Exercise-induced endocannabinoid signaling is modulated by intensity
Abstract
Endocannabinoids (eCB) are endogenous ligands for cannabinoid receptors that are densely expressed in brain networks responsible for reward. Recent work shows that exercise activates the eCB system in humans and other mammals, suggesting eCBs are partly responsible for the reported improvements in mood and affect following aerobic exercise in humans. However, exercise-induced psychological changes reported by runners are known to be dependent on exercise intensity, suggesting that any underlying molecular mechanism should also change with varying levels of exercise intensity. Here, we examine circulating levels of eCBs following aerobic exercise (treadmill running) in recreationally fit human runners at four different intensities. We show that eCB signaling is indeed intensity dependent, with significant changes in circulating eCBs observed following moderate intensities only (very high and very low intensity exercises do not significantly alter circulating eCB levels). Our results are consistent with intensity-dependent psychological state changes with exercise and therefore support the hypothesis that eCB activity is related to neurobiological effects of exercise. Thus, future studies examining the role of exercise-induced eCB signaling on neurobiology or physiology must take exercise intensity into account.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Treadmill running increases blood levels of AEA only at moderate versus low or high exercise intensity (70-85% of age-adjusted maximum heart rate).
“In another study, treadmill running resulted in increased blood levels of AEA; however, only at moderate -versus low or high -exercise intensity (i.e., at 70-85% of age-adjusted maximum heart rate) (Raichlen et al., 2013).”
From Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans (2016) · cites this paper as Raichlen et al., 2013
Studies using acute physical exercise as stressor found an increase of plasma AEA but not 2AG.
“Studies utilizing acute physical exercise as stressor have however found different responses, i.e., an increase of plasma concentrations of AEA but not 2AG (Heyman et al., 2012;Raichlen et al., 2013;Sparling et al., 2003).”
From Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans (2016) · cites this paper as Raichlen et al., 2013
Cites
Exercise training increases size of hippocampus and improves memory
Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., Kim, J. S., Heo, S., Alves, H., White, S. M., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015950108 · Cited by 4,855 · see citing works
Age-predicted maximal heart rate revisited
Tanaka, H., Monahan, K. D., & Seals, D. R. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(00)01054-8 · Cited by 3,775 · cited 1× · see citing works
“Age-adjusted maximum heart rate (AAMHR) was used to measure exercise intensity and was calculated following Tanaka et al. (2001).”
MethodThe molecular logic of endocannabinoid signalling
Piomelli, D. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1247 · Cited by 1,957 · see citing works
Endurance running and the evolution of Homo
Bramble, D. M., & Lieberman, D. E. (2004) · Nature · doi:10.1038/nature03052 · Cited by 1,748 · see citing works
Glass, M., Faull, R. L. M., & Dragunow, M. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00428-9 · Cited by 1,052 · see citing works
The Journal of Clinical Investigation
Witkin, E. M. (2016) · Journal of the American Dietetic Association · doi:10.1016/0002-8223(94)92394-9 · Cited by 920 · see citing works
An endocannabinoid mechanism for stress-induced analgesia
Hohmann, A. G., Suplita, R. L., Bolton, N. M., Neely, M. H., Fegley, D., Mangieri, R., Krey, J. F., Michael Walker, J., Holmes, P. V., Crystal, J. D., et al. (2005) · Nature · doi:10.1038/nature03658 · Cited by 778 · see citing works
The effect of acute aerobic exercise on positive activated affect: A meta-analysis
Reed, J., & Ones, D. S. (2006) · Psychology of Sport and Exercise · doi:10.1016/j.psychsport.2005.11.003 · Cited by 622 · see citing works
Endocannabinoid signaling as a synaptic circuit breaker in neurological disease
Katona, I., & Freund, T. F. (2008) · Nature Medicine · doi:10.1038/nm.f.1869 · Cited by 579 · see citing works
Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors
Agarwal, N., Pacher, P., Tegeder, I., Amaya, F., Constantin, C. E., Brenner, G. J., Rubino, T., Michalski, C. W., Marsicano, G., Monory, K., et al. (2007) · Nature Neuroscience · doi:10.1038/nn1916 · Cited by 571 · see citing works
