Grow Your Greatest: Tips & Tricks for Massachusetts Cannabis Growers

Once you’ve decided to start growing cannabis at home, you can easily fall into an overwhelming green hole of information: What strains are easiest to grow? What’s the optimum cycle for indoor lights? Should you grow in soil or coco coir? Use sprays or opt for integrated pest management? It’s enough to drive anyone mad–or at least to the nearest dispensary.

Thankfully, there are lots of excellent resources online–including Leafly’s own dedicated section on growing–and many of them provide helpful information for the general grower. But what about growing locally, right here in Massachusetts?

“You can’t just grow anything, especially with the way the climate is out here.”

Frank Golfieri, INSA asst. head grower

I wanted to know whether there were specific tips and tricks for growing here in the Bay State. So I headed to the INSA cultivation facility in Easthampton to learn more about what it takes to grow cannabis successfully in New England.

INSA’s cultivation center is state of the art and truly makes a home grower salivate. From its water filtration system to the various grow rooms where plants can be seen in different stages of their lifecycle, it was impressive to see cannabis grown on a large scale.

Thankfully, you don’t need a cutting-edge grow center to get a good harvest at home. INSA head grower Matt Livermore and assistant head grower Frank Golfieri shared some Massachusetts-specific tips they’ve cultivated over the years.

Pick the Right Plants

If you’re planning to grow outdoors in Massachusetts–the season here lasts roughly May through November, by the way–make sure you choose the right strains. “You have to find specific ones for this region,” said Golfieri. “You can’t just grow anything, especially with the way the climate is out here. You have to find strands that are more hearty, to handle these conditions.” Kush strains are good options for beginners to consider.

Both Livermore and Golfieri recommend starting from seed if possible to avoid any surprise issues that may be brought into your grow space. When starting with clippings or clones, you can’t be positive that they won’t introduce bacteria, pests, or other pathogens into your garden. Golfieri advised, if you have the space, that you keep new plants in quarantine for a little while to avoid letting introduced pathogens spread to existing plants.

Know Your Seasons

If you’re taking advantage of the outdoor grow period, it’s important to be aware that it stretches across three different seasons–spring, summer, and fall–each with its own specific weather. While fall in other regions may be more temperate, Massachusetts tends to have more rain. Our long, relatively autom thus creates perfect conditions for things like mold to develop.

And while Massachusetts isn’t not known for long periods of scorching heat in the summer, there are frequently spells of little to no rain that can cause issues if you’re unable to water your plants regularly.

Start Indoors

There’s not much that compares to the sight of a majestic, outdoor cannabis plant. When it comes down to it both INSA growers stressed that indoor cultivation is easiest for new growers in Massachusetts. “You can control the environment better,” explained Golfieri. Fluctuating temperatures, long periods of cold or rain, and even unanticipated early freezes won’t matter at all to indoor plants (and more importantly, won’t impact your yield). It’s also far easier to control light conditions indoors.

All that comes with a downside, of course: added cost.

Cleanliness Is Key

To keep plants healthy, it’s crucial to limit their exposure to contaminants. Change into clean clothes before entering your grow room, and keep a separate pair of shoes to avoid tracking in contaminants from outside. Beyond those general tips, though, there are best practices specific to the state.

Water is an often overlooked source of contamination. If you’re not using filtered or distilled water, which both INSA growers recommend, be sure to get a complete readout of your town or city’s water supply. This can usually be done by contacting your local water and sewer agency. While you can test water from the faucet yourself for things like pH levels, a more comprehensive assessment will indicate things like lead and heavy metals, which cannabis plants absorb readily. Heavy metals are of particular concern in Massachusetts, home to a lot of former mill towns.

Get Tested

When you’re dealing with new plants, you want to start with the best. So you might want to start by having the plant, flower, and/or soil tested by one of the labs in the state.

Neither Livermore nor Golfieri were keen on the tests you can order online. “If you want to get it done, spend the money and go take the time to get your terpenes, cannabinoid profile figured out,” says Livermore. “You can find out if there are any microtoxins in the soil, or other things that are a problem. If you’re really that serious about growing, you take it to a reputable lab, for sure!”

Four labs are currently open for testing cannabis in Massachusetts, all in the eastern part of the state. Costs start around $50, and you can choose what type of analysis you’d like to run, from cannabinoid and terpene profiles to various safety tests that check for common concerns such as mold, E. coli, yeast, fungus, and more.

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ICRS 2018: Report from Leiden (Part 2)

During the first week of July 2018, five-hundred-and-thirty-five delegates from five continents met at the University of Leiden in the Netherlands for the 28th annual symposium of the International Cannabinoid Research Society (ICRS). The four-day conference showcased recent scientific discoveries about cannabis components and various ways of targeting the endocannabinoid system to improve health outcomes.

Fatty acid binding proteins

During his Young Investigator Award Presentation, Stony Brook University scientist Martin Kaczocha discussed the role of fatty acid binding proteins (FABPs) as critical components of the endocannabinoid system. This is an emerging area of medical science with exciting prospects for pharmaceutical development. Kaczocha’s talk focused on preclinical investigations that underscored the potential of targeting specific FABPs to treat pain, inflammation and prostate cancer.

Why are fatty acid binding proteins important? Because fats and water don’t mix well, and that means endocannabinoids (eCBs) and other endogenous lipids must rely on FABPs to get to where they need to go.

FABPs are transport molecules – think of them as a fleet of teleporting canoes – that shuttle eCBs through the cell membrane into the aqueous cytoplasmic interior. Within the cell, eCBs act upon nuclear receptors, which regulate gene expression and mitochondria, before they translocate to enzymes that metabolize eCBs into breakdown components as part of the natural life cycle of these pivotal neurotransmitters.

In 2009, Stony Brook scientists, led by Dale Deutsch, identified several FABPs as “intracellular carriers” for the endocannabinoid anandamide. Six years later Deutsch and Koczocha scored another breakthrough when they reported that the same FABP transport molecules also serve as intracellular carriers for CBD and THC.

