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.
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United Nations Office on Drugs and Crime. World Drug Report 2020 https://wdr.unodc.org/wdr2020/index.html (2020).
Hall, W. & Lynskey, M. Evaluating the public health impacts of legalizing recreational cannabis use in the United States. Addiction 111, 1764–1773 (2016).
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).
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).
Kilmer, B. & Pacula, R. L. Understanding and learning from the diversification of cannabis supply laws. Addiction 112, 1128–1135 (2017).
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).
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).
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).
Freeman, T. P. et al. Increasing potency and price of cannabis in Europe, 2006–16. Addiction 114, 1015–1023 (2019).
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).
Ramaekers, J. G. et al. High-potency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology 31, 2296–2303 (2006).
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).
Gonzalez, R. Acute and non-acute effects of cannabis on brain functioning and neuropsychological performance. Neuropsychol. Rev. 17, 347–361 (2007).
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).
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).
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).
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).
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).
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).
Curran, H. V. et al. Keep off the grass? Cannabis, cognition and addiction. Nat. Rev. Neurosci. 17, 293–306 (2016).
Arkell, T. R. et al. Effect of cannabidiol and Δ9-tetrahydrocannabinol on driving performance: a randomized clinical trial. JAMA 324, 2177–2186 (2020).
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).
Ranganathan, M. & D’Souza, D. C. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology 188, 425–444 (2006).
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).
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).
Kloft, L. et al. False memory formation in cannabis users: a field study. Psychopharmacology 236, 3439–3450 (2019).
Kloft, L. et al. Cannabis increases susceptibility to false memory. Proc. Natl Acad. Sci. USA 117, 4585–4589 (2020).
D’Souza, D. C. et al. Blunted psychotomimetic and amnestic effects of Δ9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology 33, 2505–2516 (2008).
Ballard, M. E., Bedi, G. & de Wit, H. Effects of Δ9-tetrahydrocannabinol on evaluation of emotional images. J. Psychopharmacol. 26, 1289–1298 (2012).
Zuurman, L. et al. Effect of intrapulmonary tetrahydrocannabinol administration in humans. J. Psychopharmacol. 22, 707–716 (2008).
van Wel, J. et al. Psychedelic symptoms of cannabis and cocaine use as a function of trait impulsivity. J. Psychopharmacol. 29, 324–334 (2015).
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).
Bhattacharyya, S. et al. Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis. Eur. Neuropsychopharmacol. 25, 26–37 (2015).
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).
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).
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).
Favrat, B. et al. Two cases of “cannabis acute psychosis” following the administration of oral cannabis. BMC Psychiatry 5, 17 (2005).
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).
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).
Horwood, L. J. et al. Cannabis use and educational achievement: findings from three Australasian cohort studies. Drug Alcohol. Depend. 110, 247–253 (2010).
Silins, E. et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatry 1, 286–293 (2014).
Macdonald, S. et al. Testing for cannabis in the work-place: a review of the evidence. Addiction 105, 408–416 (2010).
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).
Hartman, R. L. & Huestis, M. A. Cannabis effects on driving skills. Clin. Chem. 59, 478–492 (2013).
Bondallaz, P. et al. Cannabis and its effects on driving skills. Forensic Sci. Int. 268, 92–102 (2016).
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).
Li, M. C. et al. Marijuana use and motor vehicle crashes. Epidemiol. Rev. 34, 65–72 (2012).
Rogeberg, O. & Elvik, R. The effects of cannabis intoxication on motor vehicle collision revisited and revised. Addiction 111, 1348–1359 (2016).
Colizzi, M. & Bhattacharyya, S. Cannabis use and the development of tolerance: a systematic review of human evidence. Neurosci. Biobehav. Rev. 93, 1–25 (2018).
Ramaekers, J. G., Mason, N. L. & Theunissen, E. L. Blunted highs: pharmacodynamic and behavioral models of cannabis tolerance. Eur. Neuropsychopharmacol. 36, 191–205 (2020).
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).
Ferland, J. N. & Hurd, Y. L. Deconstructing the neurobiology of cannabis use disorder. Nat. Neurosci. 23, 600–610 (2020).
Hashimotodani, Y., Ohno-Shosaku, T. & Kano, M. Endocannabinoids and synaptic function in the CNS. Neuroscientist 13, 127–137 (2007).
Mackie, K. Cannabinoid receptors: where they are and what they do. J. Neuroendocrinol. 20 (Suppl. 1), 10–14 (2008).
Freund, T. F., Katona, I. & Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83, 1017–1066 (2003).
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).
Iversen, L. Cannabis and the brain. Brain 126, 1252–1270 (2003).
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).
