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Every five months Irvin Rosenfeld has gets a FedEx shipment, courtesy of the federal government, containing six metal canisters, each with 300 perfectly rolled joints of what today would be considered rather mediocre weed. But the quality of the government-issue reefer matters less than the fact that Uncle Sam has been supplying him with it regularly since 1982, when Rosenfeld won the right to smoke cannabis for reasons of medical necessity under the auspices of the federal government’s Compassionate Investigational New Drug (IND) program. Rosenfeld smokes cannabis every day to treat a rare and excruciatingly painful bone disease called multiple congenital cartilaginous exotosis.

Medicine in a Can

A total of 15 patients with different incurable ailments would enroll in the Compassionate IND Program to study cannabis before it was officially shut down in 1992. As one of the last living IND participants, Rosenfeld remains a forthright and energetic medical cannabis advocate, a role he takes very seriously. His personal story is compelling. He has suffered with extreme pain for most of his life. At age 10, x-rays revealed more than 200 tumors sprouting from bones in his arms and legs. He would undergo a dozen surgeries and consume a steady diet of prescription narcotics and other pharmaceuticals.

When he first smoked marijuana as a teenager at a social gathering, it was a revelation. Before long he realized that if he smoked cannabis every couple of hours, his pain eased and he didn’t have to rely as much on doctor-prescribed muscle relaxants, opiates, and benzos to get by. Although he felt no euphoric effects from cannabis, the herb somehow kept his disease in check, inhibiting tumor growth and helping him live a decent life. A walking, talking refutation of the lazy stoner myth, he went to college, played sports, married his childhood sweetheart Debbie, and became a successful stockbroker.

There’s no doubt that cannabis helps Rosenfeld’s condition, but it’s not a cure. Though he has learned to live with his pain, at times its relentlessness makes him feel depressed, trapped in a lonely prison from which there’s no escape. At least that’s how it felt until one day in 2020, when Rosenfeld’s pain management specialist, Dr. Michele Weiner, mentioned a potential jailbreak: ketamine.

Dissociation Nation

Ketamine, an FDA-approved “dissociative anesthetic,” has been around since 1962 when it was first synthesized by chemist Calvin Stevens. Employed initially as a tranquilizer in veterinary medicine, the drug was widely utilized during the Vietnam War for treating wounded troops. Ketamine kept injured soldiers conscious but cognitively disconnected from their pain, all while maintaining their vital functions.

Earlier this year, the Food & Drug Administration disclosed that it would not regulate non-pharmaceutical CBD products, thereby putting the onus on Congress to devise an appropriate regulatory framework for cannabidiol and other hemp-derived cannabinoids. Solicited by a formal Congressional Request for Information (RFI) on ideas for how to regulate hemp-derived CBD, public feedback included a diverse range of perspectives from businesses, trade associations, and other stakeholders. But today’s “hemp” market has moved way beyond CBD, as noted by several commentators who expressed concerns about the unregulated proliferation of high-dose THC consumables and novel synthetic intoxicants thanks to loopholes in the 2018 Farm Bill, which is up for revision and renewal in the coming months. What follows are comments recently submitted by Tiffany Devitt, a longtime Project CBD supporter, in response to the Congressional RFI on a potential regulatory pathway for hemp-derived CBD. A leading California cannabis industry policy influencer, Devitt is currently Director of Regulatory Affairs at CannaCraft & March and Ash.

Current Market Dynamics

Loopholes in the 2018 Farm Bill

The 2018 Farm Bill defines “hemp” as “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.”

Within that definition, are two critical phrases: “all derivatives” and “whether growing or not.”

“All derivatives” is currently being misinterpreted to encompass any compound that can theoretically be chemically synthesized from CBD, even wholly novel compounds not found in the plant in commercially meaningful quantities (if at all).“Whether growing or not” is being misconstrued to mean that the 0.3 percent THC limit applies to the plant biomass and the final product, resulting in THC levels in consumer products labeled as “hemp” that substantially exceed THC limits set in state-regulated cannabis markets.Lastly, the omission of THCA, a natural compound that converts to THC when heated, is causing further confusion.

Collectively, this language has fostered a regulatory gap that companies are taking advantage of to sell highly intoxicating products, colloquially and misleadingly referred to in the national unregulated hemp marketplace as “legal cannabis.”1

The “Hemp” Market Has Moved Way Past CBD

In the federal discussion about hemp, “hemp” and “CBD” are often conflated. The reality is that the commercial market has largely shifted away from non-intoxicating CBD wellness products to highly intoxicating recreational products. Pseudo-hemp companies with brand names like Fuked Up2 and Clusterf*ck3 make no pretense of selling nutritional supplements. Instead, they market THC-like products that are far stronger than anything found in state-regulated cannabis markets, where the maximum dose of THC per serving is commonly capped at five to 10 milligrams.4 In the unregulated “hemp” market, brands like Chapo Extrax sell products with hundreds of milligrams of synthetic THC per serving.5 The so-called “hemp” market is no longer predominantly a wellness market. It is, in the words of Chapo Extrax, “the newest drug cartel in town.”6

I counted over 175 talks and posters at the 33rd annual gathering of the International Cannabinoid Research Society (ICRS), which convened in Toronto at the end of June. In accordance with longstanding ICRS policy, all speakers presented new findings and data that had not yet been published in a peer-reviewed journal. But this year’s 4-day ICRS conference was notable not only for its cutting-edge science. It was also the first ICRS meeting since the passing of its cofounder and guiding light Raphael Mechoulam.

