Cannabinoids

Cannabinoids From Amoebae: New Process for the Production of Active THC Compounds

Posted by

0


A research team at the Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI) in Jena, Germany has developed a new method to produce complex natural products in amoebae. These polyketides include various antibiotics but also olivetolic acid, a precursor of the herbal active ingredient tetrahydrocannabinol (THC).

Polyketides are natural products with a wide range of therapeutic applications. Among them are dietary supplements, various antibiotics such as erythromycin, and one of the key cannabinoid precursors: Olivetolic acid. It is needed for the synthesis of tetrahydrocannabinol (THC). The medical use of this psychoactive substance is being intensely researched, and it is already being used to provide relief for patients with neurological diseases and pain, among other things.

THC is a natural ingredient in the cannabis plant. “However, isolating THC in its pure form from the abundance of substances is very complex,” says Falk Hillmann, head of the junior research group “Evolution of Microbial Interactions” at Leibniz-HKI and coleader of the study. Chemical synthesis of THC on the other hand is expensive and the yield is low. That’s why he and a team are researching how such plant substances can be efficiently produced biotechnologically.

“So far, bacteria such as Escherichia coli or the yeast Saccharomyces cerevisiae are mainly used, but neither of them are native producers of natural products,” explains Vito Valiante, head of the cooperating junior research group “Biobricks of Microbial Natural Product Syntheses” at the Leibniz-HKI. Accordingly, a large number of genetic modifications is necessary to enable synthesis in these classic model organisms. The research team is thus looking for alternatives. One promising candidate is the amoeba Dictyostelium discoideum, which already possesses numerous biosynthetic genes for the production of natural products such as polyketides. “Taking a closer look at the genes, we noticed that some show a high similarity to plant biosynthetic genes,” said first author Christin Reimer, who is working on the topic for her PhD.

To test how well D. discoideum is suited as a chassis organism for biotechnological production, the researchers first had the amoeba produce the food supplement resveratrol, also a polyketide. Afterward they incorporated the plant enzyme that produces the THC precursor olivetolic acid into the amoeba’s genome. However, the addition of chemical precursors was still necessary to enable the synthesis.

To circumvent this, the researchers took advantage of the amoeba’s natural properties and combined the plant enzyme with an amoebic enzyme. “The amoeba is able to produce the required precursor, a hexane unit, directly on site,” Hillmann explains. Thus, the research team succeeded in producing a functional inter-kingdom hybrid enzyme that produces olivetolic acid without any further additives.

“Through our research, we have shown that the amoeba Dictyostelium can be used as a biotechnological production platform for polyketide-based natural products,” says Reimer. The researchers already filed a patent for the process, and are striving to improve it on an ongoing basis. “Our next goal is to insert the two enzymes that are still missing in order to be able to produce the final product THC in the amoebae,” Hillmann says.

Moreover, a team from the Bio Pilot Plant at the Leibniz-HKI was also involved in the research. Johann Kufs, joint first author of the study alongside Reimer, is in charge of developing and optimizing the synthesis process for industrial application.

Cannabinoids Are Common: Why So Many Use CBD, Delta-8, Others

Posted by

0


Some take them to manage pain, others to help improve their sleep. Known more commonly as CBD, delta-8, CBG, and CBN, these products have flooded the marketplace.

Users interviewed for this story recommend caution and encouraged others to find a reputable source or brand and sticking with it. 

So how many American adults are using these products? 

“We were surprised that over a quarter of Americans used these emerging cannabinoid products in the past year,” said Kevin Boehnke, PhD, a research assistant professor in the Department of Anesthesiology and the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor. 

The Basics: What Is Marijuana-Based CBD?

CBD is a chemical in marijuana, but it won’t give you a high. It’s known to treat seizures caused by epilepsy, but more research is needed to confirm its benefits for other medical conditions.

Boehnke was senior investigator in a study that examined how often and why Americans used these products. 

Younger adults and those living in states where cannabis use was prohibited by law were more likely to use CBD, delta-8 THC, and others. These “emerging cannabinoids” contain less than 0.3% THC (the compound in marijuana that makes one “high”) and are currently legal under federal law. 

The research reveals almost 12% of adults reported using delta-8 THC in the past year, more than 5% used CBG, and over 4% used CBN. The public health study was published online in December in the journal JAMA Network Open. 

Also, more than 21% of people reported using CBD in the nationally representative survey. So, Bill Gould, a 47-year-old real estate agent and songwriter in Temecula, CA, is in good company.

Gould uses CBD in gummy, liquid, or topical forms to help manage his migraines. He also reports better relief using topical CBD to treat “guitar elbow,” which is akin to tennis elbow but for musicians. “Compared to other times I have had strains, it definitely seems to help better,” he said.

Buyer Beware

Gould is concerned about labeling transparency and whether products are the same from brand to brand. 

“Some of them are made with [animal-derived] gelatins, some of them are not gluten-free, some of them have an enormous amount of sugar in them. If you have food allergies or dietary preferences, you really have to pay close attention,” he said.

Marsi Thrash, a 54-year-old lobbyist who lives in a suburb of Charleston, SC, agreed. “I buy CBD from very reputable places. I buy it from the local compounding pharmacy, and I’ve never had any problems,” she said.

The concerns come in part from a young and crowded marketplace where the major players have not yet emerged, she said. “There are so many different brands out there, so many different products.”

“I see all sorts of CBD brands and products. It’s definitely overwhelming,” said Jay Valter, a 52-year-old attorney working in the financial sector in Philadelphia. 

Concentrations of CBD and THC also differ among products. Regarding the hemp-derived, less than 0.3% THC product, “I would like people to know that you can get it, it’s functional, and it doesn’t get you loaded,” Gould said. In contrast, products that contain 1:1 concentration of CBD and THC “will get you buzzed” and are more likely found at dispensaries or in clubs versus health stores. 

Navigating the Delta

Thrash has tried CBD gummies, but tincture drops placed under her tongue work better and faster for her. She has aches and pains from an autoimmune condition, and the CBD is “very helpful in calming that down.” 

Thrash also has a hard time sleeping, and generally, prescription sleep aids leave her with a drowsy hangover the next day, making it more difficult to function. “CBD is the most workable,” she said. 

Delta-8 THC, in contrast, is not a good sleep option for Thrash, even though its widely available in drinks and in vape pens in her part of South Carolina. “I don’t care for it because it literally sends me into ‘Alice in Wonderland’-type dreams.”

Too many people depend on Delta-8 & 9 as a real therapeutic tool. My wife is one and I can attest to it helping her along with traditional therapy.

Legalize it, tax it, but stop harming good people for the sake of politics.

Alcohol is far more destructive! https://t.co/eDd8W8E07E— Classless J B %uD83C%uDF4A (@BigOrangeJB) January 3, 2024

But Valter prefers delta-8 THC to help treat his joint pain and as a sleep aid. “The THC gummies did the trick for me, but the problem was I would often wake up [feeling] stoned,” he said. “That was not particularly ideal.”

He tried different delta-8 products, “and I really like the one I’m using now. It really does the job, and I don’t wake up with any after-effects.” Valter also occasionally uses a topical CBD gel or tincture to ease joint pain. 

Better regulations are needed to help protect consumers, said Boehnke, the researcher from the University of Michigan. “This is especially true for delta-8 THC products, which reportedly cause similar effects to delta-9 THC, the compound people generally refer to as THC.”

Stopping for Gas, Beef Jerky, and CBD?

Valter also recommends caution when selecting a cannabinoid product. “I think there’s a lot of junk on the market, for sure, especially in terms of CBD,” he said.

Thrash is willing to pay more to get CBD from a more reputable source. “I’m very leery of the $5 stuff you can buy in a gas station. I wouldn’t buy it. Maybe it is the exact same thing – and I’m just getting hoodwinked for a hundred bucks. I don’t know.”

“But I want to buy from the person who can tell me exactly where it came from,” she said.

Unlike prescription medications with precise labeling of ingredients, “with the CBD products, there are so many companies making it,” Gould said. “I don’t buy janky products from people.”

With no required laboratory testing for safety of these products, such as for contaminants like pesticides, solvents, or heavy metals, Boehnke also urges caution. Likewise, there is no verification to prove these products contain the cannabinoid type and quantity that are on the label, he said.

Also, many cannabinoid products can be purchased online, where minimum age requirements are difficult to enforce, Boehnke said.

An Argument to Relax More Laws?

“The most important finding is that when cannabis is legal in some form in a given state, it tends to reduce or eliminate consumer desire for delta-8 THC products,” said Ethan Russo, MD, a board-certified neurologist and  psychopharmacology researcher in Vashon, WA, and founder and CEO of credo-science.com. “This is a clear indication that liberalization of the laws must continue and expand to reduce the public health dangers of synthetic unregulated products.”

Russo, who was not affiliated with the study, said the compound delta-8 THC is not the problem, “but rather its manufacture and production.” All the commercially available delta-8 THC products are synthetically produced from excess stock of CBD, he said. “Virtually none are pure, most often contaminated with a host of other synthetic molecules about which we know little or nothing as to their possible toxicology,” he said. 

Likewise, he said there is little scientific evidence to support the benefit of cannabinol, or CBN. Also, he said CBN is a breakdown product of THC, and “its presence on the market is largely a function of providing the industry an outlet and income stream for old, degraded cannabis that is otherwise unsellable.”

On the other hand, Russo said, tetrahydrocannabivarin (THCV), or delta-9, and cannabigerol, or CBG, “are very promising” as therapeutics “and deserve greater attention.”

Russo and colleague Carrie Cuttler, PhD, an associate professor at Washington State University, recently finished a randomized controlled trial of CBG for anxiety “with very positive results. We hope to publish that soon.”

Asked where he would like to take the research next, Boehnke said, “This is a first small step. We’d like to understand how people use these products, why they use them – for example, for medical versus nonmedical reasons – and health outcomes associated with their use.”

The safety and relative effectiveness of non-psychoactive cannabinoid formulations for the improvement of sleep: a double-blinded, randomized controlled trial

Posted by

0


ABSTRACT

The objective of this randomized, double-blinded controlled trial was to evaluate the safety and relative effects of different formulations containing Cannabidiol (CBD) and melatonin, with and without the addition of minor cannabinoids, on sleep. Participants (N=1,793 adults experiencing symptoms of sleep disturbance) were assigned to receive a 4-week supply of 1 of 6 products (all capsules) containing either 15mg CBD or 5mg melatonin, alone or in combination with minor cannabinoids. Sleep disturbance was assessed using Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A, administered via weekly online surveys. All formulations exhibited a favorable safety profile (12% of participants reported a side effect and none were severe) and led to significant improvements in sleep disturbance (p<0.001 in within-group comparisons). Most participants (56% to 75%) across all formulations experienced a clinically important improvement in their sleep quality. There were no significant differences in effect, however, between 15mg CBD isolate and formulations containing 15mg CBD and 15mg Cannabinol (CBN), alone or in combination with 5 mg Cannabichromene (CBC). There were also no significant differences in effect between 15mg CBD isolate and formulations containing 5 mg melatonin, alone or in combination with 15mg CBD and 15mg CBN. Our findings suggest that chronic use of a low dose of CBD is safe and could improve sleep quality, though these effects do not exceed that of 5 mg melatonin. Moreover, the addition of low doses of CBN and CBC may not improve the effect of formulations containing CBD or melatonin isolate.

INTRODUCTION

Approximately one third of American adults do not get enough sleep each night.1 Poor sleep can have a profound impact on a person’s quality of life; it can hinder cognitive functioning2 and lead to depression,3 reduced productivity,4 cardiovascular disease,5 and increased healthcare utilization.4 There is strong clinical evidence in support of pharmacologic interventions for the treatment of insomnia (difficulty getting to sleep or staying asleep6) and other sleep disorders, in particular for GABAA receptor agonists, such as benzodiazepines.7 Concerns remain, however, over their many side effects, including ‘hangover effects’, cognitive impairment, abuse, and the considerable risk of dependance.8 Consequently, there is a prevailing need to evaluate safer forms of therapeutic treatment for the improvement of sleep.

Many patients turn to complementary and alternative medicines (CAM) for the treatment of insomnia and other sleep disorders.9 Melatonin is among the most commonly used and well-studied CAM treatments for sleep,10 and clinical evidence supports its efficacy for the improvement of sleep quality, particularly for those experiencing jet lag and delayed sleep-wake phase disorder.11–14 Moreover, melatonin exhibits a favorable safety profile and does not demonstrate dependence even when administered at high doses.15

Cannabis preparations have also begun to gain attention for their potential therapeutic effects for the treatment of insomnia and other sleep disorders.16 To date, the preponderance of clinical research on Cannabis and sleep has focused on Δ9-tetrahydrocannabinol (Δ9-THC), the major active constituent of Cannabis sativa.17 Yet use of the non-psychoactive cannabinoid Cannabidiol (CBD) has proliferated in the US, with many new users seeking relief for sleep difficulties.18 Preclinical research has demonstrated that CBD possesses anxiolytic, anti-inflammatory, and analgesic properties,19 which could aid in the improvement of sleep. Evidence from retrospective and prospective observational studies also suggest that the clinical administration of cannabinoids could improve sleep and other related health issues such as pain and anxiety.20–22

Clinical research assessing the use of CBD for insomnia and other sleep disorders remains limited, though some small clinical studies have found support for the hypothesis that CBD may improve sleep. In a study of 15 individuals with insomnia, those who received 160 mg CBD reported sleeping longer than those who received placebo.23 Another study of 33 individuals with Parkinson’s Disease revealed that 300 mg of CBD per day led to a transient improvement in sleep quality relative to placebo.24 In small experimental studies, fixed doses of 300 mg, 400 mg and 600 mg of CBD were also found to induce self-reported sedative effects relative to placebo in healthy adults (11 adults, 300 and 600 mg25; 10 males, 400 mg26). Importantly, clinical evidence of CBD also indicates that the cannabinoid has a favorable safety profile,27,28 even when taken at doses as high as 1200 mg daily for up to 4 weeks,29 supporting the exploration of CBD as a potentially safer therapeutic option for the improvement of sleep.

Despite the limited clinical evidence, marketing claims regarding the effectiveness of CBD for sleep abound.30,31 Many manufacturers have also touted the superiority of their CBD products relative to melatonin32,33 though, to date, no clinical study has directly compared the effects of these compounds on sleep. Manufacturers have also combined CBD with melatonin and other minor cannabinoids, claiming that these additions could enhance the effect of CBD or melatonin alone.34 These claims, too, are unfounded. No large scale randomized clinical trial has evaluated whether CBD could impact the effects of melatonin on sleep (or vice versa). No clinical trials have also evaluated whether the addition of minor cannabinoids, such as Cannabichrome (CBC) and Cannabinol (CBN), could contribute to the therapeutic effectiveness of CBD for sleep improvement. CBN, in particular, has gained prominence as a sleep aid additive,35 though the literature is almost entirely devoid of clinical research supporting its effect on sleep quality.36 Multi-arm studies allowing for direct comparisons across cannabinoid and melatonin formulations could provide critical information on the main and interactive effects of these compounds on sleep.

Notably, few clinical trials of CBD have also tested the effect of daily usage of CBD at the lower doses commonly found within commercially available products. Most clinical trials of CBD evaluate doses ranging from 300 to 1500 mg CBD per day,37–39 while commercial products’ dosage generally range from 5 to 100 mg CBD per day. Clinical research on CBD has suggested a bell-shaped dose response curve wherein an intermediate dose of CBD exhibits a greater anxiolytic effect than a very low or high dose,40,41 though more clinical studies are needed evaluate the therapeutic benefits of chronic CBD use for sleep at dose ranges reflecting that of commercial products.