What happens when plant cannabinoids like CBD and THC compete with endogenous cannabinoids for seats on the same FABP canoe? CBD and THC reduce eCB access to FABP transport molecules, which causes eCBs to stick around longer, resulting in an increase in eCB levels in the brain.

In effect, CBD and THC function as endocannabinoid reuptake inhibitors that amplify cannabinoid receptor signaling by delaying eCB deactivation. Enhancing eCB tone via reuptake inhibition appears to be a key mechanism whereby plant cannabinoids confer neuroprotective effects and other health benefits.

Pharmaceutical researchers, meanwhile, are experimenting with synthetic compounds that delay eCB intracellular transport and reuptake. Medical scientists hope that by targeting specific fatty acid binding proteins, synthetic reuptake inhibitors will increase eCB levels in a localized manner that causes clinically verifiable, eCB-induced protective effects.

CB1 antagonists 2.0

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Several posters and oral presentations at ICRS in Leiden addressed the therapeutic potential of peripherally restricted CB1 receptor antagonists, which show promise in preclinical studies for treating alcoholism, insulin resistance, and metabolic disorders.

First identified in 1988, CB1 cannabinoid receptors are not only the most prevalent G-protein coupled receptors in the brain and central nervous system; they are also expressed in peripheral organs such as the liver, kidneys, heart, bones, and gut.

CB1 receptors mediate the psychoactive effects of cannabis. When THC binds to CB1 receptors in the brain, it makes a person feel high. When THC binds to CB1 receptors outside the central nervous system, it confers non-psychoactive, anti-inflammatory effects.

CB1 receptors in the brain and gut play a critical role in regulating energy metabolism by controlling food intake. The notorious marijuana “munchies” are linked to CB1 receptor stimulation in the brain region that regulates hunger and satiety. If activated, these CB1 receptors induce appetite; if blocked, they reduce it.

The French pharmaceutical giant Sanofi-Aventis was the first to market a synthetic CB1 antagonist as an appetite suppressant under the trade name Rimonabant in 2006. But the much-hyped blockbuster diet pill proved to be a blunt instrument, and the drug was soon pulled from European circulation because of severe side effects – anxiety, nausea, vomiting, seizures, sleep disorders, headaches, increased blood pressure, mood swings, depression, and heightened risk of suicide. Blocking CB1 receptor signaling in the brain to shed a few pounds caused the same adverse neurological conditions that CB1 activity normally protects against — the same medical conditions for which cannabis provides relief.

Big Pharma’s initial foray into cannabinoid antagonists failed miserably. But the notion of modulating the endocannabinoid system without causing a high would live on as an idee fixe among drug company researchers. Now, a dozen years after the Rimonabant debacle, medical scientists are taking another look at CB1 receptor antagonists – from a different perspective.

Instead of targeting CB1 receptors in the brain, the current emphasis is on selectively blocking only CB1 receptors outside the central nervous system. Drug developers, accordingly, have invented a new generation of experimental CB1 antagonists that don’t cross the blood-brain barrier.

Whereas CB1 receptor antagonism in the brain produces detrimental neurological outcomes, CB1 inhibition in peripheral organs has shown therapeutic potential in various animal models. A team of scientists at National Institutes of Health (NIH) in Bethesda, Maryland, reported that CB1 receptor antagonism enhances insulin sensitivity in pancreas and liver cells and delays age-related muscle loss.

Another NIH study at ICRS 2018 found that a peripheral CB1 blockade may have therapeutic possibilities for treating alcoholism. And according to researchers at RTI International in North Carolina, CB1 receptor antagonists that lack central nervous system penetration should also be considered worthy drug development candidates for liver disorders.

But problems inevitably arise when selectively targeting a cannabinoid receptor subtype and treating it as an on/off switch. There may be better whole plant options.

Metabolic tune-up

In vitro studies indicate that cannabidiol functions as a negative allosteric modulator at the CB1 receptor, meaning that CBD antagonizes or inhibits CB1 receptor signaling without entirely blocking it. In other words, if the CB1 receptor functions as a dimmer switch, CBD turns it down but not all the way.

At the same time, CBD augments CB2 receptor signaling, which regulates inflammation and immune cell activity. How and why CBD, a potent anti-inflammatory, acts like a CB2 agonist without directly binding to the CB2 receptor is still somewhat of a scientific mystery.[1]

But this much is evident: CBD can fine-tune metabolism by differentially modulating CB1 and CB2 receptor activity, down-regulating the former while boosting the latter. Both types of cannabinoid receptors, CB1 and CB2, are expressed in peripheral organs, where they may mediate opposing functions. Activating CB1, for example, has a pro-fibrogenic effect in the liver and kidneys; activating CB2 has the opposite effect, reducing fibrosis.

Fatty liver, diabetes, heart disease, obesity, and other diet-related metabolic disorders are associated with overactive CB1 receptor signaling and inadequate CB2 stimulation. Given that CBD differentially inhibits CB1 and amplifies CB2, cannabidiol appears to be particularly well-suited for treating lifestyle and diet-induced illnesses that are endemic in Western societies.

Several other plant cannabinoids, including tetrahydrocannabinolic acid (THCA), the unheated, non-intoxicating version of THC, also show promise as metabolic modulators. Spanish scientists reported on the effect of THCA in an animal model of metabolic syndrome. Daily administration of pure THCA (20 mg/kg) for 3 weeks resulted in “a significant reduction of fat mass and body weight gain” in mice fed a high fat diet. THCA also significantly ameliorated “glucose intolerance and insulin resistance.” These health-positive outcomes were attributed to THCA’s activation of PPAR-gamma, a receptor on the surface of the cell’s nucleus, which regulates energy homeostasis, mitochondria, and gene expression related to adipose tissue (body fat) accumulation. CBD also activates PPAR-gamma.

