Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.
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Tag Archives: THC
Phytocannabinoids as novel therapeutic agents in CNS disorders.
Abstract
“The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body’s endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines.”
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.”
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.”
Cannabis and cannabinoids: pharmacology and rationale for clinical use.
Abstract
“It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors, present mainly on central and peripheral neurones, and CB2 receptors, present mainly on immune cells. Endogenous cannabinoid receptor agonists (‘endocannabinoids’) have also been identified. The discovery of this ‘endogenous cannabinoid system’ has led to the development of selective CB1 and CB2 receptor ligands and fueled renewed interest in the clinical potential of cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are D 9 – tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. CB1 receptor antagonists may also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or disorders of cognition and memory. So too may CB2 receptor ligands and drugs that activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When taken orally, THC seems to undergo variable absorption and to have a narrow ‘therapeutic window’ (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration. For the therapeutic potential of cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic advantages over individual cannabinoids, (c) whether there is a need for additional drug treatments to manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 receptors to produce their sought-after effects.”
Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond.
Abstract
“A major finding–that (-)-trans-Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is largely responsible for the psychotropic effects of cannabis–prompted research in the 1970s and 1980s that led to the discovery that this plant cannabinoid acts through at least two types of cannabinoid receptor, CB(1) and CB(2), and that Delta(9)-THC and other compounds that target either or both of these receptors as agonists or antagonists have important therapeutic applications. It also led to the discovery that mammalian tissues can themselves synthesize and release agonists for cannabinoid receptors, the first of these to be discovered being arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol. These ‘endocannabinoids’ are released onto their receptors in a manner that appears to maintain homeostasis within the central nervous system and sometimes either to oppose or to mediate or exacerbate the unwanted effects of certain disorders. This review provides an overview of the pharmacology of cannabinoid receptors and their ligands. It also describes actual and potential clinical uses both for cannabinoid receptor agonists and antagonists and for compounds that affect the activation of cannabinoid receptors less directly, for example by inhibiting the enzymatic hydrolysis of endocannabinoids following their release.”
Cannabinoid receptor ligands as potential anticancer agents–high hopes for new therapies?
“OBJECTIVES:
The endocannabinoid system is an endogenous lipid signalling network comprising arachidonic-acid-derived ligands, cannabinoid (CB) receptors, transporters and endocannabinoid degrading enzymes. The CB(1) receptor is predominantly expressed in neurons but is also co-expressed with the CB(2) receptor in peripheral tissues. In recent years, CB receptor ligands, including Delta(9)-tetrahydrocannabinol, have been proposed as potential anticancer agents.
KEY FINDINGS:
This review critically discusses the pharmacology of CB receptor activation as a novel therapeutic anticancer strategy in terms of ligand selectivity, tissue specificity and potency. Intriguingly, antitumour effects mediated by cannabinoids are not confined to inhibition of cancer cell proliferation; cannabinoids also reduce angiogenesis, cell migration and metastasis, inhibit carcinogenesis and attenuate inflammatory processes. In the last decade several new selective CB(1) and CB(2) receptor agents have been described, but most studies in the area of cancer research have used non-selective CB ligands. Moreover, many of these ligands exert prominent CB receptor-independent pharmacological effects, such as activation of the G-protein-coupled receptor GPR55, peroxisome proliferator-activated receptor gamma and the transient receptor potential vanilloid channels.
SUMMARY:
The role of the endocannabinoid system in tumourigenesis is still poorly understood and the molecular mechanisms of cannabinoid anticancer action need to be elucidated. The development of CB(2)-selective anticancer agents could be advantageous in light of the unwanted central effects exerted by CB(1) receptor ligands. Probably the most interesting question is whether cannabinoids could be useful in chemoprevention or in combination with established chemotherapeutic agents.”
Marijuana May Fight Lung Tumors WebMD
“Cannabis Compound Slows Cancer Spread in Mice, Researchers Say.
… the active ingredient in marijuana may help combat lung cancer, new research suggests. In lab and mouse studies, the compound, known as THC, cut lung tumor growth in half and helped prevent the cancer from spreading, says Anju Preet, PhD, a Harvard University researcher in Boston who tested the chemical.While a lot more work needs to be done, “the results suggest THC has therapeutic potential,” she tells WebMD.Moreover, other early research suggests the cannabis compound could help fight brain, prostate, and skin cancers as well, Preet says.
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The findings were presented at the annual meeting of the American Association for Cancer Research.
The finding builds on the recent discovery of the body’s own cannabinoid system, Preet says. Known as endocannabinoids, the natural cannabinoids stimulate appetite and control pain and inflammation.
THC seeks out, attaches to, and activates two specific endocannabinoids that are present in high amounts on lung cancer cells, Preet says. This revs up their natural anti-inflammatory properties. Inflammation can promote the growth and spread of cancer.
In the new study, the researchers first demonstrated that THC inhibited the growth and spread of cells from two different lung cancer cell lines and from patient lung tumors. Then, they injected THC into mice that had been implanted with human lung cancer cells. After three weeks, tumors shrank by about 50%, compared with tumors in untreated mice.
