What is The Endocannabinoid System?
A Discovery Timeline: Part 1
Ancient cannabis cultures, evolving social understanding, and cannabinoid discovery. Uncover its history, benefits, and scientific breakthroughs.
Cannabis in Ancient Cultures
Cannabis, also known as marijuana or hemp, has a long history of use in various ancient cultures around the world. While the exact origins of cannabis use are unclear, evidence suggests that it has been cultivated and utilized for its psychoactive properties for thousands of years. Here are a few examples of cannabis in ancient cultures:
- Ancient China: Cannabis has a long history in China, dating back to at least 2,500 BCE. The Chinese used hemp fibers for textiles, paper, and rope. The plant was also valued for its medicinal properties and was included in traditional Chinese medicine. The Chinese Emperor Shen Nung is believed to have written about the therapeutic effects of cannabis around 2737 BCE.
- Ancient India: Cannabis has a significant presence in ancient Indian culture. It is mentioned in sacred texts such as the Vedas, which date back to around 1500 BCE. In India, cannabis was associated with the god Shiva and was considered a sacred plant. It was used in religious rituals, as well as for medicinal and recreational purposes.
- Ancient Egypt: Cannabis was known and used in ancient Egypt. Some evidence suggests that it was used for medicinal purposes, particularly as a treatment for pain. The Ebers Papyrus, an ancient Egyptian medical text dating back to around 1550 BCE, mentions cannabis as a remedy for various ailments.
- Ancient Greece and Rome: Cannabis was known to the ancient Greeks and Romans. It was used for its medicinal properties and mentioned by renowned physicians such as Galen and Dioscorides. However, its psychoactive effects were not as widely recognized or celebrated as in other ancient cultures.
- Ancient Central Asia: Cannabis was used by various cultures in Central Asia, particularly by the Scythians, a nomadic people who inhabited the region from the 9th century BCE to the 4th century CE. The Scythians used cannabis seeds and leaves in steam baths as a form of ritual purification.
These are just a few examples of how cannabis was used in ancient cultures. It’s important to note that the cultural significance and use of cannabis varied widely across different societies and time periods. The plant held different meanings and served different purposes depending on the beliefs and practices of the people in each culture.
Social Understanding of Cannabis
Over time, the social understanding of cannabis has evolved. Initially valued for its medicinal properties, cannabis later faced stigmatization and criminal association during the 20th century. However, recent years have witnessed a shift in public opinion driven by scientific research, changing drug policies, and recognition of its medical benefits.
Consequently, many jurisdictions have legalized or decriminalized cannabis for medical and/or recreational use. Nevertheless, opinions on its risks and benefits remain diverse. It is crucial to acknowledge that social understanding and acceptance of cannabis vary across cultures and regions.
The Discovery of Cannabinoids
A significant breakthrough came in 1964 when Israeli scientists Raphael Mechoulam and Yechiel Gaoni isolated and identified tetrahydrocannabinol (THC) as the compound causing the “high.” Mechoulam also discovered the chemical structure of cannabidiol (CBD) and other cannabinoids. These unique compounds were named “cannabinoids,” turning cannabis into a treasure trove of pharmacological potential.
Cannabis’s Effects on the Brain
Scientists studied THC to explore its psychoactive effects on the brain and how it triggers sensations of euphoria, hunger, calmness, and relief. Animal studies revealed valuable insights into THC’s molecular mechanisms. As a result, researchers made significant breakthroughs in uncovering a protective regulatory system that is activated by cannabinoids.
Timeline of Endocannabinoid Discovery
Part 1: The Endocannabinoid System
1988: CB1 Receptor
In 1988, scientists at St. Louis University Medical School made a significant discovery. They identified receptor sites in a rat’s brain that THC activates. Professor Allyn Howlett and graduate student William Devane first identified these receptors, later named “CB1.” CB1 receptors proved to be more abundant in the mammalian brain than any other G-protein-coupled receptor (GPCR).
Implications of CB1 Receptor Discovery
CB1 receptors had profound implications for medical science. GPCRs are targeted by many pharmaceuticals, making them crucial in research. CB1 receptors are mainly concentrated in the mammalian brain and central nervous system. They are also found to a lesser extent in the gut, skin, and internal organs. CB1 signalling is said to regulates various physiological processes, including stress response and pain perception.
The Internal Trigger for CB1 Receptors
The discovery of CB1 receptors prompted scientists to delve deeper into our natural cannabinoid biology. They aimed to uncover the internal compound that interacts with these receptors, essentially an inner cannabis. This quest for CB1’s internal trigger expanded our knowledge of the endocannabinoid system.
In 1992, scientists identified N-arachidonoylethanolamine as the first endogenous cannabinoid neurotransmitter. They isolated this novel lipid neurotransmitter, which binds to the CB1 receptor in pig brain tissue, and named it “anandamide” due to its mood-altering effects, reminiscent of bliss.
Although anandamide and THC have different molecular structures, they exhibit similar behavior when binding to the CB1 receptor, akin to a key fitting into a lock. Anandamide and THC, both signaling molecules, activate CB1, initiating a wide range of physiological changes in cells. These changes regulate functions such as appetite, mood swings, glucose metabolism, pain perception, and fertility. Adequate levels of anandamide are essential for ovulation, and fluctuations during the gestational cycle can impact fetal development.