Food as medicine

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Western diet and a sedentary lifestyle are major risk factors for developing metabolic syndrome (characterized by high blood pressure, high blood sugar, bulging waistlines). It’s already a massive public health crisis: 34 percent of American adults meet the criteria for metabolic syndrome, including 52 percent of Americans 60 years and older. Several ICRS presentations examined non-pharmacological approaches – including exercise and nutritional intervention – that treat prevalent metabolic disorders by targeting the endocannabinoid system.

The therapeutic effects of regular moderate exercise (weight loss, improved mood, and more) may involve changes in the basal tone of peripheral eCB signaling, according to Brazilian scientists at the Federal University of San Paulo. Simply put, exercise improves endocannabinoid tone. So does a healthy diet – low on sugar and carbs, rich in leafy greens, polyphenols, probiotics, essential fatty acids, and high fiber foods.

Wageningen University in the Netherlands has been at the forefront of researching how omega-3 polyunsaturated fatty acids (PUFAs) impact the endocannabinoid system. Omega-3 dietary deficiency depletes eCB tone, impedes eCB-mediated neuronal functions, and is linked to the onset of neuropsychiatric diseases. But this deficiency can be mitigated by fish oil-derived PUFAs – such as DHEA and DHA-5-HT – which are known to have anti-inflammatory and cardiovascular benefits. Dutch researchers reported that these fish oil compounds help to attenuate tumor growth in animal models of cancer. An omega-3 PUFA-enriched diet favorably modulates eCB signaling during obesity.

Francesca Guida, a University of Naples scientist, discussed how Vitamin D deficiency “can lead to selective alterations in endocannabinoid signaling” that contribute to pain development and hypersensitivity. Moreover, according to Guida and her colleagues, “altered Vitamin D status is responsible for deep changes in microbiota composition.” Gut microbiota modulate intestinal eCB tone, and changes in Vitamin D levels “induce modifications in composition and functions of the intestinal bacterial community” that affects microbe-host interactions.

Gut dysbiosis is implicated in several diseases, including obesity, type-2 diabetes, and depression. Fermented foods promote healthy gut flora that balance endocannabinoid tone. Endocannabinoid signaling at CB1 receptors in the gut regulates feeding behavior. University of California scientists in Riverside report that overeating associated with diet-induced obesity is driven by dysregulated gut-brain eCB signaling. The interaction between gut microbiota and the endocannabinoid system is an up-and-coming area of research with vast implications for medical science and patient care.

Looking ahead

Next summer the ICRS conference will be hosted by the National Institutes of Health in Bethesda, Maryland. The chosen venue for ICRS 2019 is a major acknowledgement by the U.S. government of the importance of this burgeoning field of study. It’s also a belated honor for the community of scientific pioneers who discovered the endocannabinoid system and who continue to unravel its mysteries.

Read part 1 of this two-part series – ICRS 2018: CBD Shines in Leiden


Project CBD director Martin A. Lee is the author of Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific.


FOOTNOTE

1. Why are CBD’s effects similar to those of CB2 activation? It may have something to do with CBD’s role as an antagonist at GPR55, a so-called orphan receptor, that signals inversely in relation to CB2. (CB2 is anti-inflammatory; GPR55 is pro-inflammatory.) Blocking GPR55 is one of several ways that CBD modulates inflammation. CBD can inhibit the reuptake of endocannabinoids and this may result in eCB-induced protective effects via heightened CB2 receptor transmission. Allosteric modulation of the the CB2 receptor could be a factor, as well. And scientists are also debating the role of receptor dimerization, whereby two receptors entangle, forming as novel signaling unit. Although CBD does not directly activate the CB2 cannabinoid receptor, CBD is a potent activator of the 5-HT1A serotonin receptor. Some researchers speculate that CBD functions like a CB2 agonist without being one because CB2 receptors “dimerize” with 5-HT1A receptors.

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ICRS 2018: CBD Shines in Leiden (Part 1)

Graft-versus-host disease (GVHD) is a common – and potentially fatal – complication following bone marrow and solid organ transplants. This life threatening condition can also occur after a patient receives a blood transfusion or other forms of transplanted tissue from a genetically different person.

The mortality rate for acute GVHD is over 80 percent. And there are no reliable molecular markers that indicate the onset or reflect the severity of a post-transplant reaction. Currently there are no FDA-approved therapies for this disease. The ability to treat acute GVHD is thus a major unmet medical need.

But hope is on the horizon, thanks to cannabidiol (CBD), a non-intoxicating component of cannabis, according to a team of Israeli scientists at the Rabin Medical Center. Data from three phase 2 clinical studies in Israel showed dramatic results when 150 mg of pure CBD was orally administered twice daily to ten patients with acute GVHD who did not respond to steroids. Although the sample size was small, the outcome proved noteworthy: “Consumption was safe and no significant adverse effects were reported. Nine out of ten patients responded to treatment, seven of them achieved complete remission and two achieved very good partial response.”

The Israeli study, “Cannabidiol – An innovative strategy for the treatment of graft versus host disease,” was featured on Day One of the 2018 International Cannabinoid Research Society conference, which convened this summer in the picturesque Dutch city of Leiden. Over 500 delegates from around the world attended the annual four-day gathering, where they discussed cutting-edge developments in cannabis science and medicine.

This year’s ICRS conference featured 58 oral presentations, including four keynotes, and 235 posters that covered a wide range of topics. CBD figured prominently in many of these reports, which also explored the health benefits of tetrahydrocannabinol (THC) and other plant cannabinoids. But the main focus, as always, was on the endocannabinoid system itself, which mediates many of the effects of cannabis.

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THC & CBD for brain health

Andras Bilkei-Gorzo, a University of Bonn scientist, linked brain aging to a decline in activity of the endocannabinoid system (characterized by diminished endocannabinoid levels and reduced coupling with CB1 cannabinoid receptors). But animal models showed that normal, age-related, cognitive decline can be counteracted with a chronic low dose of THC: “Most strikingly, THC treatment facilitated a rebalanced hippocampal gene transcription in old mice so that their expression profiles closely resembled that of young THC-free animals … Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat or prevent age-related cognitive impairments.”

