A BRIEF HISTORY OF CANNABINOID PHARMACOLOGY 1940 to 1980 - PART I
The brave men and women behind the discovery of the world's most studied medicine
The Discovery of Cannabinoids
Marijuana or cannabis is arguably the first of plant to be documented as a medicine: for religious ceremonies and probably recreational purposes. The first accounts of Marijuana use stretches back at least 5000 years and there is strong evidence of its cousin, hemp was used at least 10,000 years ago in Taiwan. It is now known that marijuana is a unique source of at least 66 compounds known as Cannabinoids, each with its own unique properties, many of which are medicinal. Most of the psychotropic effects of almost all strains of marijuana are come from a substance called d9THC, a cannabinoid that was only precisely identified in the second half of the 20th century.
Research in earnest into the pharmacology of individual Cannabinoids began in the 1940s, several decades after the the first Cannabinoid was first discovered. Experimentation on isolated cannabinoids with animals and humans led to the a basic understanding of its mechanism of action: the discovery of cellular membrane receptors, Cannabinoid *CB~1 and *CB~2 receptors and endogenous ligands, which are binding agents that modulate the ultimate activity of receptors that signal a great variety of responses in the body and mind: autoimmune response, pain, anxiety, creativity, panic, relaxation, metabolic rate, actoposis, bone growth.
The overall understanding of how THC and other cannabinoids was gradually expanded upon; *CB~1 and *CB~2 behavior is affected by selective agonists (dial up) and antagonists (dial down or moderate). In time it was established that the action of the receptors and different cannabinoids was strongly interrelated, where CBD (for example) affected the subjects response to THC. Later it was found that the terpenes, or essential oils were also interplayed with the cannabinoids and the receptor system.
A clear consensus opinion among researchers friend; that cannabinoids tap into a pre-existing endogenous (body's own) Cannabinoid system in mammals and humans. Furthermore, phytocannabinoids impact this natural system and have can play a very significant roles in both health and disease. These discoveries led to an exponential growth in research on the medical application of cannabinoids world-wide.
THE MOST ABUNDANT AND IMPORTANT CANNABINOID MOLECULES
Figure ~ d9~THC
Figure ~ CBD~ Cannabidiol
Figure ~ CBN ~ Cannabinol
Figure ~ CBC
Figure ~ d8 THC
Plant~derived Cannabinoids (Phyto-cannabinoids)
Cannabinol (CBN) and not psychoactive THC was the first cannabinoid to be isolated from a red oil extract of cannabis. It was thought at the time, and correctly, so that CBN was formed through the degradation of THC during the storage of harvested marijuana. CBN is somewhat similar in its psychoactive properties, but affects cellular receptors discretely differently. Later it was confirmed that heat and ultraviolet light accelerates the breakdown of d9THC into CBN. CBN's structure was elucidated around 1932 by R. Cahn, and it was chemical synthesized in 1940 by and American / Brit combination, R. Adams and Lord Todd.
Phytocannabinoid, cannabidiol (CBD), generally the second most abundant medicinal substance in cannabis was first isolated by Adams and colleagues. This first CBD extract was probably a mixture of cannabidiolic acid. THCs of several kinds were first extracted from marijuana in the year of 1942 by Wollner, Matchett, Levine and Loewe. This first THC extract was most likely as a mixture of d8THC, which is weakly psychoactive and d9~THC, which is the main psychoactive ingredient of nearly all forms of cannabis. Both THC and CBD are present in marijuana mainly as acids and are "activated" by decarboxylation through baking or smoking. The structures and stereochemistry of CBD and d9~THC, were completed in the laboratory of Dr. Raphael Mechoulam's laboratory from 1963 to 1964. Dr. Mechoulam subsequently earned the moniker, The Father of Marijuana, especially for the "discovery" of THC.
In 1965, Dr. Mechoulam's laboratory also chemically synthesized both THC and CBD. . These very important advances set in motion an avalanche of scientific activity throughout the world, which led to the identification of many of the other Cannabinoids of marijuana.