Jiang, W. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25509 · Cited by 527 · see citing works
Ibrahim, M. M., Deng, H., Zvonok, A., Cockayne, D. A., Kwan, J., Mata, H. P., Vanderah, T. W., Lai, J., Porreca, F., Makriyannis, A., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834309100 · Cited by 491 · see citing works
Exercise and mood: A selective review and synthesis of research employing the profile of mood states
Berger, B. G., & Motl, R. W. (2000) · Journal of Applied Sport Psychology · doi:10.1080/10413200008404214 · Cited by 468 · see citing works
The Energetic Paradox of Human Running and Hominid Evolution [and Comments and Reply]
Carrier, D. R., Kapoor, A. K., Kimura, T., Nickels, M. K., Scott, E. C., So, J. K., & Trinkaus, E. (1984) · Current Anthropology · doi:10.1086/203165 · Cited by 432 · see citing works
Heyman, E., Gamelin, F.-X., Goekint, M., Piscitelli, F., Roelands, B., Leclair, E., Di Marzo, V., & Meeusen, R. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.09.017 · Cited by 427 · see citing works
An analgesia circuit activated by cannabinoids
Meng, I. D., Manning, B. H., Martin, W. J., & Fields, H. L. (1998) · Nature · doi:10.1038/26481 · Cited by 411 · cited 2× · see citing works
“…mitigate chronic and acute pain at both central and peripheral sites (Agarwal et al. 2007; Gerdeman 2008; Hohmann and Suplita 2006; Hohmann et al. 1999, 2005; Ibrahim et al. 2003; Piomelli 2003; Richardson 2000; Meng et al. 1998) and therefore likely play a role in exercise-induced analgesia.”
BackgroundDietrich, A., & McDaniel, W. F. (2004) · British Journal of Sports Medicine · doi:10.1136/bjsm.2004.011718 · Cited by 410 · see citing works
The endocannabinoid system drives neural progenitor proliferation
Aguado, T., Monory, K., Palazuelos, J., Stella, N., Cravatt, B. F., Lutz, B., Marsicano, G., Kokaia, Z., Guzmán, M., & Galve‐Roperh, I. (2005) · The FASEB Journal · doi:10.1096/fj.05-3995fje · Cited by 327 · see citing works
Exercise activates the endocannabinoid system
Sparling, P. B., Giuffrida, A., Piomelli, D., Rosskopf, L., & Dietrich, A. (2003) · Neuroreport · doi:10.1097/00001756-200312020-00015 · Cited by 313 · see citing works
Self-citationThe Endocannabinoid System Promotes Astroglial Differentiation by Acting on Neural Progenitor Cells
Aguado, T., Palazuelos, J., Monory, K., Stella, N., Cravatt, B. F., Lutz, B., Marsicano, G., Kokaia, Z., Guzmán, M., & Galve‐Roperh, I. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3101-05.2006 · Cited by 269 · see citing works
Raichlen, D. A., Foster, A. D., Gerdeman, G. L., Seillier, A., & Giuffrida, A. (2012) · Journal of Experimental Biology · doi:10.1242/jeb.063677 · Cited by 269 · see citing works
Self-citationExercise-Induced Hypoalgesia and Intensity of Exercise
Koltyn, K. F. (2002) · Sports Medicine · doi:10.2165/00007256-200232080-00001 · Cited by 261 · see citing works
Hillard, C. J. (2000) · Prostaglandins & Other Lipid Mediators · doi:10.1016/s0090-6980(00)00051-4 · Cited by 255 · see citing works
The human gluteus maximus and its role in running
Lieberman, D. E., Raichlen, D. A., Pontzer, H., Bramble, D. M., & Cutright-Smith, E. (2006) · Journal of Experimental Biology · doi:10.1242/jeb.02255 · Cited by 233 · see citing works
Self-citationSolinas, M., Justinová, Z., Goldberg, S. R., & Tanda, G. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03880.x · Cited by 229 · see citing works
Intensity and duration threshold for aerobic exercise-induced analgesia to pressure pain
Hoffman, M. D., Shepanski, M. A., Ruble, S. B., Valić, Z., Buckwalter, J. B., & Clifford, P. S. (2004) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/j.apmr.2003.09.010 · Cited by 216 · see citing works
Endocannabinoid mechanisms of pain modulation
Hohmann, A. G., & Suplita, R. L. (2006) · The AAPS Journal · doi:10.1208/aapsj080479 · Cited by 213 · see citing works
Wolf, S. A., Bick-Sander, A., Fabel, K., Leal-Galicia, P., Tauber, S., Ramirez-Rodriguez, G., Müller, A., Melnik, A., Waltinger, T. P., Ullrich, O., et al. (2010) · Cell Communication and Signaling · doi:10.1186/1478-811x-8-12 · Cited by 208 · see citing works
Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats
Lou, S., Liu, J., Chang, H., & Chen, P. (2008) · Brain Research · doi:10.1016/j.brainres.2008.02.080 · Cited by 206 · see citing works
Endocannabinoid signalling: has it got rhythm?