The neuroprotective properties of plant cannabinoids were noted in several other presentations at ICRS 2018:

  • Alzheimer’s. Australian scientists reported that chronic CBD treatment (50mg/kg) reversed cognitive deficits in animal models of Alzheimer’s. [Keep in mind that this dosage pertains to pure single-molecule CBD, whereas whole plant, full spectrum CBD-rich oils are effective at much lower doses.]
  • Parkinson’s. Brazilian researchers found that 30 mg/kg of pure CBD reduced the loss of dopaminergic neurons in the brain regions implicated in Parkinson’s.
  • Epilepsy. Researchers at the University of Sydney, working with a mouse model of Dravet Syndrome, an infant seizure disorder, found that “sub-threshold CBD” potentiated “the anticonvulsant potential of THC.”
  • Stroke. A University of Nottingham (UK) team determined that cannabidiolic acid (CBDA, the raw version of cannabidiol that exists in the plant before it is harvested, heated and decarboxylated into CBD), acting through the 5-HT1A serotonin receptor, is neuroprotective in a cellular model of a stroke.
  • Neonatal brain trauma. Spanish scientists studied CBD’s neuroprotective properties in a neonatal rat model of hypoxia ischemia (brain damage from oxygen and nutrient restriction) and linked these effects to the CB2 cannabinoid receptor. The researchers surmised that there was no “direct action of CBD on CB2 receptors,” but noted that the data was consistent with the possible involvement of “CB2/5-HT1A heteromers.” Heteromers occur when different receptors conjoin to form novel signaling mechanisms – in this case, the CB2 cannabinoid receptor (which CBD does not activate) and 5-HT1A, a key serotonin receptor (which CBD activates).

CBD synergies

Clara Andradas, a medical scientist at the Telethon Kids Institute in Western Australia, has been researching potential applications of cannabinoids for treating pediatric cancer, specifically malignant brain tumors. Her poster disclosed that CBD and THC reduced the viability of brain cancer cells, an effect mediated in part by the CB2 cannabinoid receptor. Moreover, “the combination of cannabinoids with conventional chemotherapies enhances the anti-proliferative effects in these cells,” she concluded.

Temple University scientists assessed the therapeutic impact of CBD combined with beta-caryophyllene (BCP), a versatile terpene present in many cannabis cultivars, kitchen spices, and green vegetables. Unlike cannabidiol, BCP directly activates the CB2 receptor, which modulates immune function and neuroprotection in response to brain trauma. The two compounds together “showed a statistically significant reduction in infarct size,” according to the investigators, who concluded that “combination therapies can provide a greater benefit than single treatments alone” and should be explored further for treating ischemic stroke and other diseases.

Mark Lewis, a plant scientist with Napro Research in California, provided additional evidence that whole plant cannabis medicine may be more efficacious than pure, single-molecule cannabinoids. Lewis has bred several CBD-rich and BCP-rich cannabis chemovars. In vitro analysis showed that various CBD-BCP ratios inhibited cellular inflammation. Co-administration of CBD and BCP “produced enhanced effects as compared to each compound alone.” Of particular interest, the anti-inflammatory impact “produced by certain CBD concentrations increased by up to ten times when co-administered with certain concentrations of BCP.”

Anecdotal accounts from cannabis consumers attest to the benefits of artisanal, terpene-rich remedies. Whistler Therapeutics, a boutique medical marijuana company in British Columbia, surveyed Canadian patients to assess the analgesic impact of different aromatic terpenes in cannabis. Imbued with their own medicinal properties, terpenes interact synergistically with CBD, THC and other plant cannabinoids. For pain management purposes, the best results were obtained using cannabis varietals with noteworthy concentrations of myrcene and trans-nerolidol.

Read Part 2: ICRS 2018: Report from Leiden – “Targeting the endocannabinoid system for therapeutic relief”


Project CBD director Martin A. Lee is the author of Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific.


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Trade-In Your Ibuprofen for Cannabis

By Bonni Goldstein, MD On August 15, 2018

Pain from inflammation can and will likely affect all adults at some point in their lives, and for some, become chronic conditions that interfere with a normal quality of life.

Over-the-counter (OTC) and prescription anti-inflammatory medications are easily available, readily prescribed, and very commonly used. The most common anti-inflammatory medications are called NSAIDs: non-steroidal antiinflammatory drugs. Based on consumer survey responses, more than 17 million Americans take NSAIDs on a daily basis, with more than 70 million prescriptions and more than 30 billion OTC NSAID tablets sold annually in the United States.

OTC NSAIDS include aspirin, ibuprofen, naproxen and prescription NSAIDs include celecoxib, diclofenac, etodolac and ketoprofen. NSAIDs work by blocking enzymes called COX-1 and COX 2. These enzymes produce a group of compounds that our cells make called prostaglandins. Prostaglandins made by COX-1 enzymes activate your platelets (for blood clotting) and protect the lining of your stomach and intestines. Prostaglandins made by COX-2 enzymes are made in response to injury or infection, regulating inflammation. Most NSAIDs work non-selectively on both enzymes (except for celecoxib which is a COX-2 inhibitor). This lack of selectivity becomes an issue because pain and inflammation relief from NSAIDs come from blocking COX-2, but unfortunately COX-1 is also blocked, causing unwanted adverse side effects.

