A Correct Perspective on Our Brain’s "Endocannabinoid” System

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Cermak MD</a> </div> <div class="profile_card__blog-title"> <a href="/gb/blog/healing-addiction" hreflang="en">Healing from Addiction</a> </div> </div> </div> </div> <div class="blog-entry--header-second"> <h6 class="blog-entry__topic--full text-uppercase-primary-large"> <a href="/gb/basics/neuroscience" hreflang="en-gb">Neuroscience</a> </h6> <h1 class="blog-entry__title--full"> A Correct Perspective on Our Brain’s "Endocannabinoid” System </h1> <h2 class="blog-entry__subtitle--full"> The endocannabinoid system has no essential relationship to cannabis. </h2> <p class="blog-entry__date--full fine-print"> Posted <span class="blog_entry--date">November 14, 2024</span> <span class="blog_entry--full__review-info"> <span class="blog_entry--full__review-info-bar">|</span> <a href="/gb/docs/editorial-process" class="blog_entry--full__review-info-link"> <span class="blog_entry--full__review-info-icon"></span> <span class="blog_entry--full__review-info-text">Reviewed by Margaret Foley</span> 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href="mailto:?subject=Psychology%20Today%3A%20A%20Correct%20Perspective%20on%20Our%20Brain%E2%80%99s%20%22Endocannabinoid%E2%80%9D%20System&body=Hi%2C%0D%0A%0D%0AI%20thought%20you%27d%20be%20interested%20in%20this%20article%20on%20Psychology%20Today%3A%0D%0A%0D%0A%20A%20Correct%20Perspective%20on%20Our%20Brain%E2%80%99s%20%22Endocannabinoid%E2%80%9D%20System%0D%0Ahttps%3A//www.psychologytoday.com/gb/blog/healing-from-addiction/202411/a-correct-perspective-on-our-brains-endocannabinoid-system%3Feml%0D%0A%0D%0A%0D%0A---%0D%0AFind%20Counselling%3A%20https%3A//www.psychologytoday.com/gb&destination=node/5027087"> <div><img border="0" src="https://cdn2.psychologytoday.com/theme-assets/icons/icon-share-round-email-md.svg" alt="Share via Email" width="37" height="37" /><span class="visually-hidden">Email</span></div> </a> </div> </li> </ul> </div> </div> </div> <div class="blog-entry--body"> <div class="blog-entry--body-first"> <div class="d-none d-xl-block"> </div> </div> <div class="blog-entry--body-second"> <div class="blog_entry__key-points"> <h3 class="blog_entry__key-points-title">Key points</h3> <ul class="blog_entry__key-points-item-list"> <li class="blog_entry__key-points-item">People misperceive the function of the endocannabinoid system.</li> <li class="blog_entry__key-points-item">This system's relationship to cannabis is only incidental.</li> <li class="blog_entry__key-points-item">The endocannabinoid system's true function is to regulate all other neurotransmitter systems.</li> </ul> </div> <div class="field-name-body"> <p>At 15 years old, Sammy considered himself an expert on cannabis. When I asked what he knew about how marijuana interacts with the brain, he confidently explained, “THC activates cannabinoid receptors stronger than our natural cannabinoid transmitters.” While he was technically correct, his explanation was flawed by the “endocannabinoid” system’s cannabis-centric nomenclature, which distorts perspective on what should rightly be called a “synaptic negative feedback system” (SNF system). The following description of the SNF system contains no reference to cannabis and thereby offers an improved perspective on this foundational synaptic structure.