Updated: Apr 21
Memory formation, inhibition of pain and anxiety, and other interesting facts about the brain’s own cannabinoids
This is the second in a series of articles about the neuroscience of cannabis:
Cannabinoids and Endocannabinoids
THC, or trans-delta-9-tetrahydrocannabinol, is the main psychoactive compound in the cannabis or marihuana plants, Cannabis sativa and Cannabis indica - it is still debated if these are one or two species.
In fact, the cannabis plant contains at least 113 cannabinoids, including THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN) and trans-delta-9-tetrahydrocannabivarin (THCV) (Pertwee, 2008; Bow and Rimoldi, 2016). It is still unknown how many of these cannabinoids are psychoactive or able to bind to the cannabinoid receptors: CB1, CB2 and GPR55.
Keep in mind that a compound may not be psychoactive and yet bind to the cannabinoid receptors, acting at only one of them, or behaving as an antagonist or inverse agonist. This explains why different strains of cannabis have different effects on the brain. The many cannabinoids that they contain modulate the actions of THC.
THC is a partial agonist of CB1 and CB2 receptors.
Full agonists are compounds that completely activate the G protein when they bind to the receptor.
Partial agonists only partially activate the G protein associated with their receptor.
Antagonists bind to the receptor and they do not activate the G protein at all. Since they occupy the agonist binding site, they prevent it from activating the G protein.
Inverse agonists not only fail to activate the G protein, but decrease a basal level of G protein activation that the receptor has, called constitutive activity.
Efficacy is the level of activation of the receptor produced by a partial agonist, which varies from 100% (full agonist) to 0% (antagonist). Inverse agonists have negative efficacies.
Potency indicates the amount of a compound required to produce their full effect. It is measured as their concentration in water in moles per liter, or molar (M). Its numbers are usually micromolar (µM) - one millionth of molar or 10 to the -6 - or nanomolar (nM) - a thousandth millionth of a molar or 10 to the -9. It is expressed as the Ki, which is a chemical constant derived from the binding reaction of a drug to its receptor. The lower the Ki, the higher the potency. Compounds with smaller Ki will out-compete compounds with higher Ki at the receptor.
Efficacy and potency are unrelated. A drug could have high potency by low efficacy - it would a potent partial agonist. Or it could have low potency and high efficacy - in which case it would be less potent full agonist.
THC binds to CB1 and CB2 receptors with similar potencies (Ki of 41 nM at CB1 and 36 nM at CB2) (Pertwee, 2008), which are quite high compared to other cannabinoids.
CBD, or cannabidiol, is an antagonist of both CB1 and CB2 receptors (Pertwee, 2008).
Since CB1 and CB2 receptors have constitutive activity (they are a bit active in the absence of an agonist), CBD could be an inverse agonist instead of an antagonist. This means that CBD would not only displace agonists - THC or endocannabinoids - from the receptors, but also inhibit their constitutive activity.
CB1 receptors are the ones responsible for the psychoactive effects of THC, so CBD will decrease the effect of THC on these receptors. Therefore, the cannabis strains that have high CBD content produce milder psychoactive effects.
CBD is also an antagonist of GPR55, the third cannabinoid receptor. This is why it can be used to treat epilepsy, as I will explain in another article.
Endocannabinoids are compounds produced in the body that are able to activate cannabinoid receptors. That is, they are neurotransmitters that are the endogenous ligands of the cannabinoid receptors, just like the endorphins are the endogenous ligands of the opioid receptors. Endogenous means produced inside the body.
The two main endocannabinoids are anandamide (N-arachidonoyl-ethanolamine) (Devane et al., 1992) and 2-arachidonoyl-glycerol (2-AG). They are synthesized from arachidonic acid, which is one of the lipids found in fat and in the cell membrane. Arachidonic acid is also converted into prostaglandins, which are inflammatory substances. The name ‘anandamide’ comes from the Sanskrit word Ananda, meaning joy and bliss.
THC (Ki of 41 nM at CB1 and 36 nM at CB2) is more potent than anandamide (Ki of 61 nM at CB1 and 1930 nM at CB2) and 2-AG (Ki of 472 nM at CB1 and 1400 nM at CB2) (Bow and Rimoldi, 2016). The lower the Ki, the higher the potency. Compounds with smaller Ki will out-compete compounds with higher Ki at the receptor, so THC displaces the endocannabinoids from CB1 and CB2 receptors.
Endocannabinoids are retrograde neurotransmitters
Endocannabinoids are weird neurotransmitters. Everything about them is atypical.