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Side effects and complications of NSAIDs are common and serious. In one study, the risk of NSAIDs adverse drug reactions was found to be 26% (Gor 2011). Complications include upper gastrointestinal bleeding and ulcers, heartburn, ringing in the ears, headaches, dizziness, liver or kidney problems, leg swelling, high blood pressure, heart attack, heart failure, stroke, and death. In June of 1999, The New England Journal of Medicine estimated that 16,500 NSAID-related deaths occur among Americans with rheumatoid arthritis and osteoarthritis every year (Wolfe 1999). Over 100,000 NSAIDs users are hospitalized per year for gastrointestinal complications A review of 17 studies found that 11% of preventable drug-related hospital admissions could be attributed to NSAIDs (Howard 2007). In 2005, U.S. Food and Drug Administration issued a public health advisory warning people of the increased cardiovascular risks of NSAIDS, and again in 2007 they published a medication guide for NSAIDs recommending the lowest dose possible for patients using these drugs. In January 2016, the FDA strengthened the existing label on all NSAIDs to warn that there was an increased chance of heart attack and stroke. Some NSAIDs, such as rofecoxib (brand name Vioxx) and valdecoxib (brand name Bextra) have been taken off the market due to their risks clearly outweighing their benefits and pharmaceutical company “misrepresentation.”

As a cannabis physician, I find these statistics and multiple FDA warnings appalling. Using dangerous drugs instead of a healing and non-toxic plant is simply ridiculous.

Over the past two decades, multiple studies have proven the anti-inflammatory benefits of phytocannabinoids and terpenoids, compounds that abound in the cannabis plant (Pertwee, 1999, Klein 2005, Nagarkatti 2009, Booz, 2011, Xiong 2012, Mecha 2013, and more). The plant cannabinoids have many different mechanisms of action in their anti-inflammatory properties, including the blockage of pro-inflammatory compounds that are made in the body as a result of injury or illness. CBDA, cannabidiolic acid, the raw non-psychoactive cannabinoid precursor to CBD, showed significant COX-2 enzyme blockage when compared to placebo, two NSAIDs and other cannabinoids (Takeda 2008). Dr. Ethan Russo and Dr. Geoffrey Guy, in their excellent 2005 study, report that the phytocannabinoids work synergistically (the “entourage effect”) to provide balanced and nontoxic medicinal effects when compared with single molecule anti-inflammatories (Russo and Guy, 2005).

Patients suffering with inflammation have many choices when it comes to cannabis medicine. Along with the ability to choose “non-smokable” delivery methods, such as tinctures, edibles, topical balms and vaporizers, patients now have many choices of which combination of cannabinoids to use. For instance, one can take cannabis medicine that is THC-rich, CBD-rich, combination CBD+THC, THCA, CBDA and/or CBG. Some cannabis medicine suppliers are combining raw and heated cannabinoids in tinctures to increase the anti-inflammatory benefits. Many patients are benefitting from drinking the juice of raw cannabis plants. In my medical practice, I have seen thousands of patients eliminate or reduce the need for NSAIDs, reducing their risks of side effects and possibly even death, with the use of cannabis.

A complete list of NSAIDs can be found here: www.webmd.com/osteoarthritis/guide/anti-inflammatory-drugs#1-5
If you have high blood pressure, heart failure or chronic kidney disease, this is why you should not take NSAIDs (see number 3): www.choosingwisely.org/societies/american-society-of-nephrology/


Dr. Bonni Goldstein, a Los Angeles-based physician, is the author of Cannabis Revealed and the medical diretor of Canna-Centers, which offers educational seminars and webinars on cannabis therapeutics.


SOURCES:

  • Booz, George W. “Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress.” Free Radical Biology and Medicine 51.5 (2011): 1054-1061.
  • Gor AP, Saksena M. Adverse drug reactions of nonsteroidal anti-inflammatory drugs in orthopedic patients. Journal of Pharmacology & Pharmacotherapeutics. 2011;2(1):26-29. doi:10.4103/0976-500X.77104.
  • Howard RL, Avery AJ, Slavenburg S, et al. Which drugs cause preventable admissions to hospital? a systematic review. Br J Clin Pharmacol. 2007;63(2):136-147
  • Klein, Thomas W. “Cannabinoid-based drugs as anti-inflammatory therapeutics.” Nature Reviews Immunology 5.5 (2005): 400-411
  • Mecha, M., et al. “Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: A role for A 2A receptors.” Neurobiology of disease 59 (2013): 141-150.
  • Nagarkatti, Prakash, et al. “Cannabinoids as novel anti-inflammatory drugs.” Future medicinal chemistry 1.7 (2009): 1333-1349
  • Pertwee, R. G. “Cannabis and cannabinoids: pharmacology and rationale for clinical use.” Pharm Sci 1997;3:539-45.
  • Russo, Ethan, and Geoffrey W. Guy. “A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.” Medical hypotheses 66.2 (2006): 234-246.
  • Slone Epidemiology Unit. Prepared for McNeil Consumer Healthcare. Analgesic use in the adult population of the United States: Acetaminophen, aspirin, ibuprofen and naproxen. Results of a population-based telephone survey, 1998-2001. Report on file, 2001.
  • Takeda, Shuso, et al. “Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis.” Drug metabolism and disposition 36.9 (2008): 1917-1921.
  • Xiong, Wei, et al. “Cannabinoids suppress inflammatory and neuropathic pain by targeting ?3 glycine receptors.” Journal of Experimental Medicine (2012): jem-20120242
  • Wolfe M. MD, et al, The New England Journal of Medicine, June 17, 1999, Vol. 340, No. 24, pp. 1888-1889.

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Should You Use Cannabis to Prevent Illness?

Our bodies consist of many unique physiologic systems whose sole purpose is to maintain an internal balance called homeostasis. We know the pancreas releases insulin to balance glucose levels between the bloodstream and cells. The thyroid gland releases thyroid hormone, which regulates vital bodily functions related to metabolism, body temperature and much more. Simply put, our bodies are working constantly to stay balanced in response to our external environment.

In the quest to understand how THC causes its well-known intoxicating effects, scientists discovered that we have yet another regulatory physiologic system, called the endocannabinoid system (ECS), whose role is to maintain homeostasis of the messages sent between our cells. Further research has shown that sickness, inflammation, and injury will trigger the ECS to take action, working to reset our internal environment back to homeostasis. This system has been described as being protective and necessary for life. What if we could target this system to prevent illness and maintain better health?