Vaughn, L. K., Denning, G., Stuhr, K. L., de Wit, H., Hill, M. N., & Hillard, C. J. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00790.x · Cited by 176 · see citing works
A catalytically silent FAAH-1 variant drives anandamide transport in neurons
Fu, J., Bottegoni, G., Sasso, O., Bertorelli, R., Rocchia, W., Masetti, M., Guijarro, A., Lodola, A., Armirotti, A., Garau, G., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.2986 · Cited by 175 · see citing works
The Biodisposition and Metabolism of Anandamide in Mice
Willoughby, K. A., Moore, S. F., Martin, B. R., & Ellis, E. F. (1997) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)36812-0 · Cited by 159 · see citing works
Hill, M. N., Titterness, A. K., Morrish, A. C., Carrier, E. J., Lee, T. T. ‐., Gil‐Mohapel, J., Gorzalka, B. B., Hillard, C. J., & Christie, B. R. (2009) · Hippocampus · doi:10.1002/hipo.20647 · Cited by 129 · see citing works
Hohmann, A. G., Tsou, K., & Walker, J. M. (1999) · Journal of Neurophysiology · doi:10.1152/jn.1999.81.2.575 · Cited by 126 · see citing works
Köfalvi, A. (2007) · Springer eBooks · doi:10.1007/978-0-387-74349-3 · Cited by 110 · see citing works
Cannabinoids modulate pain by multiple mechanisms of action
Richardson, J. D. (2000) · The Journal of Pain · doi:10.1016/s1526-5900(00)90082-8 · Cited by 109 · see citing works
Justinová, Z. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0951-05.2005 · Cited by 104 · see citing works
Dubreucq, S., Koehl, M., Abrous, D. N., Marsicano, G., & Chaouloff, F. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.01.017 · Cited by 103 · see citing works
Kim, Y.-P., Kim, H.-B., Jang, M.-H., Lim, B., Kim, Y.-J., Kim, H., Kim, S.-S., Kim, E.-H., & Kim, C. (2003) · International Journal of Sports Medicine · doi:10.1055/s-2003-38202 · Cited by 96 · see citing works
Brains, Brawn, and the Evolution of Human Endurance Running Capabilities
Lieberman, D. E., Bramble, D. M., Raichlen, D. A., & Shea, J. J. (2009) · Vertebrate paleobiology and paleoanthroplogy series/Vertebrate paleobiology and paleoanthropology series · doi:10.1007/978-1-4020-9980-9_8 · Cited by 96 · see citing works
Self-citationKeeney, B. K., Raichlen, D. A., Meek, T. H., Wijeratne, R. S., Middleton, K. M., Gerdeman, G. L., & Garland, T. (2008) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e32831c3b6b · Cited by 86 · see citing works
Self-citationEffects of exercise stress on the endocannabinoid system in humans under field conditions
Feuerecker, M., Hauer, D., Tóth, R., Demetz, F., Hölzl, J., Thiel, M., Kaufmann, I., Schelling, G., & Choukèr, A. (2011) · European Journal of Applied Physiology · doi:10.1007/s00421-011-2237-0 · Cited by 79 · see citing works
Lieberman, D. E., Bramble, D. M., Raichlen, D. A., & Shea, J. J. (2007) · Journal of Human Evolution · doi:10.1016/j.jhevol.2007.07.002 · Cited by 78 · see citing works
Self-citationJustinová, Z., Yaşar, S., Redhi, G. H., & Goldberg, S. R. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.6058-10.2011 · Cited by 63 · see citing works
Keeney, B. K., Meek, T. H., Middleton, K. M., Holness, L. F., & Garland, T. (2012) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2012.02.017 · Cited by 56 · see citing works
Hardison, S. E., Weintraub, S. T., & Giuffrida, A. (2006) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2006.08.002 · Cited by 53 · see citing works
Self-citationZoerner, A. A., Gutzki, F. M., Suchy, M. T., Beckmann, B., Engeli, S., Jordan, J., & Tsikas, D. (2009) · Journal of Chromatography B · doi:10.1016/j.jchromb.2009.04.016 · Cited by 52 · see citing works
Kimbel, W. H. (2009) · Vertebrate paleobiology and paleoanthroplogy series/Vertebrate paleobiology and paleoanthropology series · doi:10.1007/978-1-4020-9980-9_4 · Cited by 42 · see citing works
Naloxone and rimonabant reduce the reinforcing properties of exercise in rats.