This study sought to address these gaps in the literature by investigating the effect of chronic use (daily use over 4 weeks) of low dose CBD and melatonin formulations, alone and in combination with certain minor cannabinoids, on sleep quality. The primary objective of the study was to compare the safety and effects of CBD isolate to CBD combination formulations (i.e., formulations containing CBD and minor cannabinoids, with and without melatonin) to determine if the addition of melatonin and these minor cannabinoids confer any therapeutic benefit to a formulation containing CBD. As a secondary aim, we also sought to determine if the addition of CBD and CBN confer any therapeutic benefit to a formulation containing melatonin.

DISCUSSION

In this randomized, double-blinded controlled trial to evaluate the effects of different orally ingested cannabinoid and melatonin formulations on sleep disturbance, we observed that a 15mg of CBD reduced self-reported sleep disturbance over the course of 4 weeks. The addition of minor cannabinoids (15mg CBN, alone or in combination with 5 mg CBC) did not impact the therapeutic effects of 15 mg CBD. Moreover, we found no evidence of a difference in effect on overall sleep disturbance score between 15mg CBD isolate and formulations containing 5 mg melatonin, alone or in combination with 15mg CBD and 15mg CBN. However, when examining changes in each PROMIS Sleep Disturbance 8a scale question score separately, we observed that those taking the 5mg melatonin in combination with 15mg CBD and 15mg CBN reported greater improvements in the restless and refreshing aspects of their sleep relative to those taking CBD isolate, though changes in self-reported sleep quality, sleep satisfaction, and in difficulties and worries over falling asleep did not vary between any formulation relative to CBD isolate. Secondary analyses also revealed that the addition of 15mg CBD and 15mg CBN did not significantly impact the therapeutic effects of a formulation containing 5mg melatonin on overall sleep disturbance score. Notably, all study arms led to significant improvements in sleep disturbance and exhibited favorable safety profiles.

Few clinical studies have examined the effect of CBD, with or without the addition of minor cannabinoids, for the improvement of sleep. This study is among the first to evaluate the safety and effectiveness of CBD dose ranges and formulations commonly found within commercially available CBD products. Our results demonstrate that the relatively lower doses of CBD found within these orally ingested products may be safe for chronic use and sufficient to produce significant improvements in symptoms of sleep disturbance. These effects, however, do not exceed that of 5 mg melatonin. Moreover, we found no evidence that the low doses of CBN and CBC can improve the effect of formulations containing low doses of CBD or melatonin isolate.

Our findings regarding the lack of additional therapeutic effect from the addition of CBN are noteworthy as cannabis product manufacturers have recently begun to tout the sleep-inducing effects of CBN,44 though preclinical and clinical research in support of these claims is scarce and outdated.36 Indeed, our study represents the first clinical trial to evaluate the use of CBN for sleep using validated sleep measures. Our findings suggest that 15mg of CBN may confer little added benefit to a sleep aid product. We note, however, that our findings reflect a relatively lower dosage of orally ingested CBN and may not be generalizable to higher dosages or other modes of administration of the cannabinoid.

In our secondary analyses, we did not find evidence that the addition of CBC to formulations containing CBD and CBN will impact their therapeutic effect on sleep quality. We did, however, observe substantially higher likelihood of experiencing a MCID among those in the CBD combination arm containing CBC (72%) compared to the arms containing just CBD and CBN (56% and 60% in the Full and Isolate spectrum CBD combination arms, respectively), suggesting CBC might impart some effect on sleep improvement. However, as this was not a planned comparison for the current study, and as the omnibus test between the CBD combination arms did not reach statistical significance, we are unable to fully interpret the meaning of this trend. Thus, further studies are needed to thoroughly characterize the impacts of CBC on sleep.

Preclinical research suggests that certain cannabinoids and other components of the Cannabis plant could work synergistically, stimulating a greater effect than that if CBD or Δ9-THC were examined in isolation – a phenomenon known as the ‘entourage effect’.45 As we observed no difference in effect between the CBD isolate and cannabinoid combination formulations, we found no evidence of an entourage effect with CBD, CBC, and CBN in these trial products. However, these findings may only be generalized to the specific dosages of these cannabinoids in this sample. We cannot exclude, from the present evidence, the possibility that higher concentrations of these minor cannabinoids could modulate the effects of CBD.

We observed that participants assigned to arms without melatonin averaged a higher daily capsule intake compared to participants taking melatonin-containing capsules. Importantly, we did not detect an increase in safety concerns in arms with a higher average daily intake. Although not statistically significant, this trend may suggest that without melatonin, higher doses of cannabinoids may be necessary to induce the desired effects on sleep quality. Moreover, it is possible that melatonin capsule dose was more optimally calibrated relative to the doses of cannabinoids.

Previous clinical research on melatonin for insomnia and other common sleep disorders suggests that its effects are modest and inferior to prescription medications.46 As we did not find any significant differences between CBD isolate and the melatonin or CBD combination formulations, such conclusions regarding modest relative effects could be extended to the formulations in this sample. Nonetheless, as melatonin and CBD both demonstrate a highly favorable safety and tolerability profile, these alternative therapies could still play a role in the treatment of common sleep disorders, especially given the harmful side effects of common pharmacological treatments for these disorders.8

This study has several limitations. First, about 28% of participants did not complete any follow-up surveys and were therefore excluded from the study. While our overall attrition levels still fell below anticipated attrition levels of 45% and the study was adequately powered to detect significant sleep changes, differential loss to follow-up could induce post-randomization confounding.47 As those who were excluded did not fill out any surveys beyond the screener, we were limited in our ability to evaluate characteristics of those excluded and assess potential imbalances across study arms. We were also unable to run a sensitivity analysis including the excluded individuals as they did not provide any PROMIS Sleep Disturbance 8a scores and imputing their data would not be appropriate as their observations were determined to be missing not at random (MNAR; as no study period surveys were completed by these individuals, the missingness is thus dependent on unobserved data). Nonetheless, we did not find any significant differences in the percentage of excluded individuals between study arms, and there were no significant differences in baseline demographic or health characteristics between study arms in the final sample, indicating that balance was maintained across study arms despite changes to the study sample post-randomization.

Additionally, as there was no placebo control within this study, we cannot determine if and how much the observed effects may be due to participant expectations/placebo. In previous clinical research, melatonin has been shown to have modest effects on sleep relative to placebo,48 though clinical evidence of CBD’s effect relative to placebo remains limited, albeit promising.23–25 Notably, previous clinical research suggests that placebo response could play a major role in the effect of CBD on stress and anxiety,49 though the impact of this response has yet to be explored for CBD and sleep. Further placebo-controlled studies are needed to determine the therapeutic effects of CBD for sleep.

We see this data as “real world” data, as it was collected from a population that was using the products in a manner and setting like that of real consumers of these products. Without exhaustive eligibility criteria and intensive monitoring, the missingness and heterogeneity of the data may be greater than that of traditional clinical trials. However, many traditional clinical trials have limited external validity because the characteristics and behaviors of participants may not reflect those of real-world users. As such, real world studies have unique value in their ability to provide complementary evidence to support clinical trial designs and help guide regulatory and clinical decisions.50,51

Our study is the first randomized, blinded, controlled trial which compares the effects of CBD and melatonin on sleep, and further investigates therapeutic benefits of combining CBD isolate with melatonin or minor cannabinoids. Our findings represent an essential scientific advancement towards thoroughly characterizing and contrasting the effects of commonly used non-prescription sleep disorder treatments.

The Scientific History of Cannabinoids

Posted by

0


Hundreds of these cannabis-related chemicals, both natural and synthetic, now exist, and researchers want to know how they can hurt and help us

Marijuana Plant
Over several decades, researchers have identified more than 140 active compounds, called cannabinoids, in the cannabis plant. 

The 1960s was a big decade for cannabis: Images of flower power, the summer of love and Woodstock wouldn’t be complete without a joint hanging from someone’s mouth. Yet in the early ’60s, scientists knew surprisingly little about the plant. When Raphael Mechoulam, then a young chemist in his 30s at Israel’s Weizmann Institute of Science, went looking for interesting natural products to investigate, he saw an enticing gap in knowledge about the hippie weed: The chemical structure of its active ingredients hadn’t been worked out.

Mechoulam set to work.

The first hurdle was simply getting hold of some cannabis, given that it was illegal. “I was lucky,” Mechoulam recounts in a personal chronicle of his life’s work, published this month in the Annual Review of Pharmacology and Toxicology. “The administrative head of my Institute knew a police officer. … I just went to Police headquarters, had a cup of coffee with the policeman in charge of the storage of illicit drugs, and got 5 kg of confiscated hashish, presumably smuggled from Lebanon.”

By 1964, Mechoulam and his colleagues had determined, for the first time, the full structure of both delta-9-tetrahydrocannabinol, better known to the world as THC (responsible for marijuana’s psychoactive “high”) and cannabidiol, or CBD.

That chemistry coup opened the door for cannabis research. Over the following decades, researchers including Mechoulam would identify more than 140 active compounds, called cannabinoids, in the cannabis plant, and learn how to make many of them in the lab. Mechoulam helped to figure out that the human body produces its own natural versions of similar chemicals, called endocannabinoids, that can shape our mood and even our personality. And scientists have now made hundreds of novel synthetic cannabinoids, some more potent than anything found in nature.

Today, researchers are mining the huge number of known cannabinoids — old and new, found in plants or people, natural and synthetic — for possible pharmaceutical uses. But, at the same time, synthetic cannabinoids have become a hot trend in recreational drugs, with potentially devastating impacts.

For most of the synthetic cannabinoids made so far, the adverse effects generally outweigh their medical uses says biologist João Pedro Silva of the University of Porto in Portugal, who studies the toxicology of substance abuse, and coauthored a 2023 assessment of the pros and cons of these drugs in the Annual Review of Pharmacology and Toxicology. But, he adds, that doesn’t mean there aren’t better things to come.

Cannabanoid Variety Graphic
The cannabis plant produces more than 140 phytocannabinoids; the most well-known are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) (top). These interact with many of the same receptors as compounds made by the body, called endocannabinoids (middle), despite their chemical differences. Synthetic compounds (bottom, three shown) that are meant to mimic the action of various cannabinoids also have a wide variety of chemical structures. Adapted from R. Roque-Bravo et al. / AR Pharmacology and Toxicology 2023 / Knowable Magazine

Cannabis’s long medical history

Cannabis has been used for centuries for all manner of reasons, from squashing anxiety or pain to spurring appetite and salving seizures. In 2018, a cannabis-derived medicine — Epidiolex, consisting of purified CBD — was approved for controlling seizures in some patients. Some people with serious conditions, including schizophrenia, obsessive compulsive disorder, Parkinson’s and cancer, self-medicate with cannabis in the belief that it will help them, and Mechoulam sees the promise. “There are a lot of papers on [these] diseases and the effects of cannabis (or individual cannabinoids) on them. Most are positive,” he tells Knowable Magazine.

That’s not to say cannabis use comes with zero risks. Silva points to research suggesting that daily cannabis users have a higher risk of developing psychotic disorders, depending on the potency of the cannabis; one paper showed a 3.2 to 5 times higher risk. Longtime chronic users can develop cannabinoid hyperemesis syndrome, characterized by frequent vomiting. Some public health experts worry about impaired driving, and some recreational forms of cannabis contain contaminants like heavy metals with nasty effects.

Finding medical applications for cannabinoids means understanding their pharmacology and balancing their pros and cons.

Mechoulam played a role in the early days of research into cannabis’s possible clinical uses. Based on anecdotal reports stretching back into ancient times of cannabis helping with seizures, he and his colleagues looked at the effects of THC and CBD on epilepsy. They started in mice and, since CBD showed no toxicity or side effects, moved on to people. In 1980, then at the Hebrew University of Jerusalem, Mechoulam co-published results from a 4.5-month, tiny trial of patients with epilepsy who weren’t being helped by current drugs. The results seemed promising: Out of eight people taking CBD, four had almost no attacks throughout the study, and three saw partial improvement. Only one patient wasn’t helped at all.

“We assumed that these results would be expanded by pharmaceutical companies, but nothing happened for over 30 years,” writes Mechoulam in his autobiographical article. It wasn’t until 2018 that the US Food and Drug Administration approved Epidiolex for treating epileptic seizures in people with certain rare and severe medical conditions. “Thousands of patients could have been helped over the four decades since our original publication,” writes Mechoulam.

Drug approval is a necessarily long process, but for cannabis there have been the additional hurdles of legal roadblocks, as well as the difficulty in obtaining patent protections for natural compounds. The latter makes it hard for a pharmaceutical company to financially justify expensive human trials and the lengthy FDA approval process.

In the United Nations’ 1961 Single Convention on Narcotic Drugs, cannabis was slotted into the most restrictive categories: Schedule I (highly addictive and liable to abuse) and its subgroup, Schedule IV (with limited, if any, medicinal uses). The UN removed cannabis from schedule IV only in December 2020 and, although cannabis has been legalized or decriminalized in several countries and most US states, it remains still (controversially), on both the US’ and the UN’s Schedule I — the same category as heroin. The US’ cannabis research bill, passed into law in December 2022, is expected to help ease some of the issues in working with cannabis and cannabinoids in the lab.

To date, the FDA has only licensed a handful of medicinal drugs based on cannabinoids, and so far they’re based only on THC and CBD. Alongside Epidiolex, the FDA has approved synthetic THC and a THC-like compound to fight nausea in patients undergoing chemotherapy and weight loss in patients with cancer or AIDS. But there are hints of many other possible uses. The National Institutes of Health registry of clinical trials lists hundreds of efforts underway around the world to study the effect of cannabinoids on autism, sleep, Huntington’s Disease, pain management and more.

In recent years, says Mechoulam, interest has expanded beyond THC and CBD to other cannabis compounds such as cannabigerol (CBG), which Mechoulam and his colleague Yehiel Gaoni discovered back in 1964. His team has made derivatives of CBG that have anti-inflammatory and pain relief properties in mice (for example, reducing the pain felt in a swollen paw) and can prevent obesity in mice fed high-fat diets. A small clinical trial of the impacts of CBG on attention-deficit hyperactivity disorder is being undertaken this year. Mechoulam says that the methyl ester form of another chemical, cannabidiolic acid, also seems “very promising” — in rats, it can suppress nausea and anxiety and act as an antidepressant in an animal model of the mood disorder.

But if the laundry list of possible benefits of all the many cannabinoids is huge, the hard work has not yet been done to prove their utility. “It’s been very difficult to try and characterize the effects of all the different ones,” says Sam Craft, a psychology PhD student who studies cannabinoids at the University of Bath in the UK. “The science hasn’t really caught up with all of this yet.”

A natural version in our bodies

Part of the reason that cannabinoids have such far-reaching effects is because, as Mechoulam helped to discover, they’re part of natural human physiology.

In 1988, researchers reported the discovery of a cannabinoid receptor in rat brains, CB1 (researchers would later find another, CB2, and map them both throughout the human body). Mechoulam reasoned there wouldn’t be such a receptor unless the body was pumping out its own chemicals similar to plant cannabinoids, so he went hunting for them. He would drive to Tel Aviv to buy pig brains being sold for food, he remembers, and bring them back to the lab. He found two molecules with cannabinoid-like activity: anandamide (named after the Sanskrit word ananda for bliss) and 2-AG.

