The Endocannabinoid System
Delta9-tetrahydrocannabinol, the psychoactive molecule from Cannabis Sativa. L, was isolated in 1964, but the cannabinoid receptors where it acts, CB1, CB2, and others were only identified about 30 years ago. In this episode we will try to summarize the current research on the actions of the endocannabinoid system on anxiety, depression, cognition, learning, and memory. The effects are very interesting and vary depending on the concentrations of cannabinoids present. We will also discuss what are the important compounds involved and how they affect CNS activity. This endogenous cannabinoid system is essential for the proper functioning of the entire human body.
History of Cannabis Research
The Assyrians (about second millennium BC to sixth century BC) used cannabis for its psychoactive, mind-altering effects as well as for its medical properties. It was named either ganzi-gun-nu (“the drug that takes away the mind”) or azzalu, which was apparently a drug for “depression of spirits,” for a female ailment (possibly amenorrhea).
The importance of cannabis intoxication seems to have been central in early Zoroastrian shamanic ecstasy. Its wide use in the Middle East has continued ever since. Indeed, it was a central theme in Arab poetry of the Middle Ages.
In China and India, it was known for the dual nature of its effects. In the Chinese classic medical pharmacopeia Ben Ts’ao, originally compiled around the first century AD, cannabis was recommended for numerous maladies, “but when taken in excess it could cause seeing devils”.
In Europe, cannabis was introduced by the Napoleonic soldiers returning from Egypt and by British physicians returning from India. Industrial hemp, which contains negligible amounts of psychoactive material, was of course grown previously, but the psychoactive variety was unknown. The psychological effects caused by cannabis preparations—presumably North African hashish—became known in Europe mostly through the writings of members of the Parisian Le Club des Hachichins in the mid-nineteenth century, particularly Baudelaire, Gautier, and Moreau.
Moreau, a psychiatrist, in his 1845 book, Hashish and Mental Illness, described in detail subjects feeling of happiness, excitement, dissociation of ideas, time warping, and delirium among others. This diversity of actions—some of them opposite to each other—has confounded cannabis research ever since. But today few cannabis users will reach a state of “delirium” in most cases, they will report an increase in relaxation and euphoria and possibly enhancement of their senses. These differences are probably due to the well-known biphasic activity of Δ9-tetrahydrocannabinol (THC)—the psychoactive constituent—whose effects at low doses may be opposite to those produced by high doses. Moreau’s volunteers presumably orally consumed large amounts of hashish, whereas today North Americans and Europeans usually smoke cannabis, and most users adjust their dose to achieve the desired effects.
Research on cannabis advanced slowly, not only because of lack of basic chemistry knowledge, but also lack of quantifiable isolated cannabis extracts. Not surprisingly, the burst of recreational cannabis use, in the mid-1960s in the United States Europe, coincided with the new wave of research on cannabis.
THC and CBD
Attempts to isolate pure THC was finally achieved in 1964 by the Israeli researchers Gaoni and Mechoulam. Shorty after in 1967 it was synthesized and became widely available for research.
The other major plant cannabinoid, now very popular in the news, is CBD. Unlike THC, it was first isolated in the 1930’s, but only resolved in 1963. It also has properties much different than CBD, in that it isn’t psychoactive and seems to attenuate some of the effects of THC.
Originally it was thought that cannabinoids acted through non-specific membrane-associated mechanisms. However, that is definitely not the case and in 1986 the first cannabinoid receptor was identified in the brain. A second receptor was then identified a few years later expressed in the body (spleen). So the first two cannabinoid receptors were named CB1 and CB2. These are G-protein coupled receptors or 7 transmembrane receptors. But in the last few years many other cannabinoid receptors have been identified, including the one I ended up doing my PhD in TRPV1.