Paul B. Fisher, PhD, a professor of clinical pathology at Columbia University, says that though the work is “interesting,” it’s still very early.
“The issue with using a drug of this type becomes the window of concentration that will be effective. Can you physiologically achieve what you want without causing unwanted effects?” he tells WebMD.”
More:http://www.webmd.com/lung-cancer/news/20070417/marijuana-may-fight-lung-tumors
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-9 Tetrahydrocannabinol inhibits growth and metastasis of lung cancer.” http://www.aacrmeetingabstracts.org/cgi/content/meeting_abstract/2007/1_Annual_Meeting/4749%20?maxtoshow&hits=80&RESULTFORMAT&fulltext=cannabinoid&searchid=1&FIRSTINDEX=1760&resourcetype=HWCIT
“Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo.” http://www.ncbi.nlm.nih.gov/pubmed/17621270
Marijuana Chemical May Fight Brain Cancer – WebMD
“Active Component In Marijuana Targets Aggressive Brain Cancer Cells, Study Says
The active chemical in marijuana promotes the death of brain cancer cells by essentially helping them feed upon themselves, researchers in Spain report.Guillermo Velasco and colleagues at Complutense University in Spain have found that the active ingredient in marijuana, THC, causes brain cancer cells to undergo a process called autophagy. Autophagy is the breakdown of a cell that occurs when the cell essentially self-digests.The team discovered that cannabinoids such as THC had anticancer effects in mice with human brain cancer cells and people with brain tumors. When mice with the human brain cancer cells received the THC, the tumor growth shrank.Two patients enrolled in a clinical trial received THC directly to the brain as an experimental treatment for recurrent glioblastoma multiforme, a highly aggressive brain tumor. Biopsies taken before and after treatment helped track their progress. After receiving the THC, there was evidence of increased autophagy activity.
The findings appear in the April 1 issue of the Journal of Clinical Investigation.
The patients did not have any toxic effects from the treatment. Previous studies of THC for the treatment of cancer have also found the therapy to be well tolerated, according to background information in journal article.
Study authors say their findings could lead to new strategies for preventing tumor growth.”
http://www.webmd.com/cancer/brain-cancer/news/20090401/marijuana-chemical-may-fight-brain-cancer
“Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells”: http://www.jci.org/articles/view/37948
Marijuana Compounds Could Beat Back Brain Cancer – ABCNews
“Preliminary research suggests that a combination of compounds in marijuana could help fight off a particularly deadly form of brain cancer.
But the findings shouldn’t send patients rushing to buy pot: the levels used in the research appear to be too high to obtain through smoking. And there’s no sign yet that the approach works in laboratory animals, let alone people.
Still, the finding does suggest that more than one compound in marijuana might boost cancer treatment, said study author Sean McAllister, an associate scientist at California Pacific Medical Center Research Institute in San Francisco. “Combination therapies might be more appropriate,” McAllister said.
Researchers have long studied the compounds in marijuana known as cannabinoids, which are thought to hold possible health benefits. One, known as THC, is well known for its role in making people high when they smoke or eat pot. Researchers have been testing it as a treatment for the brain tumors known as glioblastomas.
In the new study, researchers tested THC and cannabidiol, another compound from marijuana, on brain cancer cells. The findings appear in the January issue of Molecular Cancer Therapeutics.
The study authors found that the combination treatment seemed to work better at killing the cancerous cells and preventing them from growing back.
About 9,000 people in the United States develop glioblastomas each year, said Dr. Paul Graham Fisher, chief of the Division of Child Neurology at Stanford University and Lucile Packard Children’s Hospital. The most famous patient was the late U.S. Senator Ted Kennedy.
The prognosis for people with the condition is grim because tumors spread throughout the brain. It can be impossible for treatments to remove the entire tumor, Fisher said.
“No matter what you do, this tumor has a larger border than you ever think,” he said. “We know there are microscopic satellites all throughout one side of the brain and pretty soon in the other side of the brain. The only thing that will fix this disease is something that provides a more blanket approach.”
Instead of targeting the tumors itself, he explained, treatments need to do something like disrupt the pathways that cancer cells use to communicate.
In the big picture, “you’re seeing a lot more thinking outside the box about trying to treat glioblastoma,” he said. “I think in the next 10 to 15 years we’re going to start seeing progress forward.”
For now, he said, there’s no evidence that marijuana is good or bad for glioblastoma tumors.
Back in the laboratory, McAllister said the next step is to test the combination treatment on laboratory animals and then on people. The treatment may be given to people directly through the brain, which could be expensive. But the compounds themselves may not be expensive, McAllister said.
As for the idea of getting the same effect through a couple of marijuana joints, he had this to say: “It’s unlikely that you could reach effective concentrations by smoking the plant.””
http://abcnews.go.com/Health/Healthday/marijuana-compounds-beat-back-brain-cancer/story?id=9534388
“Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells.”
http://www.ncbi.nlm.nih.gov/pubmed/16078104