These endocannabinoids, as they’re termed, can alter our mood and affect our health without us ever going near a joint. Some speculate that endocannabinoids may be responsible, in part, for personality quirks, personality disorders or differences in temperament.

Animal and cell studies hint that modulating the endocannabinoid system could have a huge range of possible applications, in everything from obesity and diabetes to neurodegeneration, inflammatory diseases, gastrointestinal and skin issues, pain and cancer. Studies have reported that endocannabinoids or synthetic creations similar to the natural compounds can help mice recover from brain trauma, unblock arteries in rats, fight antibiotic-resistant bacteria in petri dishes and alleviate opiate addiction in rats. But the endocannabinoid system is complicated and not yet well understood; no one has yet administered endocannabinoids to people, leaving what Mechoulam sees as a gaping hole of knowledge, and a huge opportunity. “I believe that we are missing a lot,” he says.

“This is indeed an underexplored field of research,” agrees Silva, and it may one day lead to useful pharmaceuticals. For now, though, most clinical trials are focused on understanding the workings of endocannabinoids and their receptors in our bodies (including how everything from probiotics to yoga affects levels of the chemicals).

Cannabanoid Receptors in the Body Graphic
The cannabinoid receptors CB1 and CB2 are found throughout the body — from the brain to the spleen. CB1 receptors are especially common in the nervous system; CB2 receptors are concentrated in the immune system and related areas. But both receptors also are present throughout the body. This broad distribution means that compounds — from THC to endocannabinoids to synthetic cannabinoids — that bind to one or both of these receptors may affect a wide variety of systems, including pain perception, motor activity, appetite and short-term memory. Source: J.P. Connor et al. / Nature Reviews Disease Primers 2021 / Knowable Magazine

‘Toxic effects’ of synthetics

In the wake of the discovery of CB1 and CB2, many researchers focused on designing new synthetic molecules that would bind to these receptors even more strongly than plant cannabinoids do. Pharmaceutical companies have pursued such synthetic cannabinoids for decades, but so far, says Craft, without much success — and some missteps. A drug called Rimonabant, which bound tightly to the CB1 receptor but acted in opposition to CB1’s usual effect, was approved in Europe and other nations (but not the US) in the early 2000s to help to diminish appetite and in that way fight obesity. It was withdrawn worldwide in 2008 due to serious psychotic side effects, including provoking depression and suicidal thoughts.

Some of the synthetics invented originally by academics and drug companies have wound up in recreational drugs like Spice and K2. Such drugs have boomed and new chemical formulations keep popping up: Since 2008, 224 different ones have been spotted in Europe. These compounds, chemically tweaked to maximize psychoactive effects, can cause everything from headaches and paranoia to heart palpitations, liver failure and death. “They have very toxic effects,” says Craft.

For now, says Silva, there is scarce evidence that existing synthetic cannabinoids are medicinally useful: As most of the drug candidates worked their way up the pipeline, adverse effects have tended to crop up. Because of that, says Silva, most pharmaceutical efforts to develop synthetic cannabinoids have been discontinued.

But that doesn’t mean all research has stopped; a synthetic cannabinoid called JWH-133, for example, is being investigated in rodents for its potential to reduce the size of breast cancer tumors. It’s possible to make tens of thousands of different chemical modifications to cannabinoids, and so, says Silva, “it is likely that some of these combinations may have therapeutic potential.” The endocannabinoid system is so important in the human body that there’s plenty of room to explore all kinds of medicinal angles. Mechoulam serves on the advisory board of Israel-based company EPM, for example, which is specifically aimed at developing medicines based on synthetic versions of types of cannabinoid compounds called synthetic cannabinoid acids.

With all this work underway on the chemistry of these compounds and their workings within the human body, Mechoulam, now 92, sees a coming explosion in understanding the physiology of the endocannabinoid system. And with that, he says, “I assume that we shall have a lot of new drugs.”

Brain-Derived Neurotrophic Factor (BDNF) Role in Cannabinoid-Mediated Neurogenesis

Posted by

0


The adult mammalian brain can produce new neurons in a process called adult neurogenesis, which occurs mainly in the subventricular zone (SVZ) and in the hippocampal dentate gyrus (DG). Brain-derived neurotrophic factor (BDNF) signaling and cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to independently modulate neurogenesis, but how they may interact is unknown. We now used SVZ and DG neurosphere cultures from early (P1-3) postnatal rats to study the CB1R and CB2R crosstalk with BDNF in modulating neurogenesis. BDNF promoted an increase in SVZ and DG stemness and cell proliferation, an effect blocked by a CB2R selective antagonist. CB2R selective activation promoted an increase in DG multipotency, which was inhibited by the presence of a BDNF scavenger. CB1R activation induced an increase in SVZ and DG cell proliferation, being both effects dependent on BDNF. Furthermore, SVZ and DG neuronal differentiation was facilitated by CB1R and/or CB2R activation and this effect was blocked by sequestering endogenous BDNF. Conversely, BDNF promoted neuronal differentiation, an effect abrogated in SVZ cells by CB1R or CB2R blockade while in DG cells was inhibited by CB2R blockade. We conclude that endogenous BDNF is crucial for the cannabinoid-mediated effects on SVZ and DG neurogenesis. On the other hand, cannabinoid receptor signaling is also determinant for BDNF actions upon neurogenesis. These findings provide support for an interaction between BDNF and endocannabinoid signaling to control neurogenesis at distinct levels, further contributing to highlight novel mechanisms in the emerging field of brain repair.

Introduction

Constitutive neurogenesis occurs in the adult mammalian brain where NSPC are able to differentiate into three neural lineages, neurons, astrocytes and oligodendrocytes (Gage, 2000; Gross, 2000). These multipotent cells exhibit properties of self-renewal and cell proliferation that allow the maintenance of their own pool (Ma et al., 2009). Neurogenesis occurs mainly in two brain areas, the subventricular zone (SVZ) and the subgranular zone (SGZ) within the DG of the hippocampus. These regions are packed with NSPC that originate neuroblasts which migrate toward their final destinations, where they differentiate into mature neurons and are integrated into the neuronal circuitry (Lledo et al., 2006; Zhao et al., 2008; Ming and Song, 2011).

Adult neurogenesis and the neurogenic niches are highly regulated by several factors (intrinsic and extrinsic factors) that control the NSPC rates of proliferation, lineage differentiation, migration, maturation and survival (Ming and Song, 2011). Knowing and understanding the actions of these factors will further contribute to develop new therapeutic strategies useful for brain repair and regeneration. However, there is still a lack of knowledge regarding the key factors that regulate each step of postnatal neurogenesis.

The role of neurotrophins and, in particular, brain-derived neurotrophic factor (BDNF) in adult neurogenesis has been the subject of many studies (Henry et al., 2007; Chan et al., 2008; Vilar and Mira, 2016). BDNF is expressed in both SVZ and SGZ neurogenic niches (Galvão et al., 2008; Li et al., 2008) but its precise role in adult neurogenesis is still not consensual. In fact, some studies suggest that BDNF is important to positively regulate DG cell proliferation and survival (Chan et al., 2008; Li et al., 2008) while others report no BDNF-induced changes in DG neurogenesis (Choi et al., 2009). In SVZ, most studies depict that BDNF does not promote any significant changes in cell proliferation and survival (Henry et al., 2007; Galvão et al., 2008), despite having a role in the migration of SVZ-derived cells (Snapyan et al., 2009; Bagley and Belluscio, 2010). Despite the available contradictory data, BDNF, through TrkB signaling, was shown to have an essential role in the regulation of dendritic complexity as well as synaptic formation, maturation and plasticity of newborn neurons (Chan et al., 2008; Gao et al., 2009; Wang et al., 2015).

Besides expressing BDNF, NSPC present in the neurogenic niches were shown to express all the elements of the endocannabinoid system (Aguado et al., 2005; Arévalo-Martín et al., 2007), including the main cannabinoid receptors type 1 (CB1R) and type 2 (CB2R) receptors (Rodrigues et al., 2017). They are both present in the CNS, although CB2R expression is relatively higher in the immune system (Galve-Roperh et al., 2007). In recent years, the role of cannabinoids in neurogenesis has been of particular interest given their multiplicity of neuromodulatory functions (Mechoulam and Parker, 2013). Cannabinoid receptors modulate adult neurogenesis by acting at distinct neurogenic phases (Prenderville et al., 2015). Importantly, activation of type 1 (Xapelli et al., 2013) or type 2 cannabinoid receptors (Palazuelos et al., 2006) by selective agonists was found to regulate cell proliferation, neuronal differentiation and maturation (Rodrigues et al., 2017).

Several studies have provided molecular and functional evidence for a crosstalk between BDNF and endocannabinoid signaling (Maison et al., 2009; Zhao et al., 2015). Synergism between BDNF and CB1R has been observed both in vitro and in vivo (De Chiara et al., 2010; Galve-Roperh et al., 2013). In particular, BDNF was shown to regulate striatal CB1R actions (De Chiara et al., 2010). Moreover, evidence for BDNF-TrkB signaling interplay with CB1R has been shown to trigger endocannabinoid release at cortical excitatory synapses (Yeh et al., 2017). Importantly, genetic deletion of CB1R was shown to promote a decrease in BDNF expression (Aso et al., 2008) while induction of BDNF expression contributed to the protective effect of CB1R activity against excitotoxicity (Marsicano, 2003; Khaspekov et al., 2004). Moreover, CB1R activity can enhance TrkB signaling partly by activating MAP kinase/ERK kinase pathways (Derkinderen et al., 2003) but also by directly transactivating the TrkB receptors (Berghuis et al., 2005). Δ9-THC, the principal active component of cannabis, was shown to promote upregulation of BDNF expression (Butovsky et al., 2005) whereas increased levels of BDNF were shown to rescue the cognitive deficits promoted by Δ9-THC administration (Segal-Gavish et al., 2017). Interestingly, clinical data suggests that acute and chronic intermittent exposure to Δ9-THC alters BDNF serum levels in humans (D’Souza et al., 2009).

Given the evidence that BDNF and cannabinoid signaling can affect neurogenesis as well as the fact that BDNF may interact with cannabinoid receptors, we hypothesized that cannabinoid receptors could act together with BDNF signaling to fine-tune neurogenesis. We show for the first time that endogenous BDNF is crucial for the cannabinoid-mediated effects on SVZ and DG neurogenesis to happen. Moreover, we demonstrate that CB2R has a preponderant role in regulating some of the BDNF actions on neurogenesis. Taken together, our results suggest an important crosstalk between BDNF and cannabinoid signaling to modulate postnatal neurogenesis.

Discussion

The present work reveals a yet not described interaction between BDNF and cannabinoid receptors (CB1R and CB2R) responsible to modulate several aspects of SVZ and DG postnatal neurogenesis. BDNF was shown to be an important modulator of SVZ and DG postnatal neurogenesis, its actions being under control of cannabinoid receptors. The relevance of each cannabinoid receptor to control the action of BDNF upon neurogenesis is different in the two neurogenic niches. While CB2R has a preponderant role in modulating BDNF actions on DG, BDNF-mediated SVZ postnatal neurogenesis is modulated by both CB1R and CB2R. A constant and clear finding in both neurogenic niches is that BDNF is required for cannabinoid actions to occur. It thus appears that a reciprocal cross-talk between cannabinoids and BDNF exist to modulate postnatal neurogenesis.

BDNF is a neurotrophin important in the regulation of several neuronal processes such as neuronal branching, dendrite formation and synaptic plasticity (Dijkhuizen and Ghosh, 2005; Gómez-Palacio-Schjetnan and Escobar, 2013). In line with this evidence, several studies have shed light on the actions of BDNF in the survival and differentiation of newborn neurons (Benraiss et al., 2001; Henry et al., 2007; Chan et al., 2008; Snapyan et al., 2009). Our findings now demonstrate that BDNF is able to affect early steps of postnatal neurogenesis, such as cell-fate, cell proliferation and neuronal differentiation of SVZ and DG cultures. We observed that BDNF promoted self-renewal of SVZ- and DG-derived cells as observed by an increase in self-renewal divisions, i.e., an increase in the percentage of Sox2+/+ cell-pairs. BDNF-CBR crosstalk has been reported to control several processes at the synaptic level (Zhao and Levine, 2014; Zhong et al., 2015) and we now extended these findings toward very early stages of postnatal neurogenesis. Interestingly, the increase in the SVZ and DG pool of stem/progenitor cells mediated by BDNF was fully abolished in the presence of CB2R antagonist but not CB1R antagonist. An exception is the influence of BDNF upon SVZ cell proliferation, which is not affected by CB1R or CB2R selective antagonism. In what concerns neuronal differentiation, both CB1R and CB2R are required for BDNF actions on SVZ whereas at the DG, only CB2R seem to affect BDNF-promoted neuronal differentiation. Overall, cannabinoid receptor blockade appears to influence more BDNF-induced actions upon early stages of DG neurogenesis in comparison to SVZ, highlighting the fact that cannabinoids distinctly modulate the effects promoted by BDNF in SVZ and DG neurogenesis.

It was previously known that the endocannabinoid system and cannabinoid receptors are important modulators of several stages of neurogenesis (Palazuelos et al., 2012; Xapelli et al., 2013; Prenderville et al., 2015; Rodrigues et al., 2017). In accordance with our previous data, SVZ and DG cells were differently affected by the same cannabinoid pharmacological treatments (Rodrigues et al., 2017). Considering cell fate, we observed that selective activation of CB2R activation promotes self-renewal of DG cells, but not of SVZ cells. This is consistent with several pieces of evidence showing a regulation of cell fate promoted by the activation of several signaling pathways [such as mitogen-activated protein kinase (MAPK) family (ERK, JNK and p38) and the phosphoinositide-3 kinase (PI3K)/AKT pathways] triggered by CBR activation (Molina-Holgado et al., 2007; Gomez et al., 2010; Soltys et al., 2010; Compagnucci et al., 2013).

On the other hand, our results reveal, for the first time, a role of cannabinoid receptors (CB1R and CB2R) in regulating DG cell commitment.

Considering cell proliferation, it is promoted by CB1R but not CB2 at SVZ, while at DG cell proliferation was only induced by co-activation of CB1R and CB2R. These results are in accordance with previous reports that have shown an increase in SVZ cell proliferation promoted by CB1R selective activation (Trazzi et al., 2010; Xapelli et al., 2013) and an increase in DG cell proliferation triggered by CB1R/CB2R non-selective activation (Aguado et al., 2005; Rodrigues et al., 2017). Importantly, while we also detected an effect with the non-selective CB1R/CB2R agonists, none of the selective agonists when applied in the absence of the other agonist were effective to promote cell proliferation in the DG, highlighting the need of caution while interpreting negative results with each of those agonists separately.

Regarding neuronal differentiation, our data indicate that in SVZ and DG neurogenic niches both subtypes of cannabinoid receptors are able to promote neuronal differentiation. These data are in accordance with previous reports in which cannabinoid receptor activation enhanced neuronal differentiation of NSPC by CB1R- (Compagnucci et al., 2013) or CB2R-dependent (Avraham et al., 2014) mechanisms.

