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The Rise of Cannabis in Modern Medicine

The original copy of this article is available to buy as part of issue 4 of the psychedelic press UK at the link bellow,
http://www.psychedelicpress.co.uk/shop/4578961089/PsypressUK-2014/7573918
Also as an individual article from the link bellow,
http://www.scribd.com/doc/224756036/The-Rise-of-Cannabis-in-Modern-Medicine-Duncan-Thomson
The Rise of Cannabis in Modern Medicine.
Over the last 5-10 years cannabis has been coming into the global spotlight more and more, with campaigns for its legalisation growing at a massive rate. Many states*, have even made it state law that it may be prescribed by doctors for a wide variety of ailments, and other states** have made it legal or decriminalised its possession for recreational use. Conversely, state law has yet to catch up with this entirely and it is still a federal felony to grow or possess cannabis. As this movement has grown in the US, other countries around the world have seen this as an opportunity to relax their own legislation on cannabis*** and drugs in general. Whilst some countries have even gone as far as to decriminalise the possession of all drugs. With this tide of change in the legal status and cultural perception of drugs and, in particular cannabis use, it does not seem unlikely that soon the UK government may follow suit and reaproach the social and economical advantages of the legalisation of drugs and, in particular, the availability of medicinal cannabis.

The numerous medicinal properties of cannabis have been know for many years in subcultures that are associated with its consumption and use as a herb rather than a drug or narcotic substance and, with this change in cultural perception, it is becoming possible for the scientific community to openly delve into this once forbidden plant and verify the claims that many have made of its healing properties.

The initial studies that were carried out into cannabis had to adhere to the governmental view of cannabis, in that any study that had to show its narcotic properties not its medicinal value. The NIDA, National Institute Drug Abuse, in America states that drugs of abuse can only be studied as drugs of abuse. This was one of the main hurdles that members of the scientific community wanting to study this field had to overcome due, in part, to the fact that the legal status of the plant meant that anyone who wanted to carry out a publishable study had to obtain a permit to do the studies and governments were the only institutions who were legally allowed to distribute cannabis which allowed them to review any study put forward and pick and choose which they were going to back. One of the first studies of the most recent wave of research that was facilitated was a study, by Donald Abrams et al. which chose to look at cannabis use in HIV-infected users and whether it was safe for them to use cannabis or if it had a negative effect on the progression of their pathology. Essentially, this made it through the checks because it looked at cannabis in the frame of a narcotic having a negative effect on the health of an individual. The study found that there was no increase of the HIV virus in their system and in fact there were signs of an increase in the function of their immune system.

Once these results had been published, it made it a lot harder to just say that there were negative effects associated with the use of cannabis, especially as, due to the reduced immune system of HIV patients, they would normally be extremely vulnerable to the negative effects of any drug taken into their system and the results had shown to be somewhat opposed to popular opinion of the time. Thus a precedent for studies into cannabis in modern medicine was established.

As these newer studies were released, many claims have been made about the the health benefits of cannabis with some people touting it as a cure for a variety of cancers or a nutritional supplement to the point of an essential for the modern diet and even a general all-cure in the variety of forms that it can be produced. With the amount of access to the internet, and the rapid sharing of information in short consumable bites-size packets, a large amount of people one talks to have heard about some of these claims but not many have seen, or even had access to, evidence which supports some of the more well known of these claims. This article aims to provide a summary of the evidence for and against claims which have had a particular impact on cannabis’ perception and its so-called health benefits, in particular its efficacy in treating cancer.

It is thought that the benefits of cannabis against cancerous cells come through cannabis’ ability to regulate the internal metabolism of cells, by increasing their autophagy mechanism. Autophagy is the process by which cells break down the internal waste products they produce as a result of natural functioning. This speeding up of autophagy is said to be of particular benefit to one’s health as it cells functioning is sped up which leads to the effected cells dying much quicker, by a process called apoptosis, meaning that they die before they can become cancerous.

Apoptosis is the method by which cells undergo a controlled death where they break down all of their internal parts without releasing any toxins or harmful waste products into the body basically it is said that cannabis leads to early cell death and, in the case or some cancer types, particularly leukemia and colon cancer, leads directly to the death of the cancer cell putting the tumor into regression. Another method that is important in cannabis’ potency against cancer is that it slows down a process called angiogenesis, or the growth of new blood vessels. This is thought to be one of the main ways that cancer grows and develops.