Prini, P. et al. Neurobiological mechanisms underlying cannabis-induced memory impairment. Eur. Neuropsychopharmacol. 36, 181–190 (2020).
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).
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).
Bonelli, R. M. & Cummings, J. L. Frontal-subcortical circuitry and behavior. Dialogues Clin. Neurosci. 9, 141–151 (2007).
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).
Bloomfield, M. A. P. et al. The neuropsychopharmacology of cannabis: a review of human imaging studies. Pharmacol. Ther. 195, 132–161 (2019).
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).
Klumpers, L. E. et al. Manipulating brain connectivity with Δ9-tetrahydrocannabinol: a pharmacological resting state FMRI study. Neuroimage 63, 1701–1711 (2012).
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).
Zaytseva, Y. et al. Cannabis-induced altered states of consciousness are associated with specific dynamic brain connectivity states. J. Psychopharmacol. 33, 811–821 (2019).
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).
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).
Bossong, M. G. et al. Δ9-Tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 34, 759–766 (2009).
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).
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).
Ramaekers, J. G. et al. Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit. Psychopharmacology 229, 219–226 (2013).
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).
Mason, N. L. et al. Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity. Eur. Neuropsychopharmacol. 29, 247–256 (2019).
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).
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).
Colizzi, M. et al. Δ9-Tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis. Mol. Psychiatry 25, 3231–3240 (2019).
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).
Seeley, W. W. et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J. Neurosci. 27, 2349–2356 (2007).
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).
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).
Menon, V. in Brain Mapping: An Encyclopedic Reference Vol. 2 (ed. Toga, A. W.) 597–611 (Academic Press: Elsevier, 2015).
Friston, K. J. Functional and effective connectivity: a review. Brain Connect. 1, 13–36 (2011).
Hermans, E. J. et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science 334, 1151–1153 (2011).
Shafiei, G. et al. Dopamine signaling modulates the stability and integration of intrinsic brain networks. Cereb. Cortex 29, 397–409 (2019).
Seeley, W. W. The salience network: a neural system for perceiving and responding to homeostatic demands. J. Neurosci. 39, 9878–9882 (2019).
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).
Menon, V. & Uddin, L. Q. Saliency, switching, attention and control: a network model of insula function. Brain Struct. Funct. 214, 655–667 (2010).
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).
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).
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).
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).
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).
Bhattacharyya, S. et al. Cannabinoid modulation of functional connectivity within regions processing attentional salience. Neuropsychopharmacology 40, 1343–1352 (2015).
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).
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).
Raichle, M. E. The brain’s default mode network. Annu. Rev. Neurosci. 38, 433–447 (2015).
Bossong, M. G. et al. Default mode network in the effects of Δ9-tetrahydrocannabinol (THC) on human executive function. PLoS ONE 8, e70074 (2013).
Borgwardt, S. J. et al. Neural basis of Δ9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol. Psychiatry 64, 966–973 (2008).
Bhattacharyya, S. et al. Opposite effects of Δ9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35, 764–774 (2010).
Theunissen, E. L. et al. Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans. Psychopharmacology 232, 343–353 (2015).
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).
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).
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).
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).
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).
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).
Bossong, M. G. et al. Effects of Δ9-tetrahydrocannabinol on human working memory function. Biol. Psychiatry 71, 693–699 (2012).
Sherif, M., Radhakrishnan, R., D’Souza, D. C. & Ranganathan, M. Human laboratory studies on cannabinoids and psychosis. Biol. Psychiatry 79, 526–538 (2016).
Radhakrishnan, R. et al. GABA deficits enhance the psychotomimetic effects of Δ9-THC. Neuropsychopharmacology 40, 2047–2056 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Nordstrom, B. R. & Hart, C. L. Assessing cognitive functioning in cannabis users: cannabis use history an important consideration. Neuropsychopharmacology 31, 2798–2799 (2006).
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).
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).
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).
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).
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).
Ceccarini, J. et al. [18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users. Addict. Biol. 20, 357–367 (2015).
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).
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).
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).
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).
Bosker, W. M. et al. Psychomotor function in chronic daily cannabis smokers during sustained abstinence. PLoS ONE 8, e53127 (2013).
Lorenzetti, V., Solowij, N. & Yucel, M. The role of cannabinoids in neuroanatomic alterations in cannabis users. Biol. Psychiatry 79, e17–e31 (2016).
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).
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).
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).
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).
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).
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).
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).
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).
Munro, C. A. et al. Sex differences in striatal dopamine release in healthy adults. Biol. Psychiatry 59, 966–974 (2006).
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).
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).
Cooper, Z. D. & Craft, R. M. Sex-dependent effects of cannabis and cannabinoids: a translational perspective. Neuropsychopharmacology 43, 34–51 (2018).