The most important finding in the present work is that most of the cannabinoid-induced effects upon cell proliferation and neuronal differentiation depend on the presence of BDNF, suggesting the existence of a BDNF-endocannabinoid feedback loop responsible for regulating these processes. Previous reports have shed light on the existence of a putative interaction between BDNF and cannabinoid receptors (Howlett et al., 2010), but none focused upon neurogenesis. De Chiara et al. (2010) have identified a novel mechanism by which BDNF mediates the regulation of striatal CB1R function. Moreover, others have suggested that BDNF can regulate neuronal sensitivity to endocannabinoids through a positive feedback loop important for the regulation of neuronal survival (Maison et al., 2009). Evidence also shows the involvement of BDNF in the actions mediated by cannabinoids against excitotoxicity (Khaspekov et al., 2004), in synaptic transmission and plasticity (Klug and van den Buuse, 2013; Zhao et al., 2015; Yeh et al., 2017) and in several behavioral outputs (Aso et al., 2008; Bennett et al., 2017). Previous animal studies have shown that acute (Derkinderen et al., 2003) and chronic (Butovsky et al., 2005) Δ9-THC (major psychoactive constituent of cannabis; CB1R and CB2R agonist) administration is associated with an increase in BDNF gene expression. Moreover, it was shown that overexpression of BDNF is able to rescue cognitive deficits promoted by Δ9-THC administration in a mouse model of schizophrenia (Segal-Gavish et al., 2017). In human studies it was found that Δ9-THC increased serum BDNF levels in healthy controls, but not in chronic cannabis users (D’Souza et al., 2009). In fact, cyclic AMP response element-binding protein (CREB) may be the common linking element because it is an important regulator of BDNF-induced gene expression (Finkbeiner et al., 1997), and has been reported to control several steps of the neurogenic process in the adult hippocampus (Nakagawa et al., 2002) and SVZ (Giachino et al., 2005). Consistently, cannabinoids have been shown to induce CREB phosphorylation (Isokawa, 2009) and also to promote changes in BDNF and CREB gene expression (Grigorenko et al., 2002). In addition, the work done by Berghuis et al. (2005) showed that endocannabinoids stimulate TrkB receptor phosphorylation during interneuron morphogenesis. Most importantly, in the same study, the authors observed by co-immunoprecipitation the formation of heteromeric complexes in PC12 cells expressing TrkB receptors and CB1R (Berghuis et al., 2005). Our study brings new and relevant information on the interaction between cannabinoid receptors and BDNF in controlling SVZ and DG neurogenesis, and clearly highlights that this interaction is reciprocal. In fact, neurogenesis promoted by cannabinoid receptor activation depends on the presence of endogenous BDNF, while the effects mediated by BDNF upon neurogenesis are directly regulated by modulation of CB1R or CB2R.

Although our study is based on an in vitro approach, the neurosphere assay, it represents a highly relevant model. In vitro systems of NSPC allow an easier access and better control of experimental variables as well as a thorough analysis of mechanisms happening at cellular and molecular level providing useful information to be further validated in vivo (Singec et al., 2006). Moreover, the heterogeneous composition of the NSPC grown in neurospheres is extremely relevant because it holds some of the features, such as close contact with neighboring cells (newly generated neuroblasts, astrocytes and oligodendrocytes), that resemble those of the physiological niche (Casarosa et al., 2014). These well-established advantages (Aguado et al., 2007; Agasse et al., 2008; Azari et al., 2010) are the reason why we have used this in vitro approach to study the intrinsic properties of NSPC and to understand the interaction between BDNF and cannabinoids in modulating neurogenesis. It is, however, important to mention that the mechanisms governing the regulation of neurosphere dynamics might be different from the ones regulating in vivo adult neurogenesis (Casarosa et al., 2014). Indeed, further in vivo studies will be required to comprehensively understand the role of BDNF in regulating the actions of cannabinoid receptors on postnatal neurogenesis.

Taken together, our data highlight a novel level of complexity for the regulatory mechanisms involved in NSPC dynamics, which involve the interplay of multiple signaling cues, and where BDNF and cannabinoids may play a relevant role. Further in vitro studies are required to detail the molecular mechanisms involved, as well as in vivo studies to determine the functional consequences of the BDNF/cannabinoid crosstalk to control neurogenesis. Nevertheless, our study provides evidence for the need of integrative strategies whenever focusing on NSPC for brain repair.

Cannabinoids for Medical Use

Posted by

0


Abstract

Importance  Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear.

Objective  To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids.

Data Sources  Twenty-eight databases from inception to April 2015.

Study Selection  Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome.

Data Extraction and Synthesis  Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis.

Main Outcomes and Measures  Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs.

Results  A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

Conclusions and Relevance  There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

Introduction

Cannabis is a generic term used for drugs produced from plants belonging to the genus Cannabis.1 It is one of the most popular recreational drugs; worldwide, an estimated 178 million people aged 15 to 64 years used cannabis at least once in 2012.2 Cannabis was included as a controlled drug in the United Nations’ Single Convention on Narcotic Drugs, held in 1961,3 and its use is illegal in most countries.

Medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. Cannabinoids can be administered orally, sublingually,or topically; they can be smoked, inhaled, mixed with food, or made into tea. They can be taken in herbal form, extracted naturally from the plant, gained by isomerisation of cannabidiol, or manufactured synthetically.4 Prescribed cannabinoids include dronabinol capsules, nabilone capsules, and the oromucosal spray nabiximols.4 Some countries have legalized medicinal-grade cannabis for chronically ill patients. Canada and the Netherlands have government-run programs in which specialized companies supply quality-controlled herbal cannabis.5 In the United States, 23 states and Washington, DC (May 2015), have introduced laws to permit the medical use of cannabis6; other countries have similar laws. The aim of this systematic review was to evaluate the evidence for the benefits and adverse events (AEs) of medical cannabinoids across a broad range of indications.

Methods

This review followed guidance published by the Centre for Reviews and Dissemination and the Cochrane Collaboration.7,8 We established a protocol for the review (eAppendix 1 in Supplement 1).

Study Eligibility Criteria

Randomized clinical trials (RCTs) that compared cannabinoids with usual care, placebo, or no treatment in the following indications were eligible: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis (MS) or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, intraocular pressure in glaucoma, or Tourette syndrome. These indications were prespecified by the project funders, the Swiss Federal Office of Public Health. If no RCTs were available for a particular indication or outcome (eg, long-term AEs such as cancer, psychosis, depression, or suicide), nonrandomized studies including uncontrolled studies (such as case series) with at least 25 patients were eligible.

Identification and Selection of Studies

Twenty-eight databases and gray literature sources were searched from inception to April 2015 without language restriction (Embase search strategy and details of databases searched available in eAppendix 2 in Supplement 2). The search strategy was peer reviewed9 by a second information specialist. Reference lists of included studies were screened. Search results and full-text articles were independently assessed by 2 reviewers; disagreements were resolved through consensus or referral to a third reviewer.

Data Collection and Study Appraisal

We extracted data about baseline characteristics and outcomes (patient-relevant and disease-specific outcomes, activities of daily living, quality of life, global impression of change, and specified AEs). For dichotomous data such as number of patients with at least 30% improvement in pain, we calculated the odds ratio (OR) and 95% CI. For categorical data, we extracted details about each category assessed and the numbers of patients with an outcome in each category. Continuous data such as the Ashworth spasticity score10 were extracted as means and SDs at baseline, follow-up, and the change from baseline and used to calculate mean differences with 95% CIs. Results (mean difference, 95% CIs, and P values) from the between-group statistical analyses reported by the study were also extracted. All relevant sources were used for data extraction including full-text journal articles, abstracts, and clinical trial registry entries. Where available, the journal article was used as the primary publication because it had been peer reviewed.

RCTs were assessed for methodological quality using the Cochrane Risk of Bias tool.11 If at least one of the domains was rated as high, the trial was considered at high risk of bias. If all domains were judged as low, the trial was considered at low risk of bias. Otherwise, the trial was considered as having unclear risk of bias. Data extraction and risk-of-bias assessment were performed independently by 2 reviewers; disagreements were resolved by a third reviewer.

Synthesis

Clinical heterogeneity was assessed by grouping studies by indication, cannabinoid, and outcome. If there were 2 or more trials within a single grouping, data were pooled using random-effects meta-analysis.12 For continuous outcomes, we analyzed the mean difference in change from baseline; if this was not reported and could not be calculated from other data, we used the mean difference at follow-up.13 For dichotomous data, we used the OR. In order to avoid double counting, we selected a single data set from each study to contribute to the analysis. For studies evaluating multiple interventions, we selected the intervention or dose that was most similar to the other interventions being evaluated in the same analysis. Heterogeneity was investigated using forest plots and the I2 statistic. Where data were considered too heterogeneous to pool or not reported in a format suitable for pooling (eg, data reported as medians), we used a narrative synthesis.

Sensitivity analyses were used to assess the statistical effect of trial design. The primary analysis included only parallel-group trials, results from crossover trials were included in an additional analysis. For the analysis of AEs, data for all conditions were combined. We conducted stratified analyses and meta-regression to investigate whether associations varied according to type of cannabinoid, study design (parallel group vs crossover trial), indication (each of the indication categories included in this report), comparator (active vs placebo), and duration of follow-up (<24 hours, 24 hours-1 week, >1 week-4 weeks, >4 weeks) for the outcome of any AE. Statistical analyses were performed using Stata statistical software (version 10).

GRADE (Grading of Recommendations Assessment, Development and Evaluation) was used to rate the overall quality of the evidence for risk of bias, publication bias, imprecision, inconsistency, indirectness, and magnitude of effect. The GRADE ratings of very low–, low-, moderate-, or high-quality evidence reflect the extent to which we are confident that the effect estimates are correct.14

Results

The searches identified 23 754 hits (records) of which 505 were considered potentially relevant, based on title and abstract screening, and obtained as full-text studies. A total of 79 studies (6462 participants), available as 151 reports, were included; 3 studies (6 reports) were included in multiple indication categories (Figure 1). Thirty-four studies were parallel-group trials (4436 participants), and 45 were crossover trials (2026 participants). Four studies were available only as an abstract,15–18 a further 3 were available only as abstracts19–21 but with additional details available on trial registries including full results in one,19 and details of 2 trials (including full trial results) were available only as trial registry entries22,23; all other trials were reported in full-length journal articles. Where reported, the proportion of participants who were men ranged from 0% to 100% (median, 50% [57 studies]), and the proportion of white participants ranged from 50% to 99% (median, 78% [18 studies]). Publication dates ranged from 1975 to 2015 (median, 2004 [with one-third of trials published before 1990]). Studies were conducted in a wide range of countries. A variety of cannabinoids were evaluated and compared with various different active comparators or placebos; most active comparators were included in the nausea and vomiting indication (Table 1). eAppendices 3 to 12 in Supplement 1 provide an overview of the included studies and their findings.

Four (5%) trials were judged at low risk of bias, 55 (70%) were judged at high risk of bias, and 20 (25%) at unclear risk of bias (eAppendix 13 in Supplement 2). The major potential source of bias in the trials was incomplete outcome data. More than 50% of trials reported substantial withdrawals and did not adequately account for this in the analysis. Selective outcome reporting was a potential risk of bias in 16% of trials. These studies did not report data for all outcomes specified in the trial register, protocol, or methods section or changed the primary outcome from that which was prespecified. Most studies reported being double-blinded but only 57% reported that appropriate methods had been used for participant blinding and only 24% reported that outcome assessors had been appropriately blinded.

Full results from included studies are presented in eAppendices 3-12 in Supplement 2; pooled results and GRADE ratings are presented in Table 2.

Nausea and Vomiting Due to Chemotherapy

Nausea and vomiting due to chemotherapy was assessed in 28 studies (37 reports; 1772 participants).15,16,24–58 Fourteen studies assessed nabilone and there were 3 for dronabinol, 1 for nabiximols, 4 for levonantradol, and 6 for THC. Two studies also included a combination therapy group of dronabinol with ondansetron or prochlorperazine. Eight studies included a placebo control, 3 of these also included an active comparator, and 20 studies included only an active comparator. The most common active comparators were prochlorperazine (15 studies), chlorpromazine (2 studies) and domperidone (2 studies). Other comparators (alizapride, hydroxyzine, metoclopramide and ondansetron) were evaluated in single studies (Table 1). Of all 28 studies, risk of bias was high for 23 or unclear for 5. All studies suggested a greater benefit of cannabinoids compared with both active comparators and placebo, but these did not reach statistical significance in all studies. The average number of patients showing a complete nausea and vomiting response was greater with cannabinoids (dronabinol or nabiximols) than placebo (OR, 3.82 [95% CI, 1.55-9.42]; 3 trials). There was no evidence of heterogeneity for this analysis (I2 = 0%) and results were similar for both dronabinol and nabiximols.

Appetite Stimulation in HIV/AIDS Infection

Appetite stimulation in HIV/AIDS was assessed in 4 studies (4 reports; 255 participants).59–62 All studies assessed dronabinol, 3 compared with placebo (1 of which also assessed marijuana), and 1 compared with megastrol acetate. All studies were at high risk of bias. There was some evidence that dronabinol is associated with an increase in weight when compared with placebo. More limited evidence suggested that it may also be associated with increased appetite, greater percentage of body fat, reduced nausea, and improved functional status. However, these outcomes were mostly assessed in single studies and associations failed to reach statistical significance. The trial that evaluated marijuana and dronabinol found significantly greater weight gain with both forms of cannabinoid when compared with placebo.59 The active comparison trial found that megastrol acetate was associated with greater weight gain than dronabinol and that combining dronabinol with megastrol acetate did not lead to additional weight gain.60

Chronic Pain

Chronic pain was assessed in 28 studies (63 reports; 2454 participants).19,20,22,23,63–120 Thirteen studies evaluated nabiximols, 4 were for smoked THC, 5 for nabilone, 3 for THC oromucosal spray, 2 dronabinol, 1 vaporized cannabis (included 2 doses), 1 for ajuvenic acid capsules, and 1 for oral THC. One trial compared nabilone with amitriptyline64; all other studies were placebo controlled. One of these studies evaluated nabilone as an adjunctive treatment to gabapentin.121 The conditions causing the chronic pain varied between studies and included neuropathic pain (central, peripheral, or not specified; 12 studies), 3 for cancer pain, 3 for diabetic peripheral neuropathy, 2 for fibromyalgia, 2 for HIV-associated sensory neuropathy, and 1 study for each of the following indications: refractory pain due to MS or other neurological conditions, for rheumatoid arthritis, for noncancer pain (nociceptive and neuropathic), central pain (not specified further), musculoskeletal problems, and chemotherapy-induced pain.

Two studies were at low risk of bias, 9 at unclear risk, and 17 at high risk of bias. Studies generally suggested improvements in pain measures associated with cannabinoids but these did not reach statistical significance in most individual studies.