</p> <div class="markup-replacement-slot markup-replacement-slot-0" data-slot-position="0"></div> <p>The primitive hydra provides an evolutionarily early example of basic neural networks. Its synaptic connections between neurons display the typical downstream flow of neurotransmitter from presynaptic neurons to neuroreceptors on downstream postsynaptic neurons. However, this simplified concept of synaptic structure contains a potential flaw. If a presynaptic neuron increases its firing rate sufficiently, postsynaptic neurons would be expected to begin downregulating receptors. As a result, once presynaptic neurons return to their normal rate of firing, released neurotransmitter would encounter fewer receptors than existed prior to the period of increased firing rate. This would lead to ambiguity in the transfer of information because the level of postsynaptic activation during normal presynaptic firing rate would vary, depending on previous conditions. The hydra’s neural network avoided such ambiguity by contemporaneously evolving a synaptic negative feedback system as an essential element of synaptic transmission.</p> <div class="markup-replacement-slot markup-replacement-slot-1" data-slot-position="1"></div> <p>The SNF system is activated in postsynaptic neurons in proportion to the amount of stimulation of its neuroreceptors by transmitters crossing the synapse from upstream neurons. An influx of calcium ions with receptor activation leads to the synthesis of neuromodulators<a href="#_edn1" title="">[i]</a> from arachidonic acid abundantly found within cell membranes, e.g., anandamide and 2-AG.<a href="#_edn2" title="">[ii]</a> These neuromodulators pass retrograde across the synapse to active presynaptic SNF receptors<a href="#_edn3" title="">[iii]</a>. The SNF system is one element of synaptic structure.</p> <div class="markup-replacement-slot markup-replacement-slot-2" data-slot-position="2"></div> <p>Activating SNF receptors reduces the amount of transmitter released with each presynaptic neuronal firing.<a href="#_edn1" title="">[I]</a> This reduction prevents the downregulation of postsynaptic receptor sites. To be clear, anandamide and 2-AG’s negative feedback does not change the rate of presynaptic firing but only reduces the amount of transmitter expressed with each firing. As a result, postsynaptic receptors receive nearly the same amount of neurotransmitter at rapid firing rates as at normal firing rates, but at a different temporal distribution. The mechanism whereby postsynaptic neurons are more activated by reception of rapid smaller transmitter amounts than by slower larger amounts per firing needs further research. However, it is abundantly clear that our auditory neural system can easily differentiate between the beating on a tin roof by a rapid drizzle and a few larger drops, even if the total amount of rainwater is similar.</p> <div class="markup-replacement-slot markup-replacement-slot-3" data-slot-position="3"></div> <p>We can now see that the synaptic negative feedback system is a tonically active homeostatic mechanism for maintaining synaptic transmission within specific parameters. The entire system, comprising enzymes to synthesize neuromodulators from arachidonic acid, a class of “arachi-neuromodulators” such as anandamide and 2-AG, and SNF receptors, evolved well before the evolution of the cannabis plant, and it has functions that have no regard to cannabis. Misleading cannabis-centric nomenclature arose due to the role powerful analogs of THC played in discovering SNF receptors by researchers interested in how THC impacts the brain—thus the “cannabinoid” receptors CB1 and 2. A similar distorted nomenclature can be found in the acetylcholine receptor in muscles, which is called a nicotinic receptor due to the use of nicotine in its discovery.