Instead of being stored and released from synaptic vesicles, like other neurotransmitters, endocannabinoids are synthesized on demand. Because they are soluble in lipids, they can just cross the cell membrane. No fusion of synaptic vesicles with the membrane is necessary.
Endocannabinoids function as retrograde neurotransmitters: they carry signals from the postsynaptic terminals in the dendrites to the presynaptic terminals of axons. Postsynaptic terminals do not have synaptic vesicles, so this is consistent with the fact that they are not released from those vesicles.
Depolarization of the postsynaptic dendrites triggers the entry of calcium, which activates the enzymes that make endocannabinoids. Then they cross the synapse, going backwards, to activate CB1 receptors at the presynaptic terminal. There, CB1 receptors decrease the release of GABA from inhibitory interneurons in the hippocampus (Wilson and Nicoll, 2001), a brain region critical for memory formation. This whole phenomenon is called depolarization-induced suppression of inhibition (DSI) and it is thought to be involved in synaptic plasticity and, therefore, the formation of memories. This is probably the reason why cannabis decreases memory.
Later research (Iremonger et al., 2011) found that endocannabinoids released from neurons in the hypothalamus inhibit the release of glutamate, the main excitatory neurotransmitter. This is called depolarization-induced suppression of excitation (DSE). In these synapses, CB1 receptors prevent the development of long-term depression (LTD), a component of synaptic plasticity that makes synapses shrink.
Interestingly, another retrograde transmitter in these synapses is dynorphin, and endogenous opioid, which activates presynaptic kappa opioid receptors. This shows how cannabinoid and opioid receptors can work together.
Differences between THC and endocannabinoids
THC is a partial agonist at both CB1 and CB2 receptors, while the endocannabinoids are full agonists.
This means that the effect of THC depends on the amount of endocannabinoids that are being produced. If there are no endocannabinoids present, THC will behave as an agonist, activating CB1 and CB2 receptors, although not as effectively as the endocannabinoids. If there are endocannabinoids already activating the CB1 and CB2 receptors, THC will compete with them, displacing them from the receptors. Since THC is not as effective as the endocannabinoids, the end result will be a lowering of the activity of CB1 and CB2 receptors. This means that THC would act as an antagonist in this case.
Different brain regions may be releasing different amounts of endocannabinoids, so that THC may increase cannabinoid receptor activity in some brain areas and decreasing it in some others.
Endocannabinoids decrease anxiety
For example, THC sometimes increases anxiety, explaining the paranoia often felt by people who consume cannabis. CB1 receptor antagonists also increase anxiety.
In contrast, inhibiting endocannabinoid degradation decreases anxiety, as do synthetic full agonist of CB1 receptors (Patel and Hillard, 2006). Therefore, THC behaves like a CB1 antagonist, and not an agonist, when it comes to anxiety. Since the endocannabinoids are full agonists of CB1 receptors, they likely reduce anxiety. Whether THC does or does not trigger paranoia could depend on the amount of basal CB1 activation that a person is getting from their own endocannabinoids.
If this sounds complicated, it’s because it is! It would be difficult to know where in the brain THC is activating cannabinoid receptors and where it is inhibiting them. What we need to remember, however, is that the effect of endocannabinoids may be quite different from the effect of taking cannabis.
Pain inhibition by endocannabinoids
The effects of endocannabinoids are rapidly terminated by two enzymes: fatty acid amide hydrolase (FAAH), which breaks down anandamide, and monoacylglycerol lipase (MAGL), which degrades 2-AG.
Inhibiting FAAH (Ghosh et al., 2015) or MAGL (Ignatowska-Jankowska et al., 2015) decreases pain by allowing anandamide and 2-AG, respectively, to activate CB1 receptors for longer times.
This shows that one of the effects of endocannabinoids in the central nervous system is to decrease pain.
Bow EW, Rimoldi JM (2016) The Structure-Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation. Perspect Medicin Chem 8:17-39.
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946-1949.
Ghosh S, Kinsey SG, Liu QS, Hruba L, McMahon LR, Grim TW, Merritt CR, Wise LE, Abdullah RA, Selley DE, Sim-Selley LJ, Cravatt BF, Lichtman AH (2015) Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. J Pharmacol Exp Ther 354:111-120.
Ignatowska-Jankowska B, Wilkerson JL, Mustafa M, Abdullah R, Niphakis M, Wiley JL, Cravatt BF, Lichtman AH (2015) Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice. J Pharmacol Exp Ther 353:424-432.
Iremonger KJ, Kuzmiski JB, Baimoukhametova DV, Bains JS (2011) Dual Regulation of Anterograde and Retrograde Transmission by Endocannabinoids. The Journal of Neuroscience 31:12011-12020.
Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304-311.
Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199-215.
Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588-592.