The average number of patients who reported a reduction in pain of at least 30% was greater with cannabinoids than with placebo (OR, 1.41 [95% CI, 0.99-2.00]; 8 trials; Figure 2). One trial assessed smoked THC77 and reported the greatest beneficial effect (OR, 3.43 [95% CI, 1.03-11.48]), and 7 trials assessed nabiximols (Figure 2). Pain conditions evaluated in these trials were neuropathic pain (OR, 1.38 [95% CI, 0.93-2.03]; 6 trials) and cancer pain (OR, 1.41 [95% CI, 0.99-2.00]; 2 trials), with no clear differences between pain conditions. Nabiximols was also associated with a greater average reduction in the Numerical Rating Scale (NRS; 0-10 scale) assessment of pain (weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), brief pain inventory-short form, severity composite index (WMD, −0.17 [95% CI, −0.50 to 0.16]; 3 trials), neuropathic pain scale (WMD, −3.89 [95% CI, −7.32 to −0.47]; 5 trials), and the proportion of patients reporting improvement on a global impression of change score (OR, 2.08 [95% CI, 1.21 to 3.59]; 6 trials) compared with placebo. There was some evidence to support this based on continuous data but this was not consistent across trials. There was no difference in average quality-of-life scores as measured by the EQ-5D health status index (WMD, −0.01 [95% CI, −0.05 to 0.02]; 3 trials) between nabiximols and placebo. Two of the studies included in the meta-analysis for the NRS (0-10 scale) assessed patients with cancer pain, all other studies assessed patients with neuropathic pain. There were no clear differences based on cause of pain in the meta-analysis of NRS. Sensitivity analyses that included crossover trials showed results consistent with those based on parallel-group trials alone.

Spasticity Due to MS or Paraplegia

Fourteen studies (33 reports; 2280 participants) assessed spasticity due to MS or paraplegia.17,19,65,87,91,122–149 Eleven studies (2138 participants) included patients with MS and 3 included patients with paraplegia (142 participants) caused by spinal cord injury. Six studies assessed nabiximols, 3 for dronabinol, 1 for nabilone, 4 for THC/CBD (2 of these also assessed dronabinol), and 1 each for ECP002A and smoked THC. All studies included a placebo control group; none included an active comparator. Two studies were at low risk of bias, 5 were at unclear risk of bias, and 7 were at high risk of bias. Studies generally suggested that cannabinoids were associated with improvements in spasticity, but this failed to reach statistical significance in most studies. There were no clear differences based on type of cannabinoid. Only studies in MS patients reported sufficient data to allow summary estimates to be generated. Cannabinoids (nabiximols, dronabinol, and THC/CBD) were associated with a greater average improvement on the Ashworth scale for spasticity compared with placebo, although this did not reach statistical significance (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials; Figure 3). Cannabinoids (nabilone and nabiximols) were also associated with a greater average improvement in spasticity assessed using numerical rating scales (mean difference, −0.76 [95% CI, −1.38 to −0.14]; 3 trials). There was no evidence of a difference in association according to type of cannabinoid for either analysis. Other measures of spasticity also suggested a greater benefit of cannabinoid but did not reach statistical significance (Table 2). The average number of patients who reported an improvement on a global impression of change score was also greater with nabiximols than placebo (OR, 1.44 [95% CI, 1.07 to 1.94]; 3 trials); this was supported by a further crossover trial of dronabinol and oral THC/CBD that provided continuous data for this outcome.132 Sensitivity analyses that included crossover trials showed results consistent with those based on parallel group trials alone.

Depression

No studies evaluating cannabinoids for the treatment of depression fulfilled inclusion criteria. Five studies included for other indications reported depression as an outcome measure; 4 evaluated chronic pain and 1 evaluated spasticity in MS patients.67,73,75,80,129 One trial assessed dronabinol (2 doses), 3 assessed nabiximols, and 1 assessed nabilone. Two studies were rated as having unclear risk of bias and 3 as having high risk of bias. Three studies suggested no difference between cannabinoids (dronabinol and nabiximols) and placebo in depression outcomes. One parallel-group trial that compared different doses of nabiximols with placebo reported a negative effect of nabiximols for the highest dose (11-14 sprays per day) compared with placebo (mean difference from baseline, 2.50 [95% CI, 0.38 to 4.62]) but no difference between placebo and the 2 lower doses.67

Anxiety Disorder

One small parallel-group trial, judged at high risk of bias, evaluated patients with generalized social anxiety disorder.150 The trial reported that cannabidiol was associated with a greater improvement on the anxiety factor of a visual analogue mood scale (mean difference from baseline, −16.52; P value = .01)compared with placebo during a simulated public speaking test. Additional data about anxiety outcomes provided by 4 studies (1 parallel group) in patients with chronic pain also suggested a greater benefit of cannabinoids (dronabinol, nabilone, and nabiximols) than placebo but these studies were not restricted to patients with anxiety disorders.73–75,80

Sleep Disorder

Two studies (5 reports; 54 participants) evaluated cannabinoids (nabilone) specifically for the treatment of sleep problems. One was a parallel-group trial judged at high risk of bias. This reported a a greater benefit of nabilone compared with placebo on the sleep apnea/hypopnea index (mean difference from baseline, −19.64; P value = .02). The other was a crossover trial judged at low risk of bias in patients with fibromyalgia and compared nabilone with amitriptyline. This suggested that nabilone was associated with improvements in insomnia (mean difference from baseline, −3.25 [95% CI, −5.26 to −1.24]) and with greater sleep restfulness (mean difference from baseline, 0.48 [95% CI, 0.01 to 0.95]). Nineteen placebo-controlled studies included for other indications (chronic pain and MS) also evaluated sleep as an outcome.22,23,65,67–69,75,76,79–81,87,88,123–125,129–131 Thirteen studies assessed nabiximols, 1 for nabilone, 1 for dronabinol, 2 for THC/CBD capsules, and two assessed smoked THC (one at various doses). Two of the studies that assessed nabiximols also assessed oral THC and the trial of dronabinol also assessed oral THC/CBD. There was some evidence that cannabinoids may improve sleep in these patient groups. Cannabinoids (mainly nabiximols) were associated with a greater average improvement in sleep quality (WMD, −0.58 [95% CI, −0.87 to −0.29]; 8 trials) and sleep disturbance (WMD, −0.26 [95% CI, −0.52 to 0.00]; 3 trials). One trial assessed THC/CBD, all others assessed nabiximols, results were similar for both cannabinoids.

Psychosis

Psychosis was assessed in 2 studies (9 reports; 71 participants) judged at high risk of bias, which evaluated cannabidiol compared with amisulpride or placebo.21,151–158 The trials found no difference in mental health outcomes between treatment groups.

Glaucoma

One very small crossover trial (6 participants)159 judged at unclear risk of bias compared tetrahydrocannabinol (THC; 5 mg), cannabidiol (20 mg), cannabidiol (40 mg) oromucosal spray, and placebo. This trial found no difference between placebo and cannabinoids on measures of intraocular pressure in patients with glaucoma.

Movement Disorders Due to Tourette Syndrome

Two small placebo-controlled studies (4 reports; 36 participants)160–163 suggested that THC capsules may be associated with a significant improvement in tic severity in patients with Tourette syndrome.

Adverse Events

Data about AEs were reported in 62 studies (127 reports). Meta-regression and stratified analysis showed no evidence for a difference in the association of cannabinoids with the incidence of “any AE” based on type of cannabinoid, study design, indication, comparator, or duration of follow-up15,16,18,22–26,28–31,33–38,41,42,44–47,51,57,58,60,62,64–69,72–85,87,88,123–127,129–131,159,160,162; further analyses were conducted for all studies combined. Figure 4 shows the results of the meta-analyses for the number of participants experiencing any AE compared when compared with controls, stratified according to cannabinoid. Cannabinoids were associated with a much greater risk of any AE, serious AE, withdrawals due to AE, and a number of specific AEs (Table 3). No studies evaluating the long-term AEs of cannabinoids were identified, even when searches were extended to lower levels of evidence.

Discussion

We conducted an extensive systematic review of the benefits and AEs associated with medical cannabinoids across a broad range of conditions. We included 79 RCTs (6462 participants), the majority of which evaluated nausea and vomiting due to chemotherapy or chronic pain and spasticity due to MS and paraplegia. Other patient categories were evaluated in fewer than 5 studies.

Most studies suggested that cannabinoids were associated with improvements in symptoms, but these associations did not reach statistical significance in all studies. Based on the GRADE approach, there was moderate-quality evidence to suggest that cannabinoids may be beneficial for the treatment of chronic neuropathic or cancer pain (smoked THC and nabiximols) and spasticity due to MS (nabiximols, nabilone, THC/CBD capsules, and dronabinol). There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy (dronabinol and nabiximols), weight gain in HIV (dronabinol), sleep disorders (nabilone, nabiximols), and Tourette syndrome (THC capsules); and very low-quality evidence for an improvement in anxiety as assessed by a public speaking test (cannabidiol). There was low-quality evidence for no effect on psychosis (cannabidiol) and very low-level evidence for no effect on depression (nabiximols). There was an increased risk of short-term AEs with cannabinoid use, including serious AEs. Common AEs included asthenia, balance problems, confusion, dizziness, disorientation, diarrhea, euphoria, drowsiness, dry mouth, fatigue, hallucination, nausea, somnolence, and vomiting. There was no clear evidence for a difference in association (either beneficial or harmful) based on type of cannabinoids or mode of administration. Only 2 studies evaluated cannabis.59,77 There was no evidence that the effects of cannabis differed from other cannabinoids.

Understanding the many benefits of cannabis in cancer treatment

Posted by

0


Image: Understanding the many benefits of cannabis in cancer treatment

A cancer diagnosis is both devastating and terrifying. Patients are almost always directed towards conventional cancer treatments like surgery, chemotherapy and radiation, and are made to feel that any other, more “natural” treatments are not only ineffective but dangerous.

The truth is, however, that mainstream cancer treatments wreak havoc on the body, leaving it defenseless against disease and breaking it down at the exact time when it needs to be as strong as possible. With its less than impressive success rate of between 2 and 4 percent, along with its devastating effects on the body, it is unsurprising that three out of every four doctors say they would refuse chemotherapy as a treatment option if they themselves became ill.

While doctors like to promote the idea that there are no treatments scientifically proven to work besides the usual surgery/chemotherapy/radiation regimen, the truth is there is a strong body of evidence that many natural, non-invasive treatments are effective in the fight against cancer. One of the most well-researched and solidly proven of all these natural medicines is cannabis.

The miraculous power of cannabinoids

As noted by Dr. Mark Sircus, writing for Green Med Info, there is no confusion about whether marijuana is an effective cancer treatment. Cannabis has been scientifically proven to kill cancer cells without the devastating and body weakening effects of conventional cancer treatments.

The marijuana plant contains about 113 powerful chemical compounds known as cannabinoids. The most well-known of these compounds are tetrahydrocannabinol (THC) – the chemical that induces marijuana’s “high” – and cannabidiol – a non-psychoactive compound which has been extensively studied as a cure for many diseases.

The power of the elements: Discover Colloidal Silver Mouthwash with quality, natural ingredients like Sangre de Drago sap, black walnut hulls, menthol crystals and more. Zero artificial sweeteners, colors or alcohol. Learn more at the Health Ranger Store and help support this news site.

These and other cannabinoids are what make marijuana such a potent anti-cancer treatment, as reported by Green Med Info:

Cannabinoids are found to exert their anti-cancer effects in a number of ways and in a variety of tissues.

  • Triggering cell death, through a mechanism called apoptosis
  • Stopping cells from dividing
  • Preventing new blood vessels from growing into tumors
  • Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighboring tissue
  • Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

All these effects are thought to be caused by cannabinoids locking onto the CB1 and CB2 cannabinoid receptors. Almost daily we are seeing new or confirming evidence that Cannibinoids can be used to great benefit in cancer treatment of many types.

https://www.brighteon.com/embed/5849729304001

What the science says

Scientific studies published in a host of peer-reviewed journals have confirmed marijuana’s powerful ability to fight breast, lung, ovarian, pancreatic, prostate and other cancers.

A meta-analysis of over 100 published studies, performed by researchers from Germany’s Rostock University Medical Centre, concluded that cannabis both boosts immunity and fights cancer.

The Daily Mail reported:

Scientists are calling for more studies to be done on humans after studying the cancer-fighting effects of chemicals in the drug.

Studies suggest chemicals called phytocannabinoids could stop cancer cells multiplying and spreading, block the blood supply to tumors, and reduce cancer’s ability to survive chemotherapy. …

The new research review admits cannabis has ‘anti-cancer effects’ and says more research needs to be done in real patients to confirm the findings.

It takes real courage to receive a cancer diagnosis and decide not to follow mainstream advice but seek alternative treatments. But even for those who choose to receive conventional cancer treatments like radiation and chemotherapy, cannabis can still be an important part of their overall wellness plan. As Dr. Sircus admonishes, “Every cancer patient and every oncologist should put medical marijuana on their treatment maps.”

The influence of cannabinoids on generic traits of neurodegeneration

Posted by

0


Abstract

In an increasingly ageing population, the incidence of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are rising. While the aetiologies of these disorders are different, a number of common mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support. Current therapies focus on treatment of the symptoms and attempt to delay the progression of these diseases but there is currently no cure. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB1 and CB2 receptors are known to be involved in the regulation of Ca2+ homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPARγ, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment.

Introduction

Neurodegeneration is the culmination of progressive loss of structure and function in neuronal cells, resulting in severe neuronal death. The widespread prevalence of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), and the lack of effective treatments, pose a significant social and economic burden (Brookmeyer et al., 2007; Zuccato et al., 2010; Taylor et al., 2013). Age remains the highest risk factor for these diseases and with a degree of neurodegeneration also occurring during normal ageing the threat to the quality of life and health of the global population is ever present (Marchalant et al., 2009). Although neurodegenerative diseases are a heterogeneous group of disorders, current research has identified a number of common underlying mechanisms namely protein misfolding, neuroinflammation, excitotoxicity and oxidative stress. These triggers are known to contribute to the progression of symptoms, functional alteration and microanatomical deficits found in neurodegenerative states.

Inflammation within the CNS is centred around the activation of the resident immune cells, the microglia (Akiyama et al., 2000; Taylor et al., 2013). Maintained in a quiescent state and associated with the production of neurotrophic and anti-inflammatory factors, microglia become activated by the recognition of highly conserved structural motifs on either pathogens (pathogen associated molecular patterns; PAMPs) or from damaged or stressed cells (damage associated molecular patterns; DAMPs) (Arroyo et al., 2011). The binding of PAMPs or DAMPS to pattern-recognition receptors, such as the Toll-like receptors (TLR) or receptors for advanced glycation end-products (RAGE), cause the migration of microglia followed by the synthesis and release of proinflammatory cytokines and reactive oxygen species (ROS) (Yan et al., 1996; Arroyo et al., 2011). Oxidative stress is a cytotoxic condition brought on by the increased intracellular production or accumulation of ROS and reactive nitrogen species (RNS) (Taylor et al., 2013). ROS are normal products of the mitochondrial respiratory chain but activated microglia generate excessive amounts as a result of intracellular peroxidases, oxidative processes and NADPH oxidase activity (Block and Hong, 2007). Regulation of ROS and RNS is vital to cell survival as their increased production leads to the damage of proteins, lipids, carbohydrates and nucleic acids resulting in significant disruption of cellular function (Mehta et al., 2013). Furthermore, oxidative stress can lead to the activation of the mitochondrial permeability transition pore causing the collapse of the trans-membrane electrochemical gradient and the release of proapoptotic factors like cytochrome c, procaspases and caspase activated DNase (Emerit et al., 2004). Excitotoxicity is the pathological process of damaging and killing neuronal cells as a result of excessive stimulation of ionotrophic receptors by glutamate and similar substances (Mehta et al., 2013). This process leads to impairment of intracellular Ca2+ buffering, generation of ROS and RNS, activation of the mitochondrial permeability transition pore and secondary excitotoxicity (Dong et al., 2009). In an attempt to reduce the intracellular Ca2+ load, neurons expend considerable energy using ion pumps on the endoplasmic reticulum, plasma membrane and mitochondria, reducing ATP levels and causing excitotoxic lesions (Beal, 2000). Activation of the proapoptotic cascade is associated with a number of insults such as generation of ROS/RNS, mitochondrial dysfunction, excitotoxicity and trophic factor withdrawal. This process depends upon initiator and effector caspases which cause DNA cleavage, proteolytic cascades and mitochondrial permeability resulting in the release of proapoptotic factors such as cytochrome c and DIABLO (Bredesen et al., 2006). A dynamic interplay between these neurodegenerative processes has been reported in AD, PD and HD and is the focus of many prospective therapeutic agents (Bredesen et al., 2006; Lin and Beal, 2006). Decreased neurogenesis and neurotrophic support has also emerged as a common characteristic in neurodegenerative states often presenting early in disease progression (Simuni and Sethi, 2008). Genes which have been identified as problematic in neurodegenerative disorders such as those for α-synuclein, presenilin 1, tau and huntingtin are also involved in brain plasticity and their aberrant aggregation is detrimental to adult neurogenesis (Winner et al., 2011).