Cells produce anandamide as needed, particularly during stressful moments, to maintain stability. Further research has revealed that physical exercise elevates anandamide levels, leading to the sensation known as the “runner’s high.” Anandamide’s binding to CB1 protects neurons and supports neurogenesis in adult mammals, enabling the creation of new brain cells. All animals with a nervous system generate anandamide.
1993: CB-2 Receptor
In 1993, scientists discovered a second type of cannabinoid receptor called “CB2.” CB2 receptors are found throughout the immune system, peripheral nervous system, metabolic tissue, and internal organs. This finding shed light on the role of cannabinoid signaling in inflammation regulation and its potential as a treatment for autoimmune diseases. Metabolic syndrome, peripheral neuropathy, insulin resistance, liver disease, and other inflammatory conditions are linked to abnormal CB2 receptor signaling.
CB2 receptors exist in immune cells, including microglia and astrocytes, which modulate brain immune function. However, CB2 receptors are less expressed in the central nervous system compared to CB1 receptors. In response to brain injuries or neurodegenerative conditions like Alzheimer’s or multiple sclerosis, CB2 receptors become significantly upregulated.
Both types of cannabinoid receptors are stimulated by THC. However, when THC binds to CB2 receptors, it doesn’t cause the psychoactive high associated with cannabis because CB2 receptors are not concentrated in the brain. The high is caused by THC binding to CB1 receptors, which are abundant in the central nervous system. As a result, researchers focused on developing drugs that stimulate CB2 receptors while bypassing CB1 to achieve therapeutic benefits without the high. Interestingly, anandamide, the endocannabinoid that binds to CB1, has minimal affinity for CB2 receptors. This indicates the presence of another natural compound, an endogenous ligand, produced by the body that activates CB2 receptors.
Dr. Mechoulam and his team, along with Japanese scientists, discovered 2-AG, an endocannabinoid, in canine gut tissue in 1995. This molecule, also known as 2-Arachidonoylglycerol, is more potent and widely distributed in the body compared to anandamide. It binds efficiently to CB1 and CB2 cannabinoid receptors, with levels in the human brain significantly higher than anandamide.
Both anandamide and 2-AG are lipid neurotransmitters that help maintain internal homeostasis throughout the brain and body. 2-AG, as the primary ligand for CB1 and CB2, plays a crucial role in regulating immune function. It reduces the expression of pro-inflammatory cytokines and controls overactive immune cells. After head injuries or strokes, 2-AG levels in the brain increase.
Similar to anandamide, 2-AG modulates various mental and physiological processes. Although they share similarities, there are specific functional differences between these two endocannabinoids. Both compounds protect cells against oxidative damage and adapt to stress, but each in its distinct way. Additionally, they are synthesized and deactivated by different metabolic enzymes.
1997: Metabolic Enzymes – FAAH and MAGL
Endocannabinoids are born and broken down by various biosynthetic and catabolic enzymes. Thanks to these metabolic enzymes, endocannabinoids are made when needed and then degraded after serving their purpose. Anandamide is broken down by FAAH [fatty acid amide hydrolase], while 2-AG is deactivated primarily by MAGL [monoacylglycerol lipase]. The molecular structure of FAAH was characterized by Ben Cravatt at the Scripps Research Institute in 1996, and the following year Italian scientists identified MAGL as a key degradative enzyme for 2-AG.
Metabolic enzymes regulate endocannabinoid activity by controlling anandamide and 2-AG levels. Because anandamide & 2-AG degrade rather quickly, blocking their enzymatic metabolism – by inhibiting FAAH or MAGL – can elevate endocannabinoid levels and extend cannabinoid receptor signaling, with consequent neuroprotective benefits. Variations in the genes that code for FAAH and MAGL are associated with divergent health outcomes; too much of either enzyme can deplete endocannabinoid tone, resulting in what some would call a “weak constitution.”
The cloning of FAAH and MAGL marked a decade since the momentous discovery of the CB1 receptor, which really got the ball rolling in terms of cannabinoid science. The two cannabinoid receptor subtypes along with anandamide, 2-AG, and their biosynthetic and degradative enzymes, comprised the basic components of the canonical or “classical” endocannabinoid system, which modulates most biological functions. The endocannabinoid system plays a pivotal role in maintaining a healthy, stable environment inside the body, despite fluctuating external inputs and stressors. In the years ahead, new research would deepen our understanding of this ubiquitous lipid signaling ensemble.
Summary of Part 1
Cannabis has a rich history in ancient cultures like China, India, Egypt, Greece, Rome, and Central Asia. It served various purposes, such as textiles, medicine, and religious rituals. Social understanding of cannabis has evolved, initially valued for its medicinal properties, later stigmatized, and now gaining recognition for medical benefits. In 1964, THC, the compound causing psychoactive effects, was discovered, along with other cannabinoids. This led to exploring the endocannabinoid system, involving receptors like CB1 and CB2 and natural compounds like anandamide and 2-AG. These discoveries revealed their role in regulating physiological processes and potential therapeutic benefits.
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“Disclaimer: The information provided in this blog is for informational purposes only and should not be considered as medical or legal advice. The content is based on research and general knowledge available up to September 2021. The laws and regulations regarding cannabis, CBD, and related products may vary in different countries and regions. It is important to consult with healthcare professionals and abide by the laws of your jurisdiction when considering the use of cannabis or CBD products. This blog does not endorse or promote the use of illegal substances. Use cannabis and CBD products responsibly and at your own risk.”