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The ECS is the most widespread receptor system in the human body. It is made up of three main parts: cannabinoid receptors; compounds called endocannabinoids; and the enzymes that make and break down the endocannabinoids.

Endocannabinoids, often referred to as our “inner cannabis,” are synthesized on demand from healthy sources of dietary fat. Cannabinoid receptors sit on the membranes of cells in certain parts of the brain and body, namely areas in the brain that control pain, memory, emotion, motor control, nausea, and appetite, as well as the gut, immune system, and peripheral nervous system. When there is a trigger that causes an imbalance, such as an injury or illness, endocannabinoids are released, acting as “keys” that bind to the receptors, which act as “locks” on our cells. Once the receptor is activated, a chemical reaction takes place in the cell, telling the cell to change its message.

ECS functioning depends on many factors, including genetics, age, stress levels, diet, and overall level of health. There can be variants in the genes that code for the ECS which can lead to propensities for certain conditions, such as ADHD and PTSD. Additionally, chronic illness, chronic stress and/or chronic sleep deprivation may lead to depletion of the endocannabinoids. These disruptions in the normal functioning of the ECS interfere with its ability to regulate cellular imbalances and achieve homeostasis.

In 2004, Ethan Russo, a neurologist and research scientist, published Clinical endocannabinoids Deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? in the journal Neuroendocrinology Letters. Russo theorized that certain individuals with the listed conditions responded to cannabis-based treatments because they had endocannabinoid deficiencies that allowed the condition to manifest in the first place.

Subsequent research has demonstrated that endocannabinoid deficiency plays a role in autoimmune diseases, epilepsy, complex regional pain syndrome, cardiovascular disease, depression, anxiety, schizophrenia, multiple sclerosis, nausea, Huntington’s disease, Parkinson’s disease, menstrual symptoms, failure to thrive in newborns, and other difficult-to-treat conditions.

The cannabis plant produces over 100 phytocannabinoids, including tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds mimic the endocannabinoids by interacting with the ECS and restoring homeostasis. Rather than wait until illness is present, there are many ways to take good care of your ECS, which will allow it to function properly, avoid deficiencies and maintain homeostasis.

It’s common knowledge that a healthy, balanced diet is necessary for emotional and physical well-being. Our bodies rely on our diet to produce the right amount of endocannabinoids to function at optimal capacity. Cannabinoids are synthesized from the fatty acids in our diets and require a specific balance of omega-6 and omega-3 in order to be produced in the right quantities.

For maximum bioavailability, the optimal ratio of omega-6 to omega-3 fatty acids from food is between 5:1 and 1:1, the lower the better for those with chronic illness. Western diets routinely consist of ratios of 20:1, mainly due to the overconsumption of omega-6 fatty acids which come from vegetable oils in many packaged foods. Western diets with higher ratios of omega-6 to omega-3 fatty acids results in a reduction of endocannabinoids, leading to the inability to maintain homeostasis.

Another factor that promotes well being of the ECS is aerobic exercise. Animal studies report that voluntary wheel running increases cannabinoid receptors in the brain and increases the sensitivity of the receptors to endocannabinoids. Human studies have shown that exercise such as running, biking and hiking enhance endocannabinoid levels in the bloodstream. In fact, endocannabinoids are likely responsible for the phenomenon described as the “runner’s high.”

Probiotics may also benefit the ECS. Lactobacillus acidophilus, a probiotic bacteria found in fermented foods such as yogurt and sauerkraut, was shown to induce the expression of cannabinoid receptors in the gut, promoting intestinal homeostasis.

Both acupuncture and osteopathic manipulation enhance the ECS. Yoga and meditation elicit the “relaxation response,” a physiological phenomenon whereby one can consciously engage in behavior that promotes mental and physical wellness; although no studies have been done to date, most experts suspect these stress management modalities enhance the ECS thereby promoting homeostasis.

Lastly, what about the ability of cannabis to prevent illness? Plant cannabinoids are well-known to be very safe and to have anti-inflammatory, antioxidant and neuroprotective properties. In cases of endocannabinoid deficiency, cannabis use may be the correcting compound, eliminating the symptoms of the condition. Regular cannabis use can decrease chronic inflammation and buildup of free radicals, both of which are thought to be the root causes of many conditions, including autoimmune and neurodegenerative disorders.

Cannabis is associated with lower fasting insulin levels and lower insulin resistance, suggesting protection against the development of diabetes. Early this year, German scientists found that chronic low doses of THC reversed the age-related decline in cognitive performance in old mice.

Additionally, research has documented the significant reduction of the use of prescription medications in states with medical cannabis laws, resulting in about a one quarter reduction in opiate deaths.

Many patients report that cannabis use enhances their overall health by promoting quality sleep, reducing anxiety and depression, and lessening pain and inflammation so that they can continue to be active participants in their lives. Although exact doses and cannabinoid combinations for preventive indications have not been researched, it is likely that low intermittent doses that include both THC and CBD will augment the ECS without causing adverse effects. A healthy diet (including fatty acids in the correct balance), aerobic exercise and stress management will help your ECS to maintain homeostasis.

Take care of your endocannabinoid system and it will take care of you.


Dr. Bonni Goldstein, a Los Angeles-based physician, is the author of Cannabis Revealed and the medical director of Canna-Centers, which offers educational seminars and webinars on cannabis therapeutics.


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Cannabis Science: What to Believe?

Alan was disoriented and his words were not making sense. His wife thought he might be having a stroke, so she took him to the emergency room where he was seen by the on-call neurologist. When asked, Alan admitted to using cannabis on a regular basis for many years. The neurologist then brought him a printout with the title: “Marijuana Use Associated with Increased Risk of Stroke, Heart Failure.” That was when I got the call asking me if this was for real.

