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Cannabis, scientifically known as Cannabis sativa L., has been used for medicinal purposes in China for more than 4000 years. The earliest recorded medicinal use of cannabis is attributed to the legendary Chinese emperor Shen Nung, believed to have lived around 2700 BC. The medicinal use of cannabis was recorded in the Shen Nung Pen-ts’ao Ching, a 2nd-century Chinese herbal treatment book that addresses a wide range of ailments from menstruation to cognitive disorders. Originally, the Chinese primarily used cannabis seeds for medicine. The medicinal use of the plant spread to India, Persia and Assyria, and then to the Middle East, Africa, Europe and eventually the United States.
In the 19th century, William B. O’Shaughnessy, who served in India, introduced C. sativa to England. In 1839, he published On Preparations of the Indian Hemp or Gunjah, detailing his successful experiments on humans, in particular with cannabis preparations for the treatment of muscular spasms, rheumatism and convulsive seizures. Later, in the second half of the 19th and early 20th centuries, a large number of scientific papers on the therapeutic value of cannabis appeared in Europe and the United States.
Cannabis is available in several species: Cannabis sativa, Cannabis indica and Cannabis ruderalis. More than 500 compounds have been identified in cannabis species, including around 100 cannabinoids with a 21-carbon terpeno phenol structure. Of these compounds, the most common are tetrahydrocannabinol (THC), which produces psychoactive effects, and cannabidiol (CBD), which has no psychoactivity.
Phytocannabinoids are the cannabinoids produced by the cannabis plant and contain more than 100 naturally occurring chemicals. In addition to THC and CBD, terpenes and flavonoids are abundant. THC produces psychoactive effects while CBD is non-psychotropic. The recent legalisation of cannabis has led to a rapid increase in the medical use of cannabis and its products, which has prompted a review of their principles of action and pharmacokinetics.
Principles of operation
An important step in understanding the effects of cannabinoids was the identification of the endocannabinoid system (ECS). THC and CBD were key contributors to the discovery of ECS signalling pathways. THC interacts with cannabinoid type 1 receptors (CB1), which are predominantly located in the central nervous system, while CBD interacts with cannabinoid type 2 receptors (CB2), which are predominantly expressed in the immune system. Endogenous cannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) modulate ECS activity. Both CB1 and CB2 receptors are widely distributed throughout the cardiovascular system.
In addition to interacting with CB1 and CB2 receptors, endocannabinoids and phytocannabinoids also interact with a wide range of other receptors and enzymes, including a variety of G protein-coupled receptors (GPR55, GPR18, GPR3, GPR6, GPR12), and transient receptor potential channels (TRP vanilloid TRPV1- TRPV4, TRP ankyrin TRPA1, TRP M member TRPM8), peroxisome proliferator-activated receptors (PPAR2, PPARγ), monoamine transporters (norepinephrine, dopamine, serotonin 1A receptors), fatty acid amide hydrolase, monoacylglycerol lipase, fatty acid-binding transporters, adenosine equilibrium nucleoside transporters and glycine receptors α1 and α3.
Evidence is emerging that endocannabinoid function is reduced in various diseases such as migraine, fibromyalgia, irritable bowel syndrome, multiple sclerosis, diabetic neuropathy, Parkinson’s disease, etc. The endocannabinoid deficiency theory proposes that such deficiency may be genetic, congenital or acquired, due to injury or disease, and may result in characteristic pathophysiological syndromes with specific symptomatology. Phytocannabinoids with similar effects on cannabinoid receptors may provide a means of treatment for these medical conditions. Synthetic cannabinoids are compounds produced in the laboratory that are designed to replicate the structure or function of endocannabinoids or phytocannabinoids. Most of these synthetic preparations are based on THC, a natural cannabinoid. They have a high affinity for CB1 receptors, which are associated with the psychoactive effects of cannabis or the ‘high’ of cannabis. At least 180 different synthetic cannabinoids have been identified, according to the European Monitoring Centre for Drugs and Drug Addiction 2019 reports. These synthetic compounds are usually consumed either by smoking or in concentrated liquid form. Adverse effects of synthetic cannabinoids can include heart attacks, paranoia, severe anxiety, nausea, vomiting, confusion, incoordination and seizures. Interestingly, some individuals have reported strong compulsions and persistent cravings to resume use even one week after withdrawal, while others have described withdrawal symptoms such as headaches, nausea and vomiting.
Pharmacokinetics
The variation in cannabis substances depends on the route of consumption. THC is metabolized in the liver when consumed orally and rapidly absorbed through the lungs when inhaled. CBD, like THC, has complex pharmacokinetics and low oral bioavailability across species. Both THC and CBD interact with cytochrome P450 enzymes, which can alter the metabolism of various drugs. Concerns have been raised about the passage of THC through breast milk and therefore caution is stressed during pregnancy and lactation.
In conclusion, cannabis and its constituents have a rich history in medicine and their therapeutic potential and pharmacological effects are continuously being investigated in research. Understanding the mechanisms of action and pharmacokinetics of cannabis is essential to maximise its medical benefits while minimising its potential risks.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803256/