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).
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).
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).
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).
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).
Grotenhermen, F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin. Pharmacokinet. 42, 327–360 (2003).
Huestis, M. A. Human cannabinoid pharmacokinetics. Chem. Biodivers. 4, 1770–1804 (2007).
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).
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).
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).
Hollister, L. E. Structure–activity relationships in man of cannabis constituents, and homologs and metabolites of Δ9-tetrahydrocannabinol. Pharmacology 11, 3–11 (1974).
Poyatos, L. et al. Oral administration of cannabis and Δ-9-tetrahydrocannabinol (THC) preparations: a systematic review. Medicina 56, 309 (2020).
Englund, A., Freeman, T. P., Murray, R. M. & McGuire, P. Can we make cannabis safer? Lancet Psychiatry 4, 643–648 (2017).
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).
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).
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).
Bidwell, L. C. et al. Association of naturalistic administration of cannabis flower and concentrates with intoxication and impairment. JAMA Psychiatry 77, 787–796 (2020).
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).
EMCDDA. European Drug Report 2017. Trends and Developments (EMCDDA, 2017).
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).
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).
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).
Basavarajappa, B. S. & Subbanna, S. Potential mechanisms underlying the deleterious effects of synthetic cannabinoids found in Spice/K2 products. Brain Sci. 9, 14 (2019).
Auwarter, V. et al. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs? JMS 44, 832–837 (2009).
Spaderna, M., Addy, P. H. & D’Souza, D. C. Spicing things up: synthetic cannabinoids. Psychopharmacology 228, 525–540 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Deleens, R., Pickering, G. & Hadjiat, Y. Pain in the elderly and cognition: state of play. Geriatr. Psychol. Neuropsychiatr. Vieil. 15, 345–356 (2017).
Veldhuijzen, D. S. et al. Effect of chronic nonmalignant pain on highway driving performance. Pain 122, 28–35 (2006).
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).
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).
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).
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).
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).
McCutcheon, R. A., Krystal, J. H. & Howes, O. D. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry 19, 15–33 (2020).
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).
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).
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).
Singer, H. S. Motor control, habits, complex motor stereotypies, and Tourette syndrome. Ann. NY Acad. Sci. 1304, 22–31 (2013).
Kanaan, A. S. et al. Pathological glutamatergic neurotransmission in Gilles de la Tourette syndrome. Brain 140, 218–234 (2017).
Brunnauer, A. et al. Cannabinoids improve driving ability in a Tourette’s patient. Psychiatry Res. 190, 382 (2011).
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).
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).
Gjerde, H. & Morland, J. Risk for involvement in road traffic crash during acute cannabis intoxication. Addiction 111, 1492–1495 (2016).
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).
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).
Pabon, E. & de Wit, H. Developing a phone-based measure of impairment after acute oral Δ9-tetrahydrocannabinol. J. Psychopharmacol. 33, 1160–1169 (2019).
Ramaekers, J. G., Robbe, H. W. & O’Hanlon, J. F. Marijuana, alcohol and actual driving performance. Hum. Psychopharmacol. 15, 551–558 (2000).
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).
Hartman, R. L. et al. Cannabis effects on driving lateral control with and without alcohol. Drug Alcohol. Depend. 154, 25–37 (2015).
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).
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).
MacCallum, C. A. & Russo, E. B. Practical considerations in medical cannabis administration and dosing. Eur. J. Intern. Med. 49, 12–19 (2018).
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).
Ortiz-Medina, M. B. et al. Cannabis consumption and psychosis or schizophrenia development. Int. J. Soc. Psychiatry 64, 690–704 (2018).
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).
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).
Albayram, O. et al. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. Proc. Natl Acad. Sci. USA 108, 11256–11261 (2011).
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).
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).
Hall, W. & Lynskey, M. Assessing the public health impacts of legalizing recreational cannabis use: the US experience. World Psychiatry 19, 179–186 (2020).
World Health Organization. ICD-11 International Classification of Diseases for Mortality and Morbidity Statistics, 11th Revision (WHO, 2019).
American Psychiatric Publishing. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Publishing, 2013).
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).
EMCDDA. Perspectives on drugs: synthetic cannabinoids in Europe. (EMCDDA, 2013).
Tsang, C. C. & Giudice, M. G. Nabilone for the management of pain. Pharmacotherapy 36, 273–286 (2016).
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).
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).
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).
Jaklevic, M. C. CBD drug is approved for a third form of epilepsy. JAMA 324, 1026 (2020).
The authors declare no competing interests.
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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.
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.
A pharmacological concept describing a reduced reaction to a drug following repeated use.
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.
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.
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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