</p> <div class="markup-replacement-slot markup-replacement-slot-4" data-slot-position="4"></div> <p>Another reason for the misleading cannabis-centric nomenclature stems from cannabis/THC use by so many people and its abuse by a subpopulation of users, serving as the best indicator of what happens when the SNF system is driven far from equilibrium. Cannabis/THC use increases SNF tone in brain structures containing high concentrations of SNF receptors (e.g., frontal lobes, hippocampus, hypothalamus, amygdala, motor systems, etc.), and this correlates with impacts on mental functions housed in these structures, such as <a href="https://www.psychologytoday.com/gb/basics/cognition" title="Psychology Today looks at cognition" class="basics-link" hreflang="en-GB">cognition</a>, <a href="https://www.psychologytoday.com/gb/basics/memory" title="Psychology Today looks at memory" class="basics-link" hreflang="en-GB">memory</a>, appetites, affect, novelty, reduced spontaneous motor activity, <a href="https://www.psychologytoday.com/gb/basics/attention" title="Psychology Today looks at concentration" class="basics-link" hreflang="en-GB">concentration</a>, and time perception. On the other hand, suppressed SNF tone due to receptor downregulation during withdrawal from regular cannabis/THC use, which can reach 60 percent in some brain structures<a href="#_edn2" title="">[ii]</a> and averages 20 percent in the frontal lobes<a href="#_edn3" title="">[iii]</a>, produces the obverse in many mental functions, i.e., physical restlessness, <a href="https://www.psychologytoday.com/gb/basics/anxiety" title="Psychology Today looks at anxiety" class="basics-link" hreflang="en-GB">anxiety</a>/irritability, <a href="https://www.psychologytoday.com/gb/basics/insomnia" title="Psychology Today looks at insomnia" class="basics-link" hreflang="en-GB">insomnia</a>, loss of <a href="https://www.psychologytoday.com/gb/basics/appetite" title="Psychology Today looks at appetite" class="basics-link" hreflang="en-GB">appetite</a>, and <a href="https://www.psychologytoday.com/gb/basics/boredom" title="Psychology Today looks at boredom" class="basics-link" hreflang="en-GB">boredom</a>. One important measure of whether an individual is using cannabis/THC safely is whether the foundational synaptic substructure is being modified for more than a day after use.</p> <div class="markup-replacement-slot markup-replacement-slot-5" data-slot-position="5"></div> <p>The main reason to correct the nomenclature for our SNF system is to <a href="https://www.psychologytoday.com/gb/basics/dissociation" title="Psychology Today looks at dissociate" class="basics-link" hreflang="en-GB">dissociate</a> cannabis/THC from the essential brain functions it alters. Maintenance of normal, balanced SNF function is necessary for good mental health. Cannabis/THC is an invader that disturbs normal brain physiology. Too-frequent use produces impacts that can last for weeks, while occasional use appears to have little or no lasting impact except on the performance of highly skilled tasks requiring sustained concentration and good hand-eye coordination<a href="#_edn4" title="">[iv]</a> (e.g., piloting airplanes and performing surgery), as downregulation of SNF receptors begins with a single dose.<a href="//C5E7F236-72CF-4951-807F-75CDEC8FD6D2#_edn5" title="">[v]</a></p> <div class="markup-replacement-slot markup-replacement-slot-6" data-slot-position="6"></div> <p>While cannabis/THC played an important role in discovering the synaptic negative feedback system, it is now time for <a href="https://www.psychologytoday.com/gb/basics/neuroscience" title="Psychology Today looks at neuroscience" class="basics-link" hreflang="en-GB">neuroscience</a> and <a href="https://www.psychologytoday.com/gb/basics/psychiatry" title="Psychology Today looks at psychiatry" class="basics-link" hreflang="en-GB">psychiatry</a> to focus attention on this system in and of itself. Do disorders within the SNF system exist? Could altering SNF tone up or down aid various mental disorders (e.g., <a href="https://www.psychologytoday.com/gb/basics/post-traumatic-stress-disorder" title="Psychology Today looks at PTSD" class="basics-link" hreflang="en-GB">PTSD</a> and <a href="https://www.psychologytoday.com/gb/basics/dementia" title="Psychology Today looks at dementia" class="basics-link" hreflang="en-GB">dementia</a>)? Does the calming effect of calcium blockers such as verapamil stem from decreasing SNF tone? Can beneficial medications be developed to modulate SNF tone with fewer side effects than cannabis/THC and current anandamide/2-AG blockers? What behaviors naturally increase SNF tone (e.g., <a href="https://www.psychologytoday.com/gb/basics/meditation" title="Psychology Today looks at meditation" class="basics-link" hreflang="en-GB">meditation</a>, massage, and physical exercise)? What behaviors reduce tone?