Cancer is the change of a cell’s internal programming where the infected cell grows in a different manner, and often at an accelerated rate, in comparison to its surrounding tissue. As a cancerous cell dies it often does not undergo apoptosis and it releases the often toxic chemicals it contains into its surrounding environment, killing surrounding tissue and thus creating more space for the infected tumor to replicate itself and so grow. This is why the ability to control a cell’s internal waste management system, the way and rate at which it naturally decomposes and the way a group of cells grow blood vessels to supply themselves with nutrients and oxygen is essential in the management of cancer.

Cannabis has been used medicinally for millennia yet it was not until the late 1960s that the active ingredient Δ9- Tetrahydrocannabinol, (THC), was isolated, (01). It soon became available as a synthetic for research but it was not for another decade that many of its properties were discovered, when Munson ,amongst others, discovered that cannabinoids suppress lung carcinoma cell growth in 1975, (01).

Organic cannabinoids, the active ingredients in unrefined cannabis, are the most widely known but a multitude of synthetic cannabinoids (pharmaceutical compounds often derived from organic cannabinoids), have been developed over the years and are undoubtedly interesting and novel approaches to treatment for the modern medicinal community (despite their long historically cultural use) and are providing new approaches to a variety of pathologies.

“Cannabinoids is a blanket term covering a family of complex chemicals (both natural and man-made), that lock on to cannabinoid receptors – protein molecules on the surface of cells.” (2).

The raw form of the herb as well as extractions and tinctures of the active chemicals also exist for medicinal purposes and allow for individuals to find the best Route of Administration (ROA), to get the most out of the therapeutic effects of the drug, whilst managing the side effects of the medicine themselves. Canabidiol was the first cannabinoid to be isolated that did not produce the classic ‘high’, associated with smoking cannabis and was later found to slow the progression of tumors in breast cancer, (02). Later, researchers at Harvard University showed that THC cut tumour growth in lung cancer cells, both in cell cultures and in the body, (03), and that it also reduced the spread of cancers.

Synthetic cannabinoids are lab-manufactured pharmaceuticals, often derivatives of organic or endogenous cannabinoids, tailored to elicit specific traits of known cannabinoids, sometimes without any psychoactive action. Dexanabinol is one of these and it is closely related to the natural cannabinoids, (04). Another is Ajulemic Acid (AjA). Neither of these synthetic cannabinoids have any of the psychoactive properties but have been shown to prevent joint and bone damage in experimental models, (05). Some other more common synthetic cannabinoids are, Nabilone and Dronabinol. The ability for cannabinoids to provide these medicinal properties is interesting from a medicinal stand point as it has shown that it can be a beneficial analgesic, and have advantages for pathologies such as Rheumatoid Arthritis.

Some other more common synthetic cannabinoids are Nabilone and Dronabinol. Dronabinol has also been shown to began effective and well-tolerated therapy for treating sleep apnea, the sudden stopping of breathing whilst sleeping which causes one to wake up periodically to begin breathing again, (12). THC has been shown to level out breathing in all stages of sleep, decreasing occurrence of apnea by 42%, (13).

THC is one of the most well known cannabinoids and is present in the largest amounts in cannabis plants it primarily effects the CB1 receptor, whereas Canabidiol (CBD), one of the other most commonly known cannabinoids primarily affects the CB2 receptor. By 1992, endo-cannabinoids had been discovered, (1), followed by cannabinoids receptors on a large scale throughout the Central Nervous System (CNS) and the Peripheral Nervous System. Again there are two different cannabinoid receptors positioned throughout the body, with the cannabinoid 1 (CB1) receptors occurring throughout the CNS which includes the brain and the spinal column, (this is thought to attribute to the psychoactive effects of this class of compounds). whilst the cannabinoid 2 (CB2) receptors are found most often on cells associated with the Immune System as well and within the bones.

Cannabinoids exhibit their action upon target cells by interacting with proteins, or receptors on the surface of Neurons. As they approach the correct protein receptor, or ‘garage’, they effectively ‘park’, in it before being carried off to be further metabolised. There is no exchange of molecules (i.e. no chemical reaction), rather that the magnetic fields they possess interact, sending waves through to the internal areas of the Neuron promoting the release of further neurotransmitters and the propagation of endogenous reactions. Upon further investigation these cannabinoid receptors displayed an inordinate ability to mediate many vital functions throughout the body, “including helping to control brain and nerve activity (including memory and pain), energy and metabolism, heart function, the immune system and even reproduction.”, (3). Studies have shown that activation of cannabinoid CB2 receptors suppresses chemotherapy-induced neuropathic pain, (pain associated with the damage of the Nervous System). Thus CB2 receptors could represent a good target for the treatment of neurological damage, especially when produced by chemotherapy drugs, (06).