It should be noted that Mechoulam's pioneering efforts were funded, in part, from the US Federal government. His final report to the Feds concluded that cannabis and its component cannabinoid possessed important medicinal properties. The study findings were accepted and undisputed, however, they were buried in the archives to collect dust, that is until the internet illuminated this historic research effort. Today, thought the US Fed continues to battle against cannabis as a medicine, it was this US research funding that, in part, helped establish the current Israeli medical marijuana program. Ironically this Israeli program is particularly active in treating their government employees, especially the military, with PTSD,chronic pain, phantom limb syndrome among other neurological disorders.
Early research into the pharmacology of Cannabinoids
Pharmacological experiments with single Cannabinoids were first performed in the 1940s and 1950s. Many of these were carried out either with preparations of THC, CBN or CBD extracted from marijuana or with two newly synthesized Cannabinoids, d6a,10a~THC, and its hexyl analogue, syn hexyl (parahexyl, parahexyl, neither of which are naturally present in marijuana. Some decades later, synthetic cannabinoid mixtures laced with other drugs became popularly known as Spice. While natural cannabinoids are inherently safe, synthetic cannabinoids activity on the receptors can be hundreds of times more potent, which can lead to disastrous consequences. Dr. Mechoulam noted that the recreational consumption of synthetic cannabinoids is complete madness.
Among the first pharmacological observations to have been made with individual Cannabinoids are those of Loewe (1946), who noted that:
THC and isohexyl (synthetic derivative), induced seizures in mice however, not CBD
CBN induced seizures in mice however, only at high doses that were in addition lethal
THC and isohexyl had a central excitant action, particularly in rabbits and mice
THC and isohexyl however, not CBN
CBD elicited corneal areflexia in rabbits
CBN has much lower potency than THC as a psychotropic agent
CBD lacks psychotropic activity altogether
These findings were among the first indications that Cannabinoids show marked structural activity interconnectivity. It is now commonly accepted that seizures in rodents correlates well with cannabinoids psychotropic activity.
"A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that changes brain function and results in alterations in perception, mood, consciousness or behavior."
An even earlier experiment, carried out by Haagen~Smit et.al.. (1940), showed that a purified extract of marijuana was very probably mostly d9~THC, as it shared the ability of a crude marijuana preparation to produce aimless scratching behaviour and motor incoordination and seizures in dogs.
Other early findings
CBD can prolong sleep induced in mice by an unnamed barbiturate, although not by higher doses of CBN or THC ( Loewe-1944)
CBD is much more active than d9~THC as an inhibitor of the liver metabolism of phenazone a painkiller and anti-inflammatory (Paton and Pertwee 1972)
Liver inhibition depends on the ability of CBD or a CBD metabolite to inhibit some microsomal enzymes
Currently findings are that CBD can induce liver CYP3A, CYP2B and CYP2C, and that the structure, activity interconnections of CBD analogues and the derivatives for CYP inhibition and CYP induction are not one and the same.
Parahexyl is a synthetic homologue of THC, was invented in 1949 in and attempt to map the structure of Δ9-THC. Parahexyl is similar in structure and activity to THC, differing only in the position of one double bond, and one CH2 group. Parahexyl produces classic cannabis effects in animals. It has a higher oral bioavailability than THC itself but is otherwise very similar. Parahexyl was occasionally used as an anti-anxiety agent in the mid-20th century, with dosage ranging from 5 mg to 90 mg until it was banned as part of the War on Drugs as opposed to scientific reasons.
In the mid 1960s to the early 1970s, research into the pharmacology of Cannabinoids increased exponentially in response to the popularization of marijuana as a recreational drug in Western countries. Funding almost exclusively focused on negative studies, ones that attempt to prove that cannabis is harmful rather than helpful. During this period, the structural elucidation and synthesis of d9~THC was completed. Little interest in the medicinal potential of Cannabinoids was generally evident, even though tinctures of marijuana were still a licensed medicine in the parts of the Commonwealth.