</p> <div class="markup-replacement-slot markup-replacement-slot-7" data-slot-position="7"></div> <p>The prospects for valuable research will open more clearly once we develop the correct perspective on this important synaptic substructure. And perhaps young “experts” like Sammy will begin to understand the value of monitoring how cannabis/THC is altering important brain chemistry.</p> <div class="markup-replacement-slot markup-replacement-slot-last" data-slot-position="last"></div> </div> <div class="blog-entry-references" data-hide-large-count-items="true"> <p class="blog-entry-references-label">References</p> <div class="blog-entry-references-content-items"> <div class="blog-entry-references-content"> <p><a href="//C91FE55D-03C7-4A8B-A469-CA90E27E463D#_ednref1" title="">[i]</a> V. Di Marzo, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. <em>Nature</em> 1994; 372(6507): 686-91.</p> </div> <div class="blog-entry-references-content"> <p><a href="//C91FE55D-03C7-4A8B-A469-CA90E27E463D#_ednref2" title="">[ii]</a> W. A. Devane, R. Mechoulam, et al. Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor. <em>Science</em> 1992. 258: 1946-9.</p> <p>R. Mechoulam, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. <em>Biochem Pharmacol</em> 1995; 50(1): 83-90.</p> </div> <div class="blog-entry-references-content"> <p><a href="//C91FE55D-03C7-4A8B-A469-CA90E27E463D#_ednref3" title="">[iii]</a> W. A. Devane, A. Howlett, et al. Determination and Characterization of a Cannabinoid Receptor in Rat Brain. <em>Molecular Pharmacology</em> 1988, 34: 605-613.</p> <p>and</p> <p>I. Katona, et al. Presynaptically Located CB1 Cannabinoid Receptors Regulate GABA Release from Axon Terminals of Specific Hippocampal Interneurons. J. <em>Neurosci</em>. 1999; 19(11): 4544–4558.</p> </div> <div class="blog-entry-references-content"> <p><a href="//C5E7F236-72CF-4951-807F-75CDEC8FD6D2#_ednref1" title="">[iv]</a> I. Katona and T. F. Freund. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. <a href="https://www.ncbi.nlm.nih.gov/pubmed/18776886" title="Nature medicine."><em>Nat Med.</em></a> 2008, 14(9): 923-30.</p> </div> <div class="blog-entry-references-content"> <p><a href="//C5E7F236-72CF-4951-807F-75CDEC8FD6D2#_ednref2" title="">[v]</a> Romero, et al. Time-course of the cannabinoid receptor down-regulation in the adult rat brain caused by repeated exposure to delta9-tetrahydrocannabinol. <a href="///Users/tim/Desktop/Romero%20downreg.html"><em>Synapse.</em></a> 1998; 30(3): 298-308.</p> </div> <div class="blog-entry-references-content"> <p><a href="//C5E7F236-72CF-4951-807F-75CDEC8FD6D2#_ednref3" title="">[vi]</a> J. Hirvonen, et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. <em>Molecular Psychiatry </em>2012; 17: 642–649.</p> </div> <div class="blog-entry-references-content"> <p><a href="//C5E7F236-72CF-4951-807F-75CDEC8FD6D2#_ednref4" title="">[vii]</a> J. A. Yesavage and V, O. Leirer. Carry-Over of Marijuana Intoxication on Airplane Pilot Performance: A Preliminary Report, <em>Am J Psychiatry.