Many claims about the beneficial effects of cannabis and the contained cannabinoids have been made about a variety of pathologies, I shall try and elucidate upon a few of these here. Cancer is one of the main areas that the effect of cannabis and its active ingredients is being studied and it has shown promise in the treatment of many areas of chronic and neuropathic pain, neurodegenerative diseases like Lou Gehrig’s Disease, and a large variety of auto-immune and mental disorders including Tourette’s Syndrome, (01), (08), (09), (10), (11).

“Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer.” (07).

In the laboratory, various synthetic and organic cannabinoids have shown a wide range of promising anti-cancer affects, they trigger premature cell apoptosis, ‘cell death’, (thus stopping cells from dividing and reproducing) and the prevention of tumor angiogenesis (the growth of new blood vessels), which is deeply tied in with the growth and spread of tumors. This greatly aids in protection against metastasis by preventing cancerous cells migrating from the original tumor to other tissues within the body. It has also been demonstrated that some cannabinoids speed parts of the metabolism, in particular autophagy (the mechanism by which cells internally break down waste products or toxins as well as many more cellular functions), from genetic interference with cancerous cells to anti-fungal and mind-body therapy applications, (4).

“A review of the modern scientific literature reveals numerous preclinical studies and one pilot clinical study demonstrating cannabinoids’ ability to act as antineoplastic agents, particularly on glioma cell lines. Writing in the September 1998 issue of the journal FEBS Letters, investigators at Madrid’s Complutense University, School of Biology, first reported that delta-9-THC induced apoptosis in gliomal (cancerous neurons), cells in culture”, (12).

Activating CB2 receptors have been shown to interfere with the immune system’s ability to recognise and destroy tumor cells but certain synthetic cannabinoids may enhance the immune system’s defenses against cancers, (55). Some data suggesting modulation of the endo-cannabinoid system may help in gastrointestinal disorders, including Crohn’s Disease, (114).

Interestingly, due to the exceptional anti carcinogenic properties of cannabis, a cannabis smoker is no more likely to get lung cancer than a non-smoker, (56). This may go some way to explaining the beneficial effects that cannabis has on lung cancer. It is also a bronchodilator, in that it stimulates the lungs to open up their alveoli (the pockets in the lungs associated with oxygen diffusion), meaning that it not only helps with symptomatic relief of lung cancer but also benefits asthma patients and sufferers of other lung related diseases, (15). “1 delta1-trans-tetrahydrocannabinol, (delta1-THC) produces bronchodilatation in asthmatic patients.”, (16).

Research into Gliomas (brain tumors), has also been undertaken using cannabis. These are some of the most aggressive forms of cancer and often result in a patient dying within 2 years of diagnosis. There is no current cure for this form of cancer. Glial cells are associated with maintaining brain function and the general microenvironment of the Neuron, (17). Studies in 2000 and 2004 showed that THC and a synthetic cannabinoid- win 55,212-2, “inhibited glioma tumor growth in animals and in human glioblastoma multiform (GBM) tumor samples by altering blood vessel morphology.”, (18). The speeding up of cell apoptosis or regulated cell death, and antiangiogenic or halting of vessel and artery formation allowed by cannabis is an extremely powerful method of treating cancers and has been shown to be cell specific in that it only targets damaged or cancerous cells, (19), (20).

“Cannabinoids, the active components of Cannabis sativa L. and their derivatives,inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis.”, (21).

THC has also been shown to be effective in treating Alzheimer’s, by inhibiting the enzyme (AchE), that is normally responsible for the malformation of proteins associated with so many forms of Alzheimer’s, (22). Essentially acting as a neuroprotective preventative for Alzheimer’s which is considered to develop in the brain over 30 years before it displays symptomatically, (23).

“Compared to currently approved drugs prescribed for the treatment of Alzheimer’s disease, THC is a considerably superior, … this study provides a previously unrecognised molecular mechanism”, (24). Counter intuitively it has also been used to improve the memory of ageing rats, (57).

Another neurological disorder that cannabis has been shown to be effective for is Tourette’s Syndrome, though this appears to be in the early stages of development with only a few studies being published and mostly anecdotal reports,(25). Similar to Tourette’s is dystonia, when your muscles contract involuntarily creating uncontrollable or repetitive movements, (26). CBD, the non psychoactive component of cannabis, appears to have anti-dystonic effects in humans, although curiously can increase tremors in Parkinson’s, (27). Most movement disorders found in Parkinson’s etc. are caused by dysfunctions in feedback loops between the basal ganglia (related to reflex movements including balancing when walking and breathing), the thalamus (associated with sensory perception) and the cortex (associated with higher functions of thought).

Cannabinoid receptors are also located in large amounts by the output centers of the basal ganglia an area of the brain above the spinal cord. “There is evidence that endogenous cannabinoid transmission plays a role in the manipulation of other transmitter systems within the basal ganglia by increasing GABAergic transmission, inhibiting glutamate release and affecting dopaminergic uptake.”, (28).

Normal procedure to treat these symptoms would be levodopa, a metabolic precursor to dopamine but with associated nausea, or invasive brain surgery. Some research has been looking into the use of cannabis to modulate this expression of these diseases, (29). There is already evidence for the use of natural cannabinoids in Tourette’s Syndrome suggesting that there may be some value to this research, (30). Although the synthetic Nabilone was shown not to work, (31).

Deficiencies in endo cannabinoids are thought to underlie many conditions and Clinical Endo-cannabinoid Deficiency (CECD) (the lack of the correct levels of natural endogenous cannabinoids) is thought to be associated with many conditions including migraines, fibromyalgia, (32) and rheumatoid arthritis. Rheumatoid arthritis, is a form of inflammation in the joints due to an autoimmune disease and the cause is still unknown but essentially the immune systems attack the synovium, “a thin membrane that lines the joints”, (33), Resulting in a leak in the fluid held between the joints. There is no cure for this and it can lead to the degradation of the joints and organs throughout the body, (34). This is due to the T-lymphocytes, a type of white blood cell, present within the joints not undergoing apoptosis. Sativex (CBM) has been shown to be effective against Rheumatoid Arthritis, showing a significant analgesic effect, pain numbing effect, and “disease activity was significantly suppressed”, (35), (08). AjA has also shown similar effects in rats, (05), by increasing cell metabolism and so autophagy, causing the T-lymphocyte cells to undergo apoptosis, (05).

Activation at the CB2 receptor has been found to be associated with the stimulation of bone formation and maintaining bone remodeling. So by controlling the amount of cannabinoids that arrive at these receptors one can protect the skeleton from age-related bone loss, in particular it is effects against, postmenopausal osteoporosis. It may also provide opportunities to form a new way of detecting illnesses or developing drugs to treat diseases associated with bone loss, (52).

Not all the evidence for cannabis is good though. Some research has noted carcinogenic effects of some cannabinoids. It is also thought that some cannabinoids may negatively influence cancer cells and there are also some suggestions that THC can cause blood vessel cell damage although it could be that this translates to the anti-angiogenic properties seen in cancerous cells. Many of the observed effects are cell specific. Other contradictory situations where cannabis has been found to have negative effects are in Chronic Hepatitis C (CHC). In particular daily use was associated with the progression of fibrinosis, when excess amounts of a protein called fibrin can be found in the blood, (36). Fibrin is an insoluble protein and large amounts of it in circulation can lead to clots in the b­lood vessels and then heart attacks or strokes. Essentially, “Cannabis use should be discouraged in patients with CHC.”, (37). Research into other cardiovascular disorders such as cardiovascular disease (CAD), peripheral arterial disease (PAD) and strokes have also found similar problems to occur and it is generally considered to have a negative effect here, (58, 59), or is associated with an increased risk of occurrences, as in the case of strokes, (160). ­

Studies into Diabetes have also shown that it is no better than a placebo in preventing associated Diabetic Peripheral Neuropathy (DPN), disease of the nerves in the extremities, (38). Also due to the effect of cannabis on the metabolism, it may have a detrimental effect on blood glucose levels which is a serious problem for diabetics and would only exacerbate complications, (39). Due to the high association of Diabetes with the aforementioned circulatory diseases, namely CAD, PAD and strokes, it would seem that evidence is suggesting that it is not always beneficial for the user.

It is even possible to find reports of cannabis induced lung cancer, (40), although it is considered rare. “New Zealand researchers, in a study released in the European Respiratory Journal, call smoking one marijuana joint equivalent to smoking 20 cigarettes, and questioned whether rising use of marijuana in many western countries would lead to a lung cancer epidemic in years to come.”, (41). They went on to state that cannabis contains more carcinogens than tobacco and that cannabis users hold the smoke in their lungs for longer and unlike tobacco smokers, don’t use filters, so reduce their intake of the other chemicals in tobacco. As cannabis found to contain twice the amount of poly aromatic hydrocarbons than tobacco does, (42),the conclusion was drawn that cannabis smoke is more carcinogenic than tobacco. Both tobacco and cannabis smoke have similar properties but their active chemicals are what truly differ. The contents of both types of smoke can cause cancer and/or are inflammatory but some chemicals in cannabis “minimize some carcinogenic pathways”, (48). Conversely, the contents of tobacco smoke maximises them and can also promote immune responses.

Some of the chemicals present in cannabis are anti inflammatory. THC also stops the body from activating some of the chemicals in the tobacco smoke in the way it usually does when smoking pure tobacco that alone would often increases the risk of cancer, (19).

“It should be noted that with the development of vaporizers, that use the respiratory route for the delivery of carcinogen-free cannabis vapors, the carcinogenic potential of smoked cannabis has been largely eliminated”, (50).

There may be some benefit in treating various psychological and physiological symptoms of both the pathology and the side effects of cancer treatments with cannabinoids but the focus is currently on an increased quality of life as currently the evidence is not conclusive about cannabis’ benefits against cancer as a monotherapy. A more effective way of utilising the benefits of cannabinoids may be to combined chemotherapy with cannabis treatment. There are a multitude of ways to go about this and they are already being utilised in many places in the world but currently, they focus on cannabis’ ability to reduce the nausea associated with chemotherapy and to increase appetite.

Over all THC has a massive affect on the user’s body including, but not limited to, modulating glutamate via NMDA receptors (43), the potentiation of 5-HT1A and inhibition of the 5-HT2A receptors, as well as altering dopamine levels possessing anti-inflammatory properties (44), influencing the Peripheral Nervous System and GI track, and affecting blood fibrinogen content. The latter of these may suggest an underlying pathological link between low levels of endogenous cannabinoids and many other conditions (45), suggesting the mediation of endogenous cannabinoid levels may be beneficial in dealing with many conditions including some conditions like migraine or Irritable Bowl Syndrome, (46).

There is also a large amount of evidence for the psychological benefits of cannabis for suffers of chronic mental and physical illnesses which are too great to cover in full in this article. As an example, a study of with over 1000 people under the age of 65 in Baltimore between 1981 and 1996 that had used cannabis for over 12 years found that, “There were no significant differences in cognitive decline between heavy users, light users, and non users of cannabis.”, (53).

Due to the nature of the current relationship between cannabis and society it is widely believed that ethnographic studies that incorporate socio and ecological surroundings in relation to political and public opinion are important and so it is essential to provide a more objective view allowing an understanding of this subject as the subject of cannabis in medicine is still very clouded with opinion. This could be due to the emergence of many anti-drug war political debates recently and in particular the current state of affairs in America and ever increasingly around the world, where some states laws allow medical use, and/or cultivation but wider state law still sees it as illegal creating an unusual juxtaposition of state and public opinion.

As was noted earlier, there may be a causal link between THC, the cell metabolism and autophagy leading to early cell apoptosis, “We have shown that THC is a potent inducer of apoptosis”, (47). Essentially aiding in the treatment of cancerous cells. Whilst with raw cannabinoids this may present a prophylactic therapy for many conditions, (61). It can clearly be seen is that there is a great deal of evidence to demonstrate the positive effects that cannabinoids can have on a wide variety of diseases and conditions, from treatment of the symptoms of chemotherapy in cancer to management of chronic pain in Rheumatoid arthritis, and the continued study of cannabis and cannabinoids as a form of medicine is only likely to provide us with more and more evidence for their benefits.

Duncan Thomson

 *sale of medical cannabis aloud = Alaska, Arizona, California, Colorado, Hawaii, Maine, Massachusetts, Montana, Oregon, Columbia
**possession is legal or decriminalised with many having changed possession to just a misdemeanor  = Alaska, California, Connecticut, Maine, New York, North Carolina, Ohio, Oregon, Rhode island, Vermont,
***Decriminalised, Argentina, some states in Australia, Belgium, Cambodia, Columbia, Costa Rica, Croatia, Czech Republic, Estonia, Mexico, Netherlands, Peru, Portugal, Spain, Switzerland, US as mentioned, Uruguay legal,
***Legal; India, Equador, North Korea.
(Correct as of Dec. 2014)
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