Endogenous Cannabinoid Agonists
The discovery of cannabinoid receptors suggested that there were endogenous (or our own) molecules that could activate of inhibit these receptors throughout our body. It is essentially a quirk of nature that the cannabis plant has compounds that could activate them as well. The idea of these endogenous molecules was proven correct with the isolation of two compounds. One from the brain – named anandamide, from Sanskrit word Ananda (supreme joy); and a second one from peripheral tissue – with a much less creative name 2-arachidonoyl glycerol (2-AG). Others have been identified, but seem to play a much less important role so we will not talk about them.
Unlike other neurotransmitters, these molecules are not store in the brain, instead they are synthesized on demand. Unlike THC which is metabolized over several hours, endocannabinoids act fast and are hydrolyzed (broken down) quickly by fatty acid amide hydrolase (FAAH). Yet, like THC and phytocannabinoids, endocannabinoids show an entourage effect with other compounds in the brain that enhance their activity.
Most importantly though, these endocannabinoids as well as the general system they belong to are critical for normal human functioning. In particular, the activity that involves, rest, relaxation, and hunger.
The Endocannabinoid System in Anxiety and Depression
A few years ago the major pharmaceutical firm Sanofi-Aventis developed and initiated marketing for a CB1 receptor antagonist called rimonibant. Because CB1 agonists enhance appetite, such a drug could become a major weapon against obesity. This compound did indeed help manage obesity however, treated patients developed anxiety problems and suicidal tendencies and the drug had to be withdrawn from the market.
This provided evidence, indicating the importance of the CB1 cannabinoid system in anxiety. Interestingly, some studies have recently suggested that as some variants of the CB1 receptor gene contribute more significantly than others to the development of anxiety and depression, by genomic screening high-risk individuals could be identified and excluded from the treatment population and thus CB1 antagonists could still be useful.
As mentioned previously, depending on the dose, THC may cause either euphoria and relaxation or dysphoria and anxiety Pure THC may not entirely mimic the effects of cannabis, which contains additional cannabinoid constituents, such as CBD, that modulate the effect of THC.
Cannabidiol, which does not bind to either CB1 or CB2, possesses anxiolytic and antipsychotic properties both in animals and in humans.
Endocannabinoids and Depression
Experimental work done on the endocannabinoid system and depression and have concluded that research so far supports the assumption that hypofunctional endocannabinoid signaling contributes to depressive illness and that enhanced endocannabinoid signaling is associated with antidepressant efficacy.
Over the past few years, considerable data have indicated that the endocannabinoid system plays a central role in neurogenesis as well
Because depression decreases neurogenesis, the findings are particularly exciting because they not only help us understand the role of endocannabinoids as endogenous antidepressants but also suggest that synthetic endocannabinoid-like compounds may be developed as a novel type of antidepressive drug.
Effects of Cannabis on Cognition
When under the influence of THC, humans demonstrate transient impairment in short-term episodic and working memory and consolidation of these short-term memories into long-term memory, but no impairment in retrieval of information once it has been previously encoded into long-term storage. However, a recent naturalistic study revealed that cannabidiol prevented the memory-impairing effects of acute THC in humans. Therefore, the relative THC/cannabidiol ratio in cannabis will profoundly modify the effects of cannabis on memory in human marijuana smokers.
The effect of chronic cannabis exposure on cognitive abilities of abstinent individuals is very controversial and the literature is full of contradictions. The only true study looking at “pure” cannabinoid users conducted a longitudinal examination of young adults using neurocognitive tests that had been administered prior to the first experience with marijuana smoke. Individuals were defined (by urination samples and self-reports) as light (fewer than five times a week) or heavy (greater than five times a week) current or former (abstinent for at least three months) users. Current heavy users performed worse than nonusers in overall IQ, processing speed, and immediate and delayed memory tests. In contrast, former heavy marijuana smokers did not show any cognitive impairment concluding that the acute effects of cannabis on prospective memory are attenuated in long-term abstinence (at least three months).
Mechoulam R, Parker LA. The Endocannabinoid System and the Brain. Annu. Rev. Psychol. 2013. 64:21–47
Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2015;79(7):516-25