I have not seen this dangerous trend in my clinical practice, but many of my patients have used cannabis for many years so I was motivated to track down the referenced article and review it. If this was a valid concern, I wanted to know so I could inform patients about the risk.

BIAS BAKED IN

A valid study can inform, enrich, and save lives. Poor studies can create fear and ignorance. The bias can lean either pro or con. Either way detracts from our understanding of cannabis and our ability to provide patients with the best care. I obtained a copy of the original article and reviewed it carefully.

The first paragraph gave me a clue. “…cannabis is…the most widely cultivated, trafficked, and abused drug…” (emphasis added)

I had read similar statements in other scientific articles:

  • “Cannabis remains one of the world’s most widely used substances of abuse amongst pregnant women.” (emphasis added)
  • “Despite increasing public health concerns, cannabis remains the most commonly used illicit drug…” (emphasis added)

What do all these first paragraphs in published scientific articles have in common? Each one reveals a prejudice that makes the rest of the data that follows less trustworthy. Because cannabis has been illegal and vilified for so many years, many publications assume harm even before they are written.

PATIENTS ARE LOOKING FOR ANSWERS

The scientific literature is teeming with new publications every week reporting on cannabis, cannabinoids, and other medicinal uses for the plant. Some of these studies are well done, but how do you know which are valuable and which are faulty? Scary headlines like “Cannabis Use Predicts Risk of Heart Failure” are dramatic, and often circulate widely in the press and on social media.

Most health care providers know little about the medical use of cannabis; they are not taught the endocannabinoid system in medical schools and many avoid this sensitive topic altogether. Patients are educating themselves the best they can by reading news articles and reviewing scientific studies made available online, but not everything we read is accurate and not every study is well-designed. Here are a few guidelines to help you tell the difference between valid information and that which should be taken with a grain of salt.

imageANIMAL vs. HUMAN STUDIES

A study of value to real people reports on a sample that is representative of most human beings. Humans are not mice, so valid conclusions shaping clinical care cannot be reliably based on how mice respond to cannabis. This does not mean that information derived from mice, rats, pigs or other animals is not useful, but the best we can say about animal studies is that further research may be indicated.

UNRELIABLE SOURCES

“Associations between regular cannabis use and both mental illness and lung cancer have been well established.” [1] This is an untrue statement. Dr. Donald Tashkin at UCLA designed a study intending to prove that smoking cannabis was associated with increased cases of lung cancer.

To his great surprise he found that this was not true, and eventually published an article that indicated just the opposite. [2] False statements based on poorly designed studies are sometimes referenced as fact, leading to further poor conclusions. Supporting a hypothesis with weak science is often an indication of prejudgment.

OPINIONS STATED AS FACTS

“Mortality post [myocardial infarction] may additionally be increased in cannabis users…” [1] This statement was used in a scientific article reporting on the damaging effects of cannabis in the cardiovascular system. The use of the word ‘may’ here makes this an opinion, not a fact.

It is also contradicted by other data. Look out for words like “may” or “could” as they indicate a guess, assumption, or opinion rather than a fact backed by observation. The accuracy of the above statement is questionable. In 2018 Johnson-Sasso [3] published a well-done study concluding: “(Our) results suggest that, contrary to our hypothesis, marijuana use was not associated with increased risk of adverse short-term outcomes following AMI. Furthermore, marijuana use was associated with decreased in-hospital mortality post-acute myocardial infarction.”

SELECTION SKEWING

Science studies humans when possible, but selection of subjects is difficult, especially when studying the effects of cannabis. As long as the plant is federally illegal and socially suspect, most individuals will be apprehensive about disclosing information related to their use.

In many studies, information is gathered by asking patients if they use cannabis, or any illicit substances (self-reporting). The substances are often listed: “Have you used any of the following: amphetamine, marijuana, methadone, heroin, LSD, PCP, cocaine, other?” Not everyone is going to admit to using a substance included in that list. Would you?

This problem was clearly illustrated in a study done in 1995. [4] This research collected data from both self-reports and blood tests. When tested, 585 women tested positive for THC, but only 31% of these women had self-reported use of cannabis. As expected, self-reporting clearly carries the risk of under-reporting. If data is collected only on those who disclose the personal use of an illegal substance, that data will be skewed.

Lab testing to select subjects has limitations as well. Serum drug tests may underestimate the use of cannabis because the THC metabolite they test for is only present for a short period of time. A study subject could have used cannabis last week, or a few days ago, and no longer test positive.

Selection skewing leads to statements like, “Compared with non-cannabis users, cannabis users were older and predominantly men [and]…had an increased prevalence of most risk factors including hypertension, tobacco use, and alcohol use.” [1] This is most likely true for that study’s selection, but not accurate for the general population.

CONTROLLING FOR VARIABLES

Many, but certainly not all, who use cannabis also use other substances that include tobacco and alcohol. Separating out the subjects who are only affected by cannabis is difficult but must be done accurately for good data on the effects of cannabis alone. Because this task is so challenging, many study results are weakened by confusing the effects of more than one substance.

imageWE NEED FACTS–WELL-COLLECTED AND WELL-STATED

It is important to review scientific publications carefully and consider any weaknesses stated or implied. The risks and benefits of cannabis as medicine need to be known so the plant can be used safely to everyone’s best advantage. Fear and social attitudes have no place in well-done scientific studies. Unscientific enthusiasm for a widely used herb has no place in the science either. For cannabis to be trusted and appropriately used as medicine, we need impartial facts-well-collected and well-stated.

Thankfully, Alan had not had a stroke. It appeared he had a ‘TIA,’ which is a transient loss of blood flow to the brain with no long-term damage done. But they kept him overnight for tests and to make sure he was safe to discharge. He went home the next day and continued to use cannabis, knowing that the information shared with him by a well-meaning neurologist was not necessarily valid. For him, the personal benefits were worth the possible risks.