The endogenous cannabinoid (eCB) system

The eCB system is composed of the endocannabinoid signalling molecules, 2-arachidonoyl glycerol (2AG) and anandamide (AEA) and their G-protein coupled cannabinoid CB1 and CB2 receptors (Piomelli, 2003: receptor nomenclature follows Alexander et al., 2013). Endocannabinoid signalling molecules are synthesized in the post-synaptic terminal as a result of depolarization and work in a retrograde fashion on presynaptic CB receptors. The primary pathway through which AEA is synthesized involves the Ca2+-dependent cleavage of its membrane precursor N-arachidonoyl phosphatidylethanolamine by phospholipase D (Di Marzo et al., 1994). In most cases, 2AG is synthesized by the hydrolysis of two sn-1 diacylglycerol lipase isozymes, diacylglycerol lipase-α (DGLα) and diacylglycerol lipase-β (DGLβ) (Bisogno et al., 2003). The CB1 receptor is highly expressed in the CNS at the terminals of central and peripheral neurons where they regulate neurotransmitter release and psychoactivity (Sanchez and Garcia-Merino, 2012). CB2 receptor expression is associated with the peripheral immune system, neurons within the brainstem and microglia during neuroinflammation (Van Sickle et al., 2005; Nunez et al., 2008). CB1 and CB2 receptors have also been associated with postnatal oligodendrogenesis. CB1 activation increases the number of glial precursors in the subventricular zone of postnatal rats while CB2 activation increases polysialylated neural cell adhesion molecule expression which is necessary for the migration of oligodendrocyte precursors (Arevalo-Martin et al., 2007). CB receptors act via the Gi or Go protein to stimulate the MAPK pathway and inhibit adenylate cyclase, attenuating the conversion of ATP to cyclic AMP (Howlett et al., 2002). CB receptor activation is also tightly linked to ion channel regulation through inhibition of voltage-dependent Ca2+ channels and activation of K+ channels (Mackie et al., 1993; Deadwyler et al., 1995; Hampson et al., 2000). The TRPV1 receptor is also activated by the endocannabinoid AEA and has been linked to its anti-inflammatory actions (Zygmunt et al., 1999). Degradation of endocannabinoids is carried out by two enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) which act upon AEA and 2AG respectively (Cravatt et al., 1996; Ben-Shabat et al., 1998). A number of exogenous ligands to CB receptors are also known such as the phytocannabinoids derived from the Cannabis sativa plant as well as synthetic CB1/CB2 agonists and antagonists. Manipulation of the eCB system has also been carried out by the inhibition of endocannabinoid biosynthesis, membrane transport and degradation (Bisogno et al., 2005). The eCB system has been identified as a possible therapeutic target against neurodegeneration as a number of alterations in the eCB system have been noted in AD, PD and HD, as discussed below ( Figure 1).

Introduction

Neurodegeneration is the culmination of progressive loss of structure and function in neuronal cells, resulting in severe neuronal death. The widespread prevalence of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), and the lack of effective treatments, pose a significant social and economic burden (Brookmeyer et al., 2007; Zuccato et al., 2010; Taylor et al., 2013). Age remains the highest risk factor for these diseases and with a degree of neurodegeneration also occurring during normal ageing the threat to the quality of life and health of the global population is ever present (Marchalant et al., 2009). Although neurodegenerative diseases are a heterogeneous group of disorders, current research has identified a number of common underlying mechanisms namely protein misfolding, neuroinflammation, excitotoxicity and oxidative stress. These triggers are known to contribute to the progression of symptoms, functional alteration and microanatomical deficits found in neurodegenerative states.

Inflammation within the CNS is centred around the activation of the resident immune cells, the microglia (Akiyama et al., 2000; Taylor et al., 2013). Maintained in a quiescent state and associated with the production of neurotrophic and anti-inflammatory factors, microglia become activated by the recognition of highly conserved structural motifs on either pathogens (pathogen associated molecular patterns; PAMPs) or from damaged or stressed cells (damage associated molecular patterns; DAMPs) (Arroyo et al., 2011). The binding of PAMPs or DAMPS to pattern-recognition receptors, such as the Toll-like receptors (TLR) or receptors for advanced glycation end-products (RAGE), cause the migration of microglia followed by the synthesis and release of proinflammatory cytokines and reactive oxygen species (ROS) (Yan et al., 1996; Arroyo et al., 2011). Oxidative stress is a cytotoxic condition brought on by the increased intracellular production or accumulation of ROS and reactive nitrogen species (RNS) (Taylor et al., 2013). ROS are normal products of the mitochondrial respiratory chain but activated microglia generate excessive amounts as a result of intracellular peroxidases, oxidative processes and NADPH oxidase activity (Block and Hong, 2007). Regulation of ROS and RNS is vital to cell survival as their increased production leads to the damage of proteins, lipids, carbohydrates and nucleic acids resulting in significant disruption of cellular function (Mehta et al., 2013). Furthermore, oxidative stress can lead to the activation of the mitochondrial permeability transition pore causing the collapse of the trans-membrane electrochemical gradient and the release of proapoptotic factors like cytochrome c, procaspases and caspase activated DNase (Emerit et al., 2004). Excitotoxicity is the pathological process of damaging and killing neuronal cells as a result of excessive stimulation of ionotrophic receptors by glutamate and similar substances (Mehta et al., 2013). This process leads to impairment of intracellular Ca2+ buffering, generation of ROS and RNS, activation of the mitochondrial permeability transition pore and secondary excitotoxicity (Dong et al., 2009). In an attempt to reduce the intracellular Ca2+ load, neurons expend considerable energy using ion pumps on the endoplasmic reticulum, plasma membrane and mitochondria, reducing ATP levels and causing excitotoxic lesions (Beal, 2000). Activation of the proapoptotic cascade is associated with a number of insults such as generation of ROS/RNS, mitochondrial dysfunction, excitotoxicity and trophic factor withdrawal. This process depends upon initiator and effector caspases which cause DNA cleavage, proteolytic cascades and mitochondrial permeability resulting in the release of proapoptotic factors such as cytochrome c and DIABLO (Bredesen et al., 2006). A dynamic interplay between these neurodegenerative processes has been reported in AD, PD and HD and is the focus of many prospective therapeutic agents (Bredesen et al., 2006; Lin and Beal, 2006). Decreased neurogenesis and neurotrophic support has also emerged as a common characteristic in neurodegenerative states often presenting early in disease progression (Simuni and Sethi, 2008). Genes which have been identified as problematic in neurodegenerative disorders such as those for α-synuclein, presenilin 1, tau and huntingtin are also involved in brain plasticity and their aberrant aggregation is detrimental to adult neurogenesis (Winner et al., 2011).

The endogenous cannabinoid (eCB) system

The eCB system is composed of the endocannabinoid signalling molecules, 2-arachidonoyl glycerol (2AG) and anandamide (AEA) and their G-protein coupled cannabinoid CB1 and CB2 receptors (Piomelli, 2003: receptor nomenclature follows Alexander et al., 2013). Endocannabinoid signalling molecules are synthesized in the post-synaptic terminal as a result of depolarization and work in a retrograde fashion on presynaptic CB receptors. The primary pathway through which AEA is synthesized involves the Ca2+-dependent cleavage of its membrane precursor N-arachidonoyl phosphatidylethanolamine by phospholipase D (Di Marzo et al., 1994). In most cases, 2AG is synthesized by the hydrolysis of two sn-1 diacylglycerol lipase isozymes, diacylglycerol lipase-α (DGLα) and diacylglycerol lipase-β (DGLβ) (Bisogno et al., 2003). The CB1 receptor is highly expressed in the CNS at the terminals of central and peripheral neurons where they regulate neurotransmitter release and psychoactivity (Sanchez and Garcia-Merino, 2012). CB2 receptor expression is associated with the peripheral immune system, neurons within the brainstem and microglia during neuroinflammation (Van Sickle et al., 2005; Nunez et al., 2008). CB1 and CB2 receptors have also been associated with postnatal oligodendrogenesis. CB1 activation increases the number of glial precursors in the subventricular zone of postnatal rats while CB2 activation increases polysialylated neural cell adhesion molecule expression which is necessary for the migration of oligodendrocyte precursors (Arevalo-Martin et al., 2007). CB receptors act via the Gi or Go protein to stimulate the MAPK pathway and inhibit adenylate cyclase, attenuating the conversion of ATP to cyclic AMP (Howlett et al., 2002). CB receptor activation is also tightly linked to ion channel regulation through inhibition of voltage-dependent Ca2+ channels and activation of K+ channels (Mackie et al., 1993; Deadwyler et al., 1995; Hampson et al., 2000). The TRPV1 receptor is also activated by the endocannabinoid AEA and has been linked to its anti-inflammatory actions (Zygmunt et al., 1999). Degradation of endocannabinoids is carried out by two enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) which act upon AEA and 2AG respectively (Cravatt et al., 1996; Ben-Shabat et al., 1998). A number of exogenous ligands to CB receptors are also known such as the phytocannabinoids derived from the Cannabis sativa plant as well as synthetic CB1/CB2 agonists and antagonists. Manipulation of the eCB system has also been carried out by the inhibition of endocannabinoid biosynthesis, membrane transport and degradation (Bisogno et al., 2005). The eCB system has been identified as a possible therapeutic target against neurodegeneration as a number of alterations in the eCB system have been noted in AD, PD and HD, as discussed below.

Alzheimer’s disease

AD is a progressive age-related neurodegenerative disorder that affects over 26 million people worldwide (Brookmeyer et al., 2007). It is estimated that 10% of people over 65 and 25% of people over 80 years of age are afflicted by this debilitating disease, and that number is set to rise to 1 in every 85 people by 2050 (Hebert et al., 2003; Brookmeyer et al., 2007). AD is defined by the progressive deterioration of cognition and memory and is the most common form of dementia among the elderly (Minati et al., 2009). The characteristic hallmarks of AD include the formation of neuritic plaques, containing aggregated forms of the amyloid-β (Aβ) peptide and dystrophic neurites, and neurofibrillary tangles caused by the hyperphosphorylation of the microtubule associated protein, tau, resulting in severe neurodegeneration.

Over the past two decades, neuroinflammation has emerged as an integral process in the pathogenesis of AD. Post-mortem analysis of the brains of AD patients has revealed an increase in the amount of activated microglia and astrocytes as well as a significantly higher levels of proinflammatory cytokines, IL-1, IL-6 and TNF-α and ROS (Akiyama et al., 2000; Rojo et al., 2008). Furthermore, clinical studies have identified a positive correlation between TNF-α levels and cognitive decline (Holmes et al., 2009) and numerous trials have shown that anti-inflammatory drugs delay the onset or slow the progression of AD (Arroyo et al., 2011). Fibrillated Aβ can be recognized by immune cells and phagocytosed. However, once the peptides oligomerize, aggregate and form neuritic plaques this is not possible, leading to the chronic activation of the immune system (Salminen et al., 2009). Activation of TLR, nucleotide-binding oligomerization domain-like receptors and RAGE by Aβ can stimulate phagocytosis but also results in reduced antioxidant defence and the release of proinflammatory cytokines and proapoptotic mediators (Salminen et al., 2009; Heneka et al., 2010). The pathophysiological relevance of neuroinflammation to neurodegeneration in AD has been well established through multiple lines of evidence. Direct evidence of neurotoxicity has been shown as a result of the release of IL-1, IL-6 and TNF-α (Allan and Rothwell, 2001). Colocalization of the inflammatory response to areas most affected by AD pathology and the absence of such a response in areas less affected implies a strong relationship between the two (Akiyama et al., 2000).

The dysregulation of intracellular Ca2+ concentration and excessive activation of NMDA receptors are characteristic of AD (Sonkusare et al., 2005). Accumulation of glutamate as a result of Aβ-mediated reduction in astrocytic uptake, as well as direct activation of NMDA receptors, leads to excessive NMDA activity and excitotoxicity (Sonkusare et al., 2005; Texido et al., 2011). Aβ has been shown to increase voltage-dependant Ca2+ channel activity (MacManus, 2000) and to form Ca2+ permeable pores in membrane bilayers (Alarcon et al., 2006). Aβ-induced excitotoxicity has long been associated with the neurodegenerative process as rises in intracellular Ca2+ concentration have been shown to activate a number of apoptotic pathways including the activation of caspase-3, calpain and lysosomal cathepsins (Hajnoczky et al., 2003; Harvey et al., 2012). Activated microglia, which can be seen in excess around neuritic plaques, are a major source of ROS production and oxidative stress in the CNS. ROS can further perpetuate the inflammatory response by activating proinflammatory pathways (Taylor et al., 2013).

Several components of the eCB system are altered in AD. In the post-mortem brains of patients with AD, CB2 receptor expression was significantly increased in areas containing microglia associated with the neuritic plaques, such as the entorhinal cortex and parahippocampus (Benito et al., 2003; Solas et al., 2013). This increase in CB2 expression is thought to be an attempt to counteract the chronic inflammation found in AD as CB2 receptor activation reduces microglial activation and cytokine production (Ramirez et al., 2005; Koppel and Davies, 2010). CB1 receptor expression in the AD brain remains a contentious issue with reports of both intact and increased expression levels (Lee et al., 2010; Solas et al., 2013). However, Farkas et al. (2012) have recently reported an initial rise, followed by a steady decline in CB1 receptor expression in the prefrontal cortex of AD patients. When patients were grouped depending on the progression of AD, at the earliest stages of disease progression (Braak stages I-II) CB1 receptor density was at its highest when compared to aged-matched controls and those CB1 receptor levels were found to decline with the progression of AD while remaining above age-matched control levels (Farkas et al., 2012). Furthermore, pharmacological investigation has shown that the CB1 receptor becomes functionally impaired by nitrosylation in the AD brain, affecting the G protein coupling and downstream signaling (Ramirez et al., 2005). Lipidomic analysis of post-mortem brain tissue from AD patients has revealed significantly reduced levels of AEA and its precursors in the midfrontal and temporal cortex when compared to age-matched controls (Jung et al., 2012). Interestingly, increased degradation of AEA may also occur as a consequence of the up-regulation of the metabolizing enzyme, FAAH, on plaque-associated astrocytes that has been noted in the AD brain (Benito et al., 2003). Inhibition of MGL in an in vivo model of AD has recently been shown to suppress the production and accumulation of Aβ via reduced expression of β-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the synthesis of Aβ (Chen et al., 2012). 2AG signalling in AD patients (Braak stage VI) is functionally impaired with increased expression of DGLα and DGLβ as well as the hydrolyzing enzyme MGL although membrane-associated 2AG hydrolysis by MGL was decreased (Mulder et al., 2011).

