“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”
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Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.
“Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive ‘multi-targeting’.” https://www.ncbi.nlm.nih.gov/pubmed/23108552
“Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities” http://rstb.royalsocietypublishing.org/content/367/1607/3353.long
History of cannabis as a medicine: a review
” Cannabis as a medicine was used before the Christian era in Asia, mainly in India. The introduction of cannabis in the Western medicine occurred in the midst of the 19th century, reaching the climax in the last decade of that century, with the availability and usage of cannabis extracts or tinctures. In the first decades of the 20th century, the Western medical use of cannabis significantly decreased largely due to difficulties to obtain consistent results from batches of plant material of different potencies. The identification of the chemical structure of cannabis components and the possibility of obtaining its pure constituents were related to a significant increase in scientific interest in such plant, since 1965. This interest was renewed in the 1990’s with the description of cannabinoid receptors and the identification of an endogenous cannabinoid system in the brain. A new and more consistent cycle of the use of cannabis derivatives as medication begins, since treatment effectiveness and safety started to be scientifically proven.”
“Cannabis Sativa (cannabis) is among the earliest plants cultivated by man. The first evidence of the use of cannabis was found in China, where archeological and historical findings indicate that that plant was cultivated for fibers since 4.000 B.C.1 With the fibers obtained from the cannabis stems, the Chinese manufactured strings, ropes, textiles, and even paper. Textiles and paper made from cannabis were found in the tomb of Emperor Wu (104-87 B.C.), of the Han dynasty.“
“The Chinese also used cannabis fruits as food. These fruits are small (3 to 5 mm), elliptic, smooth, with a hard shell, and contain one single seed. The first evidence of the use of these seeds was found during the Han dynasty (206 B.C. – 220 A.D.). In the beginning of the Christian Era, with the introduction of new cultures, cannabis was no longer an important food in China, although, until today, the seeds are still used for making kitchen oil in Nepal.“
“The use of cannabis as a medicine by ancient Chinese was reported in the world’s oldest pharmacopoeia, the pen-ts’ao ching which was compiled in the first century of this Era, but based on oral traditions passed down from the time of Emperor Shen-Nung, who lived during the years 2.700 B.C. Indications for the use of cannabis included: rheumatic pain, intestinal constipation, disorders of the female reproductive system, malaria, and others.In the beginning of the Christian Era, Hua T’o, the founder of Chinese surgery (A.D. 110 – 207), used a compound of the plant, taken with wine, to anesthetize patients during surgical operations.“
“The Chinese used mainly the seeds of cannabis for medical purposes; therefore, it may be assumed that they were referring to that part of the plant when describing its medicinal properties. Until today, cannabis seeds continue to be used as a laxative by Chinese physicians. It is acknowledged that the seeds are practically deficient in D9-tetrahydrocannabinol (D9-THC), which is considered the plant’s main active constituent, and is mainly composed of essential fatty acids and proteins. Today some of these fatty acids are considered as having therapeutic effects, such as the g-linoleic acid, whose topical use is recommended for eczema and psoriasis, and its oral use for atherosclerosis, osteoporosis, rheumatoid arthritis, and other inflammatory diseases. In China, the medical use of cannabis never reached the importance it did in India.”
Therapeutic aspects of cannabis and cannabinoids
“HISTORY OF THERAPEUTIC USE
The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic. There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.”
“It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O’Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, anti-spasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its use-fulness as an anti-emetic.”
“After these observations were published in 1842, medicinal use of cannabis expanded rapidly. It soon became available ‘over the counter’ in pharmacies and by 1854 it had found its way into the United States Dispensatory. The American market became flooded with dozens of cannabis-containing home remedies.”
“Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.”
“In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive ‘compassionate reefers’. Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.”
“Results and Conclusions Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.”
The therapeutic potential of novel cannabinoid receptors.
“Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.” http://www.ncbi.nlm.nih.gov/pubmed/19248809