Rasmussen, E. B., & Hillman, C. N. (2011) · Experimental and Clinical Psychopharmacology · doi:10.1037/a0024142 · Cited by 29 · see citing works
Ex Vivo Imaging of Fatty Acid Amide Hydrolase Activity and Its Inhibition in the Mouse Brain
Glaser, S. T., Gatley, S. J., & Gifford, A. N. (2006) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.094748 · Cited by 26 · see citing works
Endocannabinoids at the Synapse: Retrograde Signaling and Presynaptic Plasticity in the Brain
Gerdeman, G. L. (2007) · Springer eBooks · doi:10.1007/978-0-387-74349-3_11 · Cited by 11 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Basso, J. C., & Suzuki, W. A. (2016) · Brain Plasticity · doi:10.3233/bpl-160040 · Cited by 911 · see citing works
The Theory of Effort Minimization in Physical Activity
Cheval, B., & Boisgontier, M. P. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000252 · Cited by 224 · see citing works
Physical activity and the endocannabinoid system: an overview
Tantimonaco, M., Ceci, R., Sabatini, S., Catani, M. V., Rossi, A., Gasperi, V., & Maccarrone, M. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1575-6 · Cited by 112 · see citing works
Vijay, A., Kouraki, A., Gohir, S., Turnbull, J., Kelly, A., Chapman, V., Barrett, D. A., Bulsiewicz, W. J., & Valdes, A. M. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1997559 · Cited by 93 · see citing works
Cedernaes, J., Fanelli, F., Fazzini, A., Pagotto, U., Broman, J.-E., Vogel, H., Dickson, S. L., Schiöth, H. B., & Benedict, C. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.09.014 · Cited by 59 · see citing works
Do Endocannabinoids Cause the Runner’s High? Evidence and Open Questions
Siebers, M., Biedermann, S. V., & Fuss, J. (2023) · The Neuroscientist · doi:10.1177/10738584211069981 · Cited by 46 · see citing works
Rodrigues, R. S., Moreira, J. B., Mateus, J. M., Barateiro, A., Paulo, S. L., Vaz, S. H., Lourenço, D. M., Ribeiro, F. F., Soares, R., Loureiro-Campos, E., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02877-0 · Cited by 12 · see citing works
Endocannabinoids and Stroke Prevention: Review of Clinical Studies
Scharf, E. L., & Ebbert, J. O. (2020) · Cannabis & Cannabinoid Research · doi:10.1089/can.2018.0066 · Cited by 8 · see citing works
- Authors
- Raichlen, D. A., Foster, A. D., Seillier, A., Giuffrida, A., & Gerdeman, G. L.
- Affiliations
- University of Arizona (US)
- The University of Texas at San Antonio Health Science Center (US)
- Eckerd College (US)
- Corresponding author
- Raichlen, David A.
- Venue
- European Journal of Applied Physiology
- Published
- 2012-09-19
- Volume
- 113
- Issue
- 4
- Pages
- 869-875
- ISSN
- 0020-9376 (ISSN-L)
- 1439-6319
- 1439-6327
- OpenAlex
- W2081400245
- Semantic Scholar
- ead7a056401c8a54ff38b910a4f9234438a5bb3b
- Cited by
- 181
- References
- 51
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 12 · 2023: 11 · 2022: 22 · 2021: 22 · 2020: 18 · 2019: 18 · 2018: 11 · 2017: 8 · 2016: 13 · 2015: 4 · 2014: 8 · 2013: 11
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Applied Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Physiology › Physical Activity and Health
- Keywords
- endocannabinoids, exercise intensity, aerobic exercise, treadmill running, cannabinoid receptors, mood, affect, runners, exercise psychology
- MeSH terms
- Adolescent, Adult, Analysis of Variance, Arachidonic Acids, Arizona, Brain, Exercise Test, Female, Humans, Male, Muscle Contraction, Running, Signal Transduction, Exercise, Muscle, Skeletal, Polyunsaturated Alkamides, Young Adult, Endocannabinoids
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