Parkinson’s disease

PD is the second most common neurodegenerative disease affecting 1% of people over 60 and 4% of people over 80 years of age (de Lau and Breteler, 2006). PD is characterized by the progressive loss of dopaminergic neurons primarily in the substantia nigra (SN) affecting the circuits of the basal ganglia resulting in bradykinesia, rigidity and tremors (Bartels and Leenders, 2009). In a rat model of PD, symptomatology followed an approximate 50% reduction of dopaminergic neurons in the SN combined with an 80% loss of dopamine levels in the striatum (Deumens et al., 2002). In degenerating neurons, Lewy bodies form containing neurofilaments with aggregated α-synuclein (Wakabayashi et al., 2007). The disease has been associated with genetic mutations, inflammation, exogenous toxins and oxidative stress (Bartels and Leenders, 2009).

The link between PD and dopamine loss has been affirmed by PET studies showing a presynaptic dopamine deficit in PD patients and post mortem biochemical analysis revealing decreased levels of dopamine metabolites in the affected areas (Bartels and Leenders, 2009). Intracellular degradation of dopamine generates high levels of ROS, promotes H+ leakage from the mitochondria and reduces levels of glutathione, a key antioxidant enzyme (Hald and Lotharius, 2005). This intrinsic increase in ROS and concomitant decrease in antioxidant enzymes may be the reason for the high levels of oxidative stress found in PD patients. Furthermore, ROS have been shown to induce excitotoxicity through the activation of NMDA receptors and induction of proinflammatory cascades (Barnham et al., 2004). Indeed, PET scans and post-mortem analysis have reported an increased number of activated microglia in the PD brain (McGeer et al., 1988; Gerhard et al., 2006). In line with this, post mortem analysis has also revealed an increased amount of proinflammatory cytokines, namely IL1-β, IL-2, IL-4, IL-6 and TNF-α (Taylor et al., 2013).

The eCB system has been shown to modulate GABAergic and glutamatergic transmission in the basal ganglia (Kofalvi et al., 2005) which affects motor function (Fernández-Ruiz, 2009) and has therefore gained interest as a possible therapeutic target for motor disorders. A recent study has shown a decrease in the availability of CB1 receptors in the SN of PD patients when compared with healthy controls (Van Laere et al., 2012). However, a marked increase in CB1 receptors was found in the nigrostriatal, mesolimbic and mesocortical dopaminergic projection areas of the same patients. It is important to note that no difference in CB1 availability was found between patients that had developed levodopa-induced dyskinesias and those without such symptoms (Van Laere et al., 2012). AEA levels in the cerebrospinal fluid of untreated PD patients were found to be more than double that found in age-matched controls. Interestingly, AEA levels returned to control levels in patients receiving chronic dopamine replacement therapy (Pisani et al., 2010). Furthermore, a sevenfold increase in 2AG levels was found in the globus pallidus of the reserpine-treated animal model of PD and this has been linked to suppression of locomotion (Di Marzo et al., 2000). A decrease in endocannabinoid degradation has also been noted in an animal model of PD with reduced levels of FAAH and AEA membrane transporter found in the striatum (Gubellini et al., 2002). This increase in endocannabinoid tone and CB1 receptor activity in the brain of PD patients has been proposed to be an attempt to normalize striatal function following dopamine depletion as enhanced CB1 receptor signalling reduces glutamate release and activates the pool of G-proteins usually activated by the dopamine D2 receptor (Meschler and Howlett, 2001; Brotchie, 2003).

Huntington’s disease

HD is a progressive neurodegenerative disease that affects 4–10 people per 100 000. The average age of onset is 40 years and it is fatal within 15–20 years (Ross and Tabrizi, 2011). The disease is inherited in an autosomal dominant fashion and is caused by an expanded cytosine, adenine, guanine repeat in the huntingtin gene. Expansion of this gene results in an elongated glutamine repeat at the NH2 terminus of the huntingtin protein (HTT) (Macdonald, 1993). The exact functions of HTT are not fully known although it is believed to play a role in vesicular transport and regulation of gene transcription (Cattaneo et al., 2005; Sadri-Vakili and Cha, 2006). Mutation of HTT can result in intracellular toxic protein aggregation through the formation of abnormal conformations, typically β-sheet structures, protein modifications and the disruption of cellular processes such as protein degradation and metabolic pathways (Ross and Tabrizi, 2011). The resulting clinical features of this are atrophy of the cerebral cortex, severe striatal neuronal loss and up to a 95% reduction of GABAergic medium spiny projection neurons (Halliday et al., 1998; Vonsattel, 2008). The pathological processes implicated in HD are the loss of trophic factors, specifically brain-derived neurotrophic factor (BDNF), excitotoxicity, oxidative stress and inflammation resulting in progressive neurodegeneration. Symptoms associated with HD include progressive motor dysfunction, cognitive decline and psychiatric disturbance (Ross and Tabrizi, 2011).

A number of studies have reported the dependency of medium spiny neurons on BDNF which is depleted by approximately 35% in animal models of HD (Baquet et al., 2004; Zuccato and Cattaneo, 2007). Reduced BDNF mRNA expression has also been reported in the post mortem analysis of brain tissue from HD patients (Zuccato et al., 2008). Decreased levels of BDNF have been closely linked to the HD phenotype since BDNF partial knock-out mice showed very similar phenotypes to HD models, namely progressive brain damage and hindlimb clasping as well as reduced striatal volumes (Baquet et al., 2004). Indeed, BDNF replacement is believed to be a possible therapeutic for HD and has been shown to decrease excitotoxicity and attenuate motor dysfunction and cell loss in animal models of HD (Kells et al., 2004; Kells et al., 2008). This may prove beneficial as mounting evidence implicates excitotoxicity in the pathophysiology of HD. Hassel et al. (2008) have reported a 43% decrease in glutamate uptake in HD patients and defective activity of the glutamate transporter, GLT1. The subsequent accumulation of extracellular glutamate could well be the cause of excessive NMDA activity and excitotoxicity. Mutant HTT has also been found to bind directly to mitochondria, disrupting metabolic activity and up-regulating the proapoptotic factors Bcl2-associated X protein and p53-up-regulated modulator of apoptosis (Bae et al., 2005). Neuroinflammatory processes are also gaining interest in the investigation of HD. PET imaging, in vitro studies and post-mortem analysis have reported an increase in microglial activation in HD which correlates with neurodegeneration and the severity of the condition (Ross and Tabrizi, 2011).

A clear parallel has been made between the graded progression of HD and decreasing CB1 receptor density, particularly in the caudate nucleus, putamen and the globus pallidus (Glass et al., 2000). Recently, it has been reported that CB1 receptor down-regulation is specific to certain striatal subpopulation such as medium spiny neurons and neuropeptide Y/neuronal nitric oxide synthase-expressing interneurons (Horne et al., 2013). Much work has been carried out in analysing the components of the eCB system in R6/2 transgenic mice, a common model of HD. A loss of CB1 receptor density was found presymptomatically (Denovan-Wright and Robertson, 2000) as a result of mutant HTT-associated impairment of CB1 receptor gene expression (Blazquez et al., 2011). Genetic ablation of CB1 receptors aggravated HD symptoms in mice while pharmacological activation by Δ9-tetrahydrocannabinol (THC) attenuated symptomatology indicating that impairment of CB1 receptor function may be a primary pathogenic feature of HD (Blazquez et al., 2011). CB2 receptor expression, however, was found to increase in the striatal microglia of these transgenic mice and HD patients and this may confer neuroprotection as genetic ablation of CB2 receptors in transgenic HD mice results in increased microglial activation, aggravation of disease symptomatology and decreased life span (Palazuelos et al., 2009). In the striatum, a reduction in AEA, 2AG and their respective biosynthetic enzymes N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and diacylglycerol lipase activity was found (Bisogno et al., 2008; Bari et al., 2013). In the cortex, a reduction in 2AG levels was accompanied by an increase in AEA levels while their respective hydrolytic enzymes MGL, was decreased, and FAAH increased (Bisogno et al., 2008; Bari et al., 2013). These data clearly indicate the alteration of multiple components of the eCB system in the progression of HD.

Ageing

Ageing is a time-dependent and progressive deterioration of biological function that leads to death. The typical characteristics of ageing include a decrease in physiological capacity, reduced adaptive capabilities to changes in environment and an increased vulnerability to disease and death (Farooqui and Farooqui, 2009). Indeed, normal ageing presents many of the same pathophysiologic mechanisms found in neurodegenerative diseases and is believed to further aggravate disease progression. Many theories have been put forward to explain the degenerating nature of age such as Ca2+ dyshomeostasis, oxidative stress and mitochondrial dysfunction but a consensus is yet to be reached.

The atrophy of the human brain with age is believed to be as a result of neurodegeneration and the loss of myelinated axons (Peters, 2002). Increased Ca2+ influx has been reported in the CA1 hippocampal region of aged rats, mediated by increased voltage-operated Ca2+ channels (Landfield and Pitler, 1984; Thibault and Landfield, 1996). Furthermore, intracellular Ca2+ regulation is altered in the aged brain. Efflux of Ca2+ through plasma membrane pumps as well as its uptake to mitochondrial sinks is affected by ageing (Michaelis et al., 1996; Toescu, 2005) resulting in impairments in intracellular Ca2+ homeostasis. Oxidative stress is also prominent in the aged brain. Membrane lipid peroxidation coupled with oxidative damage of proteins and DNA is reported to increase with age (Sohal and Weindruch, 1996). Prolonged oxidative damage of mitochondrial DNA and lipids increases ROS generation resulting in further oxidative damage and vulnerability towards apoptosis (Paradies et al., 2011). Chronic activation of microglia and alterations in their morphologic and immunophenotypic nature have also been reported. Normal ageing is believed to prime microglia for an exaggerated response, preferentially releasing proinflammatory cytokines. Increased basal levels of IL-6 and enhanced LPS-induced levels of IL-6 and IL-1β have been reported in the aged brain (Nakanishi and Wu, 2009).

Conflicting reports have emerged on the state of the eCB system as a result of ageing. Decreased CB1 receptor density has been reported in the cerebellum and cerebral cortex of aged rats, while reduced CB1 mRNA levels were found in the hippocampus and brainstem (Berrendero et al., 1998). Conversely, Wang et al. (2003) have shown that there is no change in endocannabinoid tone or CB1 receptor density in the hippocampus limbic forebrain, amygdala or cerebellum of aged mice. However, decreased coupling of CB1 receptor to G-proteins was reported in the limbic forebrain.

The eCB system as a therapeutic target

The use of cannabinoids as a therapeutic remains a controversial issue. However, some success has been gained with the use of cannabinoid-based drugs to regulate appetite, sleep, pain and some psychotic tendencies. Dronabinol, derived from the phytocannabinoid THC, is beneficial in reducing anorexia, increasing body weight and improving behaviour in elderly AD patients (Volicer et al., 1997). Dronabinol has more recently been assessed in a pilot study with AD patients where it improved nocturnal motor activity and reduced agitation and aggression, without undesired side effects (Walther et al., 2006). In animal models of PD, THC attenuates motor inhibition and the loss of tyrosine hydroxylase-positive (dopamine producing) neurons. Furthermore, preclinical studies have investigated the anti-inflammatory and antioxidant capabilities of the phytocannabinoid cannabidiol (CBD), combined with THC, in the form of the cannabis-based medicine Sativex, which is already used as a therapeutic agent for multiple sclerosis. Sativex has been shown to successfully treat neuropathic pain and spasticity in multiple sclerosis patients (Nurmikko et al., 2007; Notcutt et al., 2012). Maresz et al. (2007) have demonstrated that CB1 and CB2 receptors are required for mediation of the immune system in animal models of multiple sclerosis. This combination is now emerging as a viable therapeutic option for PD and HD (Valdeolivas et al., 2012; Fernandez-Ruiz et al., 2013). The eCB system is believed to be a promising therapeutic target for delaying disease progression and ameliorating Parkinsonian symptoms (Garcia et al., 2011).

Cannabinoids and neuroinflammation

Chronic neuroinflammation has been identified as a key mediator of neurodegeneration in AD, PD and HD. Various models of inflammation have reported the beneficial effects of cannabinoid action on reducing the inflammatory burden ( Figure 2). The CB2 selective agonist, JWH015 a synthetic cannabinoid, has been shown to reduce interferon-γ-induced up-regulation of CD40 in cultured mouse microglial cell through interfering with the JAK/STAT pathway. Furthermore, this intervention suppressed the production of proinflammatory cytokines and promoted the phagocytosis of Aβ (Ehrhart et al., 2005). Mobilization of intracellular Ca2+ in response to ATP is a key mediator of microglial activation and inducer of the inflammatory response. CBD, along with the synthetic cannabinoids WIN 55212-2, a mixed CB1/CB2 receptor agonist and JWH-133, a CB2 receptor selective agonist, were all shown to decrease the ATP-induced rise in intracellular Ca2+ concentration in the N13 microglial cell line (Martin-Moreno et al., 2011). The effects of WIN 55212-2 and JWH-133 were fully reversed by the selective CB2 antagonist, SR144528 (100 nM) indicating a CB2 receptor-mediated effect. This antagonism was not seen in CBD-treated cells suggesting that CB2-independent mechanisms may also be beneficial. Furthermore, the Aβ-induced rise in the proinflammatory cytokine IL-6 was reduced almost sixfold by 20 mg kg−1 CBD or 0.5 mg kg−1 WIN 55212-2 in vivo (Martin-Moreno et al., 2011). Further in vivo studies using transgenic APP 2576 mice have reported that oral administration of JWH-133 (0.2 mg kg−1 day−1 for 4 months) decreased microglial activation, reduced COX-2 and TNF-α mRNA and reduced cortical levels of Aβ, with no impact on cognitive performance (Martin-Moreno et al., 2012). A number of studies have identified the PPARγ as a key mediator of the cannabinoid anti-inflammatory effect. The PPAR family are a group of nuclear hormone receptors known to be involved in gene expression, lipid and glucose metabolism and the inflammatory response. In cultured rat astrocytes, reactive gliosis was induced by treatment with 1 mg mL−1 Aβ for 24 h and this was significantly reduced by CBD in a concentration-dependant manner. The beneficial effects of CBD were blunted by PPARγ antagonism by GW9662, suggesting the involvement of PPARγ in the anti-inflammatory effects of CBD (Esposito et al., 2011). Hippocampal fractions isolated from adult rats injected with Aβ (10 μg mL−1) to the CA1 region and treated with CBD (10 mg kg−1) intraperitoneally for 15 days replicated the results found in vitro. Fakhfouri et al. (2012) have further elucidated the relationship between cannabinoids and PPARγ in vivo and have identified that Aβ, when administered intrahippocampally to adult rats, increased PPARγ transcriptional activity and protein expression is observed which was further increased as a result of i.c.v. administration of WIN 55212-2. The beneficial effects caused by WIN 55212-2 were partially halted by the antagonism of PPARγ by i.c.v. administration of GW9662.

A common model for inflammation in the brain is the infusion of lipopolysaccharide into the fourth ventricle of young rats. Marchalant et al. (2007) have shown that daily i.p. injections of WIN 55212-2 (0.5 mg kg−1) successfully reduced microglial activation in this model. However, when the dosing regimen was raised to 1 mg kg−1 day−1, microglial activation was potentiated by WIN 55212-2. Normal aging has also been shown to cause neuroinflammation and in this context cannabinoids have also been shown to confer neuroprotection. In rats aged 23 months, WIN 55212-2 injections of 2 mg kg−1 i.p. for 4 weeks reduced the number of activated microglia in the hippocampus and dentate gyrus (Marchalant et al., 2009). Interestingly, when incubated with the CB1 receptor antagonists SR141716A and SR144528, WIN 55212-2 had no effect. The same treatment was found to decrease the mRNA levels of the proinflammatory cytokine IL-6 as well as the anti-inflammatory cytokine IL1-RA. Protein levels of TNF-α and IL-1β were decreased while an increase in IL1-RA was seen (Marchalant et al., 2009). It is now clear that at multiple steps throughout the inflammatory process, cannabinoids can help to reduce the inflammatory burden during neurodegeneration.

Cannabinoids, excitotoxicity and mitochondrial dysfunction

The excitotoxic increase of intracellular Ca2+ concentration in neurodegenerative disorders can lead to the activation of apoptotic and proinflammatory pathways, as well as disrupting metabolic processes leading to cell death. Endocannabinoids are most commonly synthesized in a Ca2+-dependent fashion as a result of depolarization and are believed to help reduce excitotoxic damage. Indeed, AEA levels increase rapidly in the hippocampi of mice after administration of the excitotoxin kainic acid (KA) (30 mg kg−1) and genetic ablation of the CB1 receptor lowered the threshold for KA-induced seizures with more than 75% of CB1-null mice dying within 1 h of KA injection. The neuroprotective capabilities of CB1 are suggested to act primarily on principal glutamatergic neurons. Furthermore, the intracellular events involved in this neuroprotection have been attributed to the CB1-mediated activation of ERKs and the subsequent expression of the immediate early genes c-fos and zif268 (Marsicano et al., 2003). Cannabinoid action, via CB1 receptors in particular, regulates intracellular Ca2+ levels through a number of mechanisms (Figure 2). Exposure of murine cortical cultures to 20 μM NMDA for 24 h results in 70% cell death and WIN 55212-2 has been shown to decrease cell death though the inhibition of nitric oxide signalling and PKA (Kim et al., 2006a). This CB1 receptor-mediated regulation of PKA has long been associated with neuroprotection against excitotoxicity (Kim et al., 2005). Another route for Ca2+ influx is through TNF-α mediated surface delivery of Ca2+ permeable AMPA receptors which contribute to in vitro excitotoxicity. WIN 55212-2 inhibits this TNF-α-induced increase in surface AMPA receptors and reduces excitotoxic damage in rat hippocampal cultures (Zhao et al., 2010). TNF-α also increased PKA activity (Zhang et al., 2002) which in turn can phosphorylate AMPA receptors at Ser845 and traffic them to the plasma membrane (Oh et al., 2006). It is therefore believed that the inhibition of PKA by CB1 receptor stimulation is beneficial in reducing excitotoxic damage by interfering with AMPA trafficking. Furthermore, the CB1 receptor agonists, WIN 55212-2 and AEA, inhibited glutamate release from rat hippocampal synaptosomes which would reduce NMDA activation and the resulting Ca2+ influx (Wang, 2003). As well as reducing the influx of Ca2+, cannabinoid action regulates intracellular Ca2+ homeostasis. WIN 55212-2 reduced the NMDA-mediated release of Ca2+ from intracellular stores in cultured rat hippocampal cells thereby increasing cell viability. This involved the CB1-mediated reduction in cAMP-dependant PKA phosphorylation of ryanodine receptors (Zhuang et al., 2005). Furthermore, in high-excitability conditions CBD (1 μM) increased the levels of Ca2+ uptake by mitochondria in cultured rat hippocampal neurons (Ryan et al., 2009). Intense elevation of intracellular Ca2+ is known to induce proapoptotic cascades. Activation of cytosolic calpains by Ca2+ results in permeabilization of the lysosome and the release of proapoptotic proteins such as the caspase and cathepsin family (Yamashima and Oikawa, 2009). Noonan et al. (2010) have shown in vitro that increasing endocannabinoid tone through inhibiting FAAH degradation of 2AG prevented the Aβ-induced increase in calpain activation, permeabilization of the lysosome and the resulting neurodegeneration.

Mitochondrial dysfunction has also been addressed by cannabinoid research (Figure 2). Oxygen-glucose deprivation/reoxygenation of neuronal-glial cultures causes mitochondrial depolarization and oxidative stress. In rat neuronal-glial cultures, the cannabinoid trans-caryophyllene (1 μM) has been shown to increase neuronal viability through a reduction of mitochondrial depolarization and oxidative stress, and by increasing the expression of BDNF. This study has identified CB2 receptor activation as a mechanism for enhancing the phosphorylation of AMP-activated protein kinase and cAMP responsive element-binding protein and increasing expression of the CREB target protein, BDNF (Choi et al., 2013). In an in vitro model of PD, 1-methyl-4-phenylpyridinium iodide, paraquat and lactacystin were used to inhibit mitochondrial function, generate free radicals and inhibit the ubiquitin proteasome respectively. These treatments resulted in cell death brought on by ROS generation, caspase-3 activation and cytotoxicity. THC (10 μM) was shown to reduce these effects in human neuroblastoma cells (SH-SY5Y) while increasing cell viability. This result was not reproduced by the CB1 receptor agonist WIN 55212-2 (1 μM) but was blocked by inhibition of PPARγ, the activity of which was increased by THC treatment (Carroll et al., 2012).

Cannabinoids and adult neurogenesis

Adult neurogenesis is the process by which new neurons are generated and integrated into the developed brain. Regulation of neurogenesis is strictly controlled through a number of different factors such as adrenal and sex hormones, neurotransmitter systems, trophic factors and inflammatory cytokines. The formation of new neurons and neuronal connections may prove vital to sustaining neuronal function in neurodegenerative disorders where neurogenesis is impaired such as AD and HD (Molero et al., 2009; Crews et al., 2010). The eCB system has been closely linked to the process of adult neurogenesis. DGLα and DGLβ synthesize the endocannabinoid 2AG, and DGLα and DGLβ null mice have an 80 and 50% reduction in 2AG respectively. These transgenic mice were shown to have impaired neurogenesis, believed to be as a result of the loss of 2AG-mediated transient suppression of GABAergic transmission at inhibitory synapses (Gao et al., 2010). Furthermore, mice lacking CB1 receptors displayed an almost 50% reduction in neurogenesis in the dentate gyrus and subventricular zone when compared to wild type. In line with this, the mixed CB1/CB2 receptor agonist WIN 55212-2 enhanced BrdU incorporation into murine neuronal culture in a CB1 receptor-mediated fashion (Kim et al., 2006b). CB1 receptor-mediated stimulation of adult neurogenesis has been shown to act through its opposition of the antineurogenic effect of nitric oxide (Kim et al., 2006b; Marchalant et al., 2009). Neuronal precursor cell proliferation and the number of migrating neurons have been shown to increase in neurogenic regions in response to seizure, ischaemia and excitotoxic and mechanical lesions indicating a possible contributing factor in the repair of lesioned circuits (Gould and Tanapat, 1997; Arvidsson et al., 2001; Parent et al., 2002; Lie et al., 2004). KA-induced neural progenitor proliferation is reduced in CB1 receptor deficient mice as well as in wild-type mice administered with the selective CB1 receptor antagonist SR141716A. This effect was attributed to the CB1-dependent expression of basic fibroblast growth factor and epidermal growth factor (Aguado et al., 2007). BDNF is vital for the survival of new neurons and is significantly reduced in neurodegenerative conditions such as HD (Zuccato and Cattaneo, 2007). De March et al. (2008) have shown that 2 weeks post-excitotoxic lesion in rats, transient up-regulation of BDNF coincides with higher binding activity and protein expression of CB1 receptor. This is believed to be an attempt to rescue the striatal neuronal population. In a reciprocal fashion, BDNF (10 ng mL−1) was shown in vitro to increase neuronal sensitivity to the endocannabinoids 2AG and noladin ether as measured by the phosphorylation of Akt (Maison et al., 2009). Indeed, CB1 receptor activation has been implicated in neural precursor proliferation and neurogenesis while CB1 and CB2 receptor activation is involved in neural progenitor cell proliferation, both of which are vital to the generation and survival of new neurons (Palazuelos et al., 2006; Aguado et al., 2007).

bph12492-fig-0003

Chemical structures of the common CB receptor agonists.

Summary

Neurodegenerative diseases are a heterogeneous group of age-related disorders. While AD, PD and HD have a variety of different genetic and environmental causes, the principal factor involved is the progressive and severe loss of neurons. It is widely accepted that neuroinflammation, excitotoxicity and oxidative stress are key mediators of neurodegeneration, and impaired neurogenesis as well as reduced trophic support leave neuronal systems unable to cope. The eCB system is emerging as a key regulator of many neuronal systems that are relevant to neurodegenerative disorders. Activation of CB1 receptors regulates many neuronal functions such as Ca2+ homeostasis and metabolic activity while the CB2 receptor is mainly involved in regulating the inflammatory response.

Here, we have put forward the mechanisms of neurodegeneration in the three most prevalent neurodegenerative disorders, AD, PD and HD, as well as showing the vulnerability of the brain as a result of age. We have summarized evidence of the beneficial role of modulating the cannabinoid system to reduce the burden of neurodegeneration. Pharmacological modulation of the eCB system ( Figure 3) has been shown to reduce chronic activation of the neuroinflammatory response, aid in Ca2+ homeostasis, reduce oxidative stress, mitochondrial dysfunction and the resulting proapoptotic cascade, while promoting neurotrophic support.

Cannabinoids, like those found in marijuana, occur naturally in human breast milk

Posted by

0


Woven into the fabric of the human body is an intricate system of proteins known as cannabinoid receptors that are specifically designed to process cannabinoids such as tetrahydrocannabinol (THC), one of the primary active components of marijuana. And it turns out, based on the findings of several major scientific studies, that human breast milk naturally contains many of the same cannabinoids found in marijuana, which are actually extremely vital for proper human development.

Cell membranes in the body are naturally equipped with these cannabinoid receptors which, when activated by cannabinoids and various other nutritive substances, protect cells against viruses, harmful bacteria, cancer, and other malignancies. And human breast milk is an abundant source of endocannabinoids, a specific type of neuromodulatory lipid that basically teaches a newborn child how to eat by stimulating the suckling process.

If it were not for these cannabinoids in breast milk, newborn children would not know how to eat, nor would they necessarily have the desire to eat, which could result in severe malnourishment and even death. Believe it or not, the process is similar to how adult individuals who smoke pot get the “munchies,” as newborn children who are breastfed naturally receive doses of cannabinoids that trigger hunger and promote growth and development.

“[E]ndocannabinoids have been detected in maternal milk and activation of CB1 (cannabinoid receptor type 1) receptors appears to be critical for milk sucking … apparently activating oral-motor musculature,” says the abstract of a 2004 study on the endocannabinoid receptor system that was published in the European Journal of Pharmacology.

“The medical implications of these novel developments are far reaching and suggest a promising future for cannabinoids in pediatric medicine for conditions including ‘non-organic failure-to-thrive’ and cystic fibrosis.”

Studies on cannabinoids in breast milk help further demystify the truth about marijuana

There are two types of cannabinoid receptors in the body — the CB1 variety which exists in the brain, and the CB2 variety which exists in the immune system and throughout the rest of the body. Each one of these receptors responds to cannabinoids, whether it be from human breast milk in children, or from juiced marijuana, for instance, in adults.

This essentially means that the human body was built for cannabinoids, as these nutritive substances play a critical role in protecting cells against disease, boosting immune function, protecting the brain and nervous system, and relieving pain and disease-causing inflammation, among other things. And because science is finally catching up in discovering how this amazing cannabinoid system works, the stigma associated with marijuana use is, thankfully, in the process of being eliminated.

In another study on the endocannabinoids published in the journal Pharmacological Reviews back in 2006, researchers from the Laboratory of Physiologic Studies at the National Institute on Alcohol Abuse and Alcoholism uncovered even more about the benefits of cannabinoids. These include their ability to promote proper energy metabolism and appetite regulation, treat metabolic disorders, treat multiple sclerosis, and prevent neurodegeneration, among many other conditions.

With literally thousands of published studies now showing their safety and usefulness, cannabinoids, and particularly marijuana from which it is largely derived, truly are a health-promoting “super” nutrient with virtually unlimited potential in health promotion and disease prevention.

Be sure to check out how juicing raw marijuana leaves, which contain a diverse array of health-promoting cannabinoids, is an excellent non-psychoactive way to prevent and treat a host of diseases, including cancer:

Learn more: http://www.naturalnews.com/036526_cannabinoids_breast_milk_THC.html#ixzz3w7GpAcul

The US Finally Admits Cannabis Kills Cancer Cells

Posted by

1


A group of federal researchers commissioned by the government to prove that cannabis has “no accepted medical use” may have unwittingly let information slip through the cracks, revealing how cannabis actually kills cancer cells. 

The research, which was conducted by a team of scientists at St. George’s University of London, found that the two most common cannabinoids in marijuana, tetrahydrocannabinol (THC) and cannabidiol (CBD), weakened the ferocity of cancer cells and made them more susceptible to radiation treatment, said Mike Adams of Herbal Dispatch.

The study, which was published last year in the medical journal Molecular Cancer Therapies, details the “dramatic reductions” in fatal variations of brain cancer when these specific cannabinoids were used in conjunction with radiation therapy.

“We’ve shown that cannabinoids could play a role in treating one of the most aggressive cancers in adults,” wrote lead researcher Dr. Wai Liu, in a November 2014 op-ed for The Washington Post. “The results are promising… it could provide a way of breaking through glioma [tumors] and saving more lives.”

“Recent animal studies have shown that marijuana can kill certain cancer cells and reduce the size of others,” the NIDA report said. “Evidence from one animal study suggests that extracts from whole-plant marijuana can shrink one of the most serious types of brain tumours. Research in mice showed that these extracts, when used with radiation, increased the cancer-killing effects of the radiation.”

NIDA’s newfound pro-pot position is especially curious given that it was revealed on the heels of a recent proposal introduced to both Congress and the House of Representatives which attempts to legalize medical marijuana on a national level. The bill, which is called the CARERS Act, seeks to downgrade the Schedule I status of marijuana to a Schedule II in order to make the herb more flexible in the eyes of the federal government as an accepted form of medicine.
In addition, the bill would also remove cannabidiol, the non-intoxicating compound of the pot plant, from the Controlled Substances Act and allow it to be distributed on a state-to-state basis without violating federal statutes.

Cannabis became a schedule I drug in 1970 with the passing of the Controlled Substances Act, which classified cannabis as having a high potential for abuse, no medical usage, and unsafe to use without medical supervision.

This federal research basically contradicts cannabis’ schedule I status. Could this mean reform is closer than we’d originally imagined?

Stay tuned for the latest updates on cannabis reform.

What are your thoughts on this? Do you think we are about to see a major change in the legal status of cannabis? Do you feel it should be looked at as a potent medicine? Share with us in the comment section below!