Subsequent cannabinoid experiments in the 1970's focused mainly on cannabis main psychoactive properties which were believed to be largely attributable to d9~THC. This was achieved by comparing various effects of marijuana and d9~THC, in animal and human studies and included:
the ability of marijuana to elevate mood
precipitate psychopathological symptoms of anxiety, panic or paranoia
motivate ‘felt time' to pass more slowly than ‘clock time'
produce changes in auditory and visual perception
The results obtained indicated that the psychotropic properties of marijuana were indeed attributed essentially to d9~THC.
Pharmacological research of the 1970s was directed at seeking out and characterizing the properties of marijuana or the individual Cannabinoids and their effects on particular biological systems and to compare the properties of marijuana with other recreational drugs while exploring the dependence liability of cannabis d9~THC. Early research was not all biased, and a more complete description of the pharmacological properties of marijuana and d9~THC was formed however, there was little data that explained a mechanisms of action.
Further, in the 1970s, a the CYP system of drug~metabolizing enzymes attracted a great deal of attention, coupled with an attempt to characterize the pharmacokinetics and metabolic fate of d9~THC and other Phyto-Cannabinoids in a several species. including man. The finding of this research was that the in the metabolism and elimination of d9~THC, hydroxylation via enzymes took place in the liver resulting in 11~hydroxy~d9~THC and similar compounds, which retains much of d9~THC pharmacological activity.
The mechanism of excretion of THC was explained, where the phase I metabolites of d9~THC are converted in the liver to glucuronides and, after their biliary excretion into the intestinal tract, these glucuronides undergo enzymic hydrolysis to 11~hydroxy~d9~THC and d9~THC~11~oic acid. This research would have great implications in drug testing for illicit substances, like THC, and provided an understanding on how long it takes to clear the body of measurable amounts.
"Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that includes gait abnormality."
For the Cannabinoids, two bioassays were successful in measuring ‘static ataxia' in canines and changes , like sedation, ptosis and body sag in primates. These bioassays produced data that supported the idea that d9~THC is the main psychotropic components of marijuana. Rodents, instead of canines and primates were explored, which led to the development of several new in bioassay techniques. These included four tests that became known as the ‘rodent-animal tetrad'. In the developed ring test bioassay, mice were placed across an elevated horizontal ring and monitored the proportion of time they remain immobile/cataleptic (immobility index) over a 5 minute period.
"Bioassay, a measurement of the concentration or potency of a substance by its effect on living cells or tissues."
DISCOVERY OF THE CB1 RECEPTOR
Psychoactive Cannabinoids, like d9~THC immobility are proportional to dose. This finding was based on an observation by Loewe (1946) that THC extracted from marijuana resin induced a cataleptic state in the rodents'. Eventually, in vitro assays for Cannabinoids were developed such as the measurement of adenylate cyclase activity and a radioligand binding assay, that provided conclusive scientific data for the existence of the Cannabinoid *CB~1 receptor.
"Catalepsy is a nervous condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain."
The discovery of Cannabinoid receptors
Early indications of the existence of Cannabinoid receptors came from reports the pharmacological activity of psychoactive Cannabinoids is influenced by its chemical structure, chiral centres show stereoselectivity, and the potency of d9~THC matches agonists for some established classes of receptors.
This scientific data toward the existence of Cannabinoid receptors was weakened by findings that psychoactive Cannabinoids can produce changes in the physical properties of artificial membranes containing only cholesterol and phospholipid, and that there is a correlation between the ability of certain Cannabinoids to produce these changes.
End of Part I
420EVALUATIONSONLINE Notes: California was both one of the first states to outlaw cannabis and was the first state to legalize the use of medical marijuana. In 2016, recreatonal marijuana was also legalized, with the inclusion of taxation, which amounts to about 35 %. Official medical marijuana patients are exempt from paying much of this new tax. Citizens can come medical marijuana patients by completing an 420 evaluation online. The process takes only a few minutes to complete and may be approved shortly thereafter, by a licensed medical doctor that reviews your file remotely on a tablet. Our documents are used at dispensaries, online delivery services, cannabis clubs, cooperatives, compassion clubs within the State of California.
*** Based in part on the work of Roger G Pertwee