Stacey Kerr, M.D. is a teacher, physician, and author living and working in Northern California. After several years working with the Society of Cannabis Clinicians, and co-developing the first comprehensive online course in cannabinoid medicine, she now serves as Medical Director for Hawaiian Ethos. Dr. Kerr is a Project CBD contributing writer. This article was originally published by Hawaiian Ethos.


SOURCES

1. Kalla et al. Cannabis use predicts risks of heart failure and cerebrovascular accidents. J Cardiovasc Med, 2018, 19:000-000 doi:10.2459/JCM.0000000000000681

2. Tashkin. Effects of Marijuana Smoking on the Lung. Ann Am Thorac Soc Vol 10, No 3, pp 239-247, Jun 2013

3. Johnson-Sasso CP et al. Marijuana use and short-term outcomes in patients hospitalized for acute myocardial infarction. PLoS ONE 13(7): e0199705. 2018.

4. Shiono et al. The Impact of cocaine and marijuana use on low birth weight and preterm birth: A multicenter study. Am J Obstet Gynecol. 1995 Jan;172(1 Pt 1):19-27.

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Cannabidiol and Epilepsy Meta-Analysis

How often have we heard, “More research is needed,” from those who would prefer to see no change in policies that should be informed by science? From climate denial to cannabis prohibition, the demand for absolute scientific certainty is a call for inaction.

It begs the question: When is there “enough” research?

How about not enough to eliminate all uncertainties, but enough to recommend medical treatment or change policy?

Published in September 2018, a meta-analysis of CBD treatment for epilepsy provides “enough” research – both to say that CBD is effective in certain kinds of epilepsy, and that CBD-rich extracts are generally better medicine than CBD isolates1.

Three Brazilian scientists – Fabricio Pamplona, Lorenzo Rolim da Silva and Ana Carolina Coan – examined data from 11 different studies comprising 670 patients who were treated for an average of 6 months. The meta-analysis focused specifically on three kinds of childhood seizures (Dravet, Lennox-Gastaut, and those caused by CDKL5 deficiency), and sought to describe the effectiveness, required doses, and side effects associated with cannabidiol.

The authors further analyzed the differences between CBD-rich extracts and CBD isolates. Epidiolex (FDA-approved pharmaceutical CBD) and some unregulated, hemp-derived CBD products are considered isolates, as they lack the full spectrum of other cannabinoids and terpenes that are present in whole-plant extracts.

It works!

Seventy-one percent of people using CBD-rich extracts had reduced seizure frequency, compared with 46% of those using CBD isolates.1 Both of these numbers are incredible. What’s more, the population was treatment-resistant, having tried between 4-12 medications for three years before using CBD.

The authors also examine whether the improvements met specific thresholds: How many people had greater than 50% reduction of seizures (a typical threshold used in medicine)? How many had greater than 70%? Complete cessation of seizures?

Both the whole-plant extracts and CBD isolates helped cut the number of seizures in half for roughly 40% of patients, once again suggesting that both formulations – single-molecule and whole-plant – can be highly effective medicines.

Both formulations reduced seizures by 70% in about one quarter of the patients, but fewer studies recorded this. And roughly one in 10 patients using CBD became seizure-free, although not enough studies reported this metric to compare different formulations.

Less is more

Perhaps the most striking conclusion of this study is the dramatic difference in doses for isolates compared to full spectrum CBD-rich oil extracts. The mean dosage for people using pure CBD was 25.3 mg/kg/day, but for CBD-rich extracts it was 6.0 mg/kg/day.

In other words, CBD in a whole plant extract was over 4 times more potent than isolated CBD. This result is a reflection of what’s known as the “entourage effect,” whereby the therapeutic impact of the whole plant is greater than a single compound or even the sum of the plant’s individual medicinal components.

We can say that “more research is needed” to fully understand the biochemical basis of the entourage effect in epilepsy, but we are well past the point of questioning its existence and importance.

Adverse events

Whole-plant cannabidiol also distinguished itself from isolate CBD with a lower rate of side effects. Isolate CBD was associated mild adverse events2 in 73% of patients, whereas whole-plant CBD was associated with mild adverse events in only 33% of cases. The authors suggest that this difference is due primarily to the lower dose of CBD used when formulated as a whole-plant extract.

It’s worth noting that many of these “side effects” are present in the absence of CBD, and that adding CBD to treatment tends to reduce these side effects, so the numbers may be overestimates.

What’s a meta-analysis?

A meta-analysis is a specific kind of study meant to draw firmer conclusions once many papers have been published on a single topic. It is used to determine quantitative information, and can also help determine the basis for different results that the initial studies did not have the power to prove.

Meta-analyses, however, are prone to bias when the studies used very different designs, and there was one notable difference between the whole-plant extract and CBD-isolate research. All the isolate studies were prospective, meaning that participants were treated according to a protocol written by the researchers. The whole-plant extract studies, on the other hand, were retrospective analyses or surveys.

The lack of prospective studies with whole-plant extracts is due to the schedule 1 status of marijuana, which seriously hinders research into the medical uses of cannabis. Retrospective studies are slightly more prone to bias, such as underreporting of side effects. Despite the potential for bias, this meta-analysis demonstrates that whole-plant cannabidiol extracts are as effective as CBD isolates, if not more so, and can treat refractory epilepsy at much lower doses.


Adrian Devitt-Lee, a Project CBD contributing writer, is a graduate from Tufts University with a degree in mathematics and chemistry.


FOOTNOTES

1. The numbers reported here are not exactly the same as those reported in the meta-analysis. There were a few minor mathematical errors due to complications when consolidating the various data. The mistakes do not change the conclusions of the original study, and the authors have issued a correction. The correct numbers are reported here.
2. “Adverse events” were defined by the authors of each individual study, which could lead to some bias. Mild events included weight loss, fatigue or sedation, gastrointestinal problems, and nausea. Severe events included alterations in liver function.

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