</em></p> </div> </div> <button class="btn btn-default btn-md blog-entry-references-more" type="button" data-show-large-count-items="true"> <span class="blog-entry-references-more__primary-text"> More </span> <span class="visually-hidden blog-entry-references-more__secondary-text"> references </span> </button> </div> <div class="social-links-bottom"> <div class="pt-social-media blog-entry-divider"> <ul class="share-buttons"> <li> <a title="Share on Facebook" class="facebook-share-button open-dialog" target="_blank" data-lang="en" href="https://facebook.com/dialog/share?app_id=220580041311284&display=page&href=https%3A//www.psychologytoday.com/gb/blog/healing-from-addiction/202411/a-correct-perspective-on-our-brains-endocannabinoid-system&redirect_uri=https%3A//www.psychologytoday.com/gb/blog/healing-from-addiction/202411/a-correct-perspective-on-our-brains-endocannabinoid-system" onclick="window.open(this.href,'newWindow','toolbar=no,location=no,status=no,menubar=no,scrollbars=no,resizable=yes,width=640,height=480');return false;"> <div><img border="0" src="https://cdn2.psychologytoday.com/theme-assets/icons/icon-share-round-facebook-md.svg" alt="Share on Facebook" width="37" height="37" /><span class="visually-hidden">Share</span></div> </a> </li> <li> <a title="Share on Twitter" class="twitter-share-button open-dialog" target="_blank" data-lang="en" href="https://twitter.com/share?text=A%20Correct%20Perspective%20on%20Our%20Brain%E2%80%99s%20%22Endocannabinoid%E2%80%9D%20System%20%7C%20Psychology%20Today&url=https%3A//www.psychologytoday.com/gb/blog/healing-from-addiction/202411/a-correct-perspective-on-our-brains-endocannabinoid-system&related=PsychToday" onclick="window.open(this.href,'newWindow','toolbar=no,location=no,status=no,menubar=no,scrollbars=no,resizable=yes,width=640,height=480');return false;"> <div><img border="0" src="https://cdn2.psychologytoday.com/theme-assets/icons/icon-share-round-twitter-md.svg" alt="Share on Twitter" width="37" height="37" /><span class="visually-hidden">Tweet</span></div> </a> </li> <li> <a title="Share on LinkedIn" class="linkedin-share-button open-dialog" target="_blank" data-lang="en" href="https://www.linkedin.com/sharing/share-offsite/?url=https%3A//www.psychologytoday.com/gb/blog/healing-from-addiction/202411/a-correct-perspective-on-our-brains-endocannabinoid-system" onclick="window.open(this.href,'newWindow','toolbar=no,location=no,status=no,menubar=no,scrollbars=no,resizable=yes,width=640,height=480');return false;"> <div><img border="0" src="https://cdn2.psychologytoday.com/theme-assets/icons/icon-share-round-linkedin-md.svg" alt="Share on LinkedIn" width="37" height="37" /><span class="visually-hidden">Share</span></div> </a> </li> <li><div class="form-item-type-email js-form-item form-item js-form-type-email form-item- js-form-item- form-no-label"> <a title="Share via Email" class="email-share-button open-dialog" data-lang="en" href="mailto:?subject=Psychology%20Today%3A%20A%20Correct%20Perspective%20on%20Our%20Brain%E2%80%99s%20%22Endocannabinoid%E2%80%9D%20System&body=Hi%2C%0D%0A%0D%0AI%20thought%20you%27d%20be%20interested%20in%20this%20article%20on%20Psychology%20Today%3A%0D%0A%0D%0A%20A%20Correct%20Perspective%20on%20Our%20Brain%E2%80%99s%20%22Endocannabinoid%E2%80%9D%20System%0D%0Ahttps%3A//www.psychologytoday.com/gb/blog/healing-from-addiction/202411/a-correct-perspective-on-our-brains-endocannabinoid-system%3Feml%0D%0A%0D%0A%0D%0A---%0D%0AFind%20Counselling%3A%20https%3A//www.psychologytoday.com/gb&destination=node/5027087"> <div><img border="0" src="https://cdn2.psychologytoday.com/theme-assets/icons/icon-share-round-email-md.svg" alt="Share via Email" width="37" height="37" /><span class="visually-hidden">Email</span></div> </a> </div> </li> </ul> </div> </div> </div> </div> </article> </div> <div class="pt-ad pt-ad--300x250 d-block d-none d-md-block d-lg-none block" id="block-adblock-20"> <div class="pt-ad--container pt-ad-show-text"> <div class="pt-ad--text"> <span>advertisement</span> </div> <div id="div-gpt-ad-1424993595349-0" class="pt-ad--content"> <script type="text/javascript"> if (window.googletag && googletag.apiReady) { googletag.cmd.push(function () { googletag.display('div-gpt-ad-1424993595349-0'); 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