compounds found in cannabis or that are synthetically produced to mimic naturally occurring cannabinoids.

Psychomotor deficits

Impairments of cognitive and motor functions that interfere with skilled performance.

Psychotomimetic effects

Effects that resemble psychotic symptoms.

Endocannabinoids

Endogenous ligands that bind to cannabinoid receptors.

Xenon-enhanced computed tomography

A neuroimaging method in which the subject inhales xenon gas to assess changes in cerebral blood flow.

Positron emission tomography

A magnetic resonance imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities such as receptor occupancy.

Arterial spin labelling

A non-invasive magnetic resonance imaging technique that uses arterial water as an endogenous tracer to measure cerebral blood flow.

Functional connectivity

A measure of similarity or correlation between brain signals arising from anatomically separated brain regions that indicates that the regions are functionally connected.

Executive network

A frontoparietal brain network involved in sustained attention, complex problem-solving and working memory.

Magnetic resonance spectroscopy

A non-invasive proton imaging technique that allows for the quantitative assessment of regional brain biochemistry.

Functional magnetic resonance imaging

A non-invasive technique for measuring and mapping brain activity based on changes in blood oxygen level-dependent signals that indicate underlying neural activity.

Default mode network

A brain network primarily consisting of the medial prefrontal cortex, the posterior cingulate cortex and the angular gyrus that is active when a person is focused on internal mental state processes and the brain is at wakeful rest.

Inhibitory control

A cognitive process that permits an individual to inhibit their impulses in order to select a more appropriate goal-directed response.

Single-nucleotide polymorphisms

Common genetic variations occurring when a single nucleotide at a single position in the genome differs among people.

Tolerance

A pharmacological concept describing a reduced reaction to a drug following repeated use.

Dependence

A disorder arising from repeated or continuous substance use characterized by preoccupation with and impaired control over substance use, as well as physiological features such as tolerance and withdrawal.

Trait levels

The quantification of personality traits in an individual.

Pharmacokinetics

The disposition of a drug within the body over a period of time as characterized by the four main phases of absorption, distribution, metabolism and elimination.

Field sobriety tests

Tests of balance, coordination and divided attention that are performed by the police to determine whether a driver is impaired.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ramaekers, J.G., Mason, N.L., Kloft, L. et al. The why behind the high: determinants of neurocognition during acute cannabis exposure. Nat Rev Neurosci 22, 439–454 (2021). https://doi.org/10.1038/s41583-021-00466-4

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing