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.”

Read More: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462006000200015&lng=en&nrm=iso&tlng=en

Pharmacokinetics and pharmacodynamics of cannabinoids.

Abstract

“Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.”

http://www.ncbi.nlm.nih.gov/pubmed/12648025

Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.

“Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions).

The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol.

Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol,

the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/19729208

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

“The roots of cannabis synergy.”

“Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL−1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.”

“Cannabis has been a medicinal plant of unparalleled versatility for millennia, but whose mechanisms of action were an unsolved mystery until the discovery of tetrahydrocannabinol (THC), the first cannabinoid receptor, CB1, and the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG). While a host of phytocannabinoids were discovered in the 1960s: cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC) (Gaoni and Mechoulam, cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV), the overwhelming preponderance of research focused on psychoactive THC. Only recently has renewed interest been manifest in THC analogues, while other key components of the activity of cannabis and its extracts, the cannabis terpenoids, remain understudied. The current review will reconsider essential oil (EO) agents, their peculiar pharmacology and possible therapeutic interactions with phytocannabinoids.”

“Should positive outcomes result from such studies, phytopharmaceutical development may follow. The development of zero-cannabinoid cannabis chemotypes has provided extracts that will facilitate discernment of the pharmacological effects and contributions of different fractions. Breeding work has already resulted in chemotypes that produce 97% of monoterpenoid content as myrcene, or 77% as limonene (E. de Meijer, pers. comm.). Selective cross-breeding of high-terpenoid- and high-phytocannabinoid-specific chemotypes has thus become a rational target that may lead to novel approaches to such disorders as treatment-resistant depression, anxiety, drug dependency, dementia and a panoply of dermatological disorders, as well as industrial applications as safer pesticides and antiseptics. A better future via cannabis phytochemistry may be an achievable goal through further research of the entourage effect in this versatile plant that may help it fulfil its promise as a pharmacological treasure trove.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/

Plant, synthetic, and endogenous cannabinoids in medicine.

Abstract

“Although used for more than 4000 years for recreational and medicinal purposes, Cannabis and its best-known pharmacologically active constituents, the cannabinoids, became a protagonist in medical research only recently. This revival of interest is explained by the finding in the 1990s of the mechanism of action of the main psychotropic cannabinoid, Delta9-tetrahydrocannabinol (THC), which acts through specific membrane receptors, the cannabinoid receptors. The molecular characterization of these receptors allowed the development of synthetic molecules with cannabinoid and noncannabinoid structure and with higher selectivity, metabolic stability, and efficacy than THC, as well as the development of antagonists that have already found pharmaceutical application. The finding of endogenous agonists at these receptors, the endocannabinoids, opened new therapeutic possibilities through the modulation of the activity of cannabinoid receptors by targeting the biochemical mechanisms controlling endocannabinoid tissue levels.”

http://www.ncbi.nlm.nih.gov/pubmed/16409166

Phytocannabinoids and endocannabinoids.

“Progress in understanding the molecular mechanisms of cannabis action was made after discovery of cannabinoid receptors in the brain and the finding of endogenous metabolites with affinity to them. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity

. Neuromodulation of synapses by the cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some mental disorders and neurodegenerative illnesses. Cannabis contains a large amount of substances with affinity for the cannabinoid receptors. The endocannabinoids are a family of lipid neurotransmitters that engage the same membrane receptors targeted by tetrahydrocannabinol and that mediate retrograde signal from postsynaptic neurons to presynaptic ones.

 Discovery of endogenous cannabinoids and studies of the physiological functions of the cannabinoid system in the brain and body are producing a number of important findings about the role of membrane lipids and fatty acids in nerve signal transduction. Plant, endogenous and synthetic cannabinoids are using in these studies. The role of lipid membranes in the cannabinoid system follows from the fact that the source and supply of endogenous cannabinoids are derived from arachidonic acid, an important membrane constituent

. The study of structure-activity relationships of molecules which influence the cannabinoid system in the brain and body is crucial in search of medical preparations with the therapeutic effects of the phytocannabinoids without the negative effects on cognitive function attributed to cannabis.”

http://www.ncbi.nlm.nih.gov/pubmed/19630737

Cannabinoids in health and disease

Abstract

“Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, Alzheimer’s disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable – instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and – in cases where it is impossible to separate the desired clinical action and the psychoactivity – just to monitor these side effects carefully.”

Cancer

“The antiproliferative action of cannabinoids on cancer cells was first noticed in the 1970s. Since then cannabinoids were found to act on various cancer cell lines, through various mechanisms. Cannabinoids were also found to be suppressors of angiogenesis and tumor invasion. Our knowledge on the anticancer activity of cannabinoids is rapidly expanding.”

Conclusion

“Many drugs used today can cause addiction and are misused and abused, for example opiates, cocaine, benzodiazepines, barbiturates, cholinergic agonists, ketamine, dopaminergic agonists, amphetamines, and others. Nevertheless they are still an important part of our pharmacopeia. Marijuana was used for centuries as a medicinal plant, but during the last century, because of its abuse and addictive potential it was taken out of clinical practice. Now, we believe that its constituents and related compounds should be brought back to clinical use. The reasons are: (i) the therapeutic potential of CB1 agonists is huge, as described in this review; (ii) for local action, topical CB1 agonists, or agonists that do not penetrate the blood-brain barrier, can be used; (iii) cannabinoids acting specifically on CB2 receptors, which cause no psychoactivity, may be used on peripheral targets (such as osteoporosis, which is only one of many examples); (iv) there are additional, new cannabinoid targets distinct from the CB1/CB2 receptors which do not cause psychoactivity; (v) there are cannabinoids, such as CBD, which do not cause psychoactivity, but have various therapeutic effects.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202504/

Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids.

“Cannabinoids, the active components of the cannabis plant, have some clinical merit both as an anti-emetic and appetite stimulant in cachexic patients. Recently, interest in developing cannabinoids as therapies has increased following reports that they possess anti-tumour properties.

 Research into cannabinoids as anti-cancer agents is in its infancy, and has mainly focussed on the pro-apoptotic effects of this class of agent. Impressive anti-cancer activities have been reported; actions that are mediated in large part by disruptions to ubiquitous signalling pathways such as ERK and PI3-K. However, recent developments have highlighted a putative role for cannabinoids as anti-inflammatory agents. Chronic inflammation has been associated with neoplasia for sometime, and as a consequence, reducing inflammation as a way of impacting cancer presents a new role for these compounds.

 This article reviews the ever-changing relationship between cannabinoids and cancer, and updates our understanding of this class of agent. Furthermore, the relationship between chronic inflammation and cancer, and how cannabinoids can impact this relationship will be described.”

http://www.ncbi.nlm.nih.gov/pubmed/20925645

Established and potential therapeutic applications of cannabinoids in oncology.

Abstract

“Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.”

http://www.ncbi.nlm.nih.gov/pubmed/12618922

Cannabis Cures Cancer

“I’m a cancer patient. I use an experimental chemotherapy that is an extraction of the cannabis plant. I don’t use it to feel good. I use it for the purpose of killing the cancer.

Right now, there are about fifty people making this experimental chemotherapy in the state of Michigan. As a result of the opinion issued by the attorney general, the number of people willing to create this substance may now be reduced to two or three. All are working at a fevered pace trying to keep patients alive. The clock is ticking. Most of the time we have one single chance to get it right. Most of the patients we deal with will die before we get a second try.

It takes about one pound of the highest quality cannabis flowers to make enough of this extract for one single procedure, for one single patient. This extract is eaten by the patient within sixty to 90 days. This is a much higher dose that normally used to get “high.”

The procedure cannot be stopped and restarted. It is used in a way that is similar to antibiotics. You can’t stop and start antibiotics. If you do, the infection gets stronger and more difficult to get rid of. The same seems to hold true for cancer. You simply can’t play the hit and miss game with cancer. If you are on target, it MUST be completed. What is required, to stay alive, is an uninterrupted supply of the medicine. Enough to last through the entire 90 day procedure.

It is very difficult to find enough material for a single patient. Within the community we have been begging for scraps for the last two years. Begging over and over again just to supply the needs for one single patient. So we work with left over trimmings that normally would have been burned or buried. Material that no one would want. Thieves that break into our growing areas would ignore the scrap. They view it as worthless.

This useless material has had negative impact on many court cases in this state. By law, if you forget to burn some scrap, it gets counted toward the limit of 2.5 ounces. Most of us are attempting to avoid that extra scrap excess. We burn and bury any hint of excess material as quickly as possible. If we’re caught trying to do so it could well mean a felony conviction. If we delay by just a few hours we could be arrested and convicted.

Those that have been already growing marijuana and receive fresh news that they have cancer are the lucky ones. The just might have the material needed to stay alive. Might. It depends on if they have been successful in growing, if they’ve avoided fungus and insect attacks long enough to produce usable material. If they’ve learned the right nutrient combinations to apply to their indoor growing plants that afford the maximum yield.

If the patient has luck after luck, they are then at a place they can attempt to make this extract for themselves.

For a very long time, there have been many studies that show the compounds in cannabis kill cancer cells. These studies first started reporting this effect in 1974. Hundreds, if not thousands, of such scientific studies have been published but our government and most other governments of the world have refused to allow testing in humans, with very few exceptions.  Only one or two such studies have been allowed. Not one single human study has been allowed in the US in the last seventy years. Without human testing, our government relies on the statement “this hasn’t been proven in human testing,” which is technically correct because such testing isn’t allowed.

The voters of Michigan have told the government that it is acceptable to use this plant for medical purposes. It’s time for those officials to obey the voters.

While it is a noble thing to decrease the suffering of someone that is dying, I would rather see these same people survive. Wouldn’t you?

Gersh Avery is Cofounder of the Cannabis Cancer Project. He lives in Dexter.”

http://themidwestcultivator.com/marijuana-news-editorial/02-2012/cannabis-cures-cancer