Several colleagues paid homage to Mechoulam in a moving memorial session that honored his many contributions to the burgeoning field of cannabinoid science, which has grown to encompass numerous academic and clinical disciplines. The wide range of topics addressed at the conference is both a reflection of the endocannabinoid system’s ubiquitous role in health and disease and a testament to the enduring mysteries of plant medicine.

CBD & THC

Cannabidiol (CBD) figured prominently in several noteworthy oral presentations and posters that explored the therapeutic potential of plant cannabinoids from various angles. A few highlights:

CBD for breast cancer recovery. Researchers from McGill University in Montreal reported a case study of a 52-yr-old breast cancer survivor who experienced significant improvement in neuropathy symptoms and quality of life following self-administration of 300 mg/day of CBD isolate for six weeks.

CBD for post-concussion syndrome. John Patrick Neary and a team of scientists in Western Canada examined CBD’s impact on 3 female patients who suffered from post-concussion syndrome. They found that cannabidiol helped restore blood pressure dynamics and improve cardiac function in patients who consumed doses as low as 50 mg/day or as high as 400 mg/day.

Dr. Mark A. Scialdone, a recognized expert in the field of organic chemistry who specializes in natural product chemistry, is an inventor of 37 issued US patents and the author of 17 peer-reviewed articles in science publications. From 1994 to 2013, he was employed as a principal investigator at DuPont Central Research and Development. Dr. Scialdone is a founding member of the Cannabis Chemistry Subdivision of the American Chemical Society from which he received the 2018 CANN-CHAS Heidolph Award for Excellence in Cannabis Chemistry. Scialdone is currently founder and president of BetterChem Consulting, which provides consulting services worldwide in the chemical, food, plant essential oil, and cannabis industries. He has guided clients on license applications, facility design and build out, equipment installation and optimization, and plant oil extraction for cannabis and hemp processing facilities.

Project CBD: Your presentation with Allyn Howlett at the International Cannabinoid Research Society conference in Toronto (June 2023) discussed the chemical conversion of CBD into Δ8-THC (delta-8 THC) and “numerous additional THC isomers . . . with unknown pharmacological and safety profiles.” Explain what an isomer is and why the lack of information regarding novel THC isomers is problematic.

Dr. Mark A. Scialdone: Isomers are similar molecules having different discrete arrangements of the same atoms creating molecules with different chemical and physical properties. The Δ8-THC being produced from the acid-catalyzed conversion of CBD is an unpurified reaction mixture that contains multiple, non-natural THC isomers, including Δ8-iso-THC and Δ4(8)-iso-THC. These are not present in cannabis and are only formed in the chemical conversion, whose impact on human health is unknown. What’s more, these non-natural THC isomers are difficult to measure — and they are also difficult, if not impossible, to remove from the reaction mixture to purify the Δ8-THC that’s produced. You need access to sophisticated analytical methods to discern product purity from the isomeric byproducts formed, which is why production from hemp-derived cannabinoid products needs to be done under the appropriate FDA regulations for API [active pharmaceutical ingredient] synthesis and manufacturing.

Project CBD: Are there other byproducts from CBD conversion to Δ8-THC that we should be concerned about in addition to these THC isomers?

Scialdone: In addition to the iso-isomers of THC, there are also abnormal isomers called regioisomers that are formed in the conversion reaction. Recently, degradation products such as olivetol as well as chlorinated compounds, have been found in commercial Δ8-THC products tested. The conversion of hemp-derived CBD into Δ8-THC and other synthetic compounds such as HHC (hexahydrocannabinol) occurs without proper regulatory oversight to ensure process standardization, product specification, and accurate third-party testing, all of which are mandated in state-licensed cannabis programs.

It was once a common assumption within the cannabis community that plant cannabinoids aren’t “activated” or useful until they are “decarbed” — short for decarboxylated — which refers to the process of heating cannabis before it is consumed. But that notion has proven to be way off the mark.

The major and minor cannabinoids in raw, unprocessed cannabis plants are found in their acid form: THCA, CBDA, CBGA, CBCA, and THCVA. When decarboxylated at a particular temperature, these cannabinoid acids are converted into their neutral counterparts: THC, CBD, CBG, CBC, THCV, etc. (and the ‘A’ vanishes). This process also occurs naturally, though much more slowly, as dried cannabis ages.

Jump to raw cannabis smoothie recipes.

Cannabinoid Acids

Thus far, medical scientists have focused primarily on the therapeutic properties of decarbed or neutral cannabinoids. But increasingly, researchers, physicians, and patients are recognizing the value of cannabinoid acids as well as other compounds found in the raw cannabis plant, which contains various enzymes, vitamins, minerals, protein, fiber, essential fatty acids, flavonoids, carotenoids, terpenes, and other polyphenols.

Concentrated in the resinous trichomes of raw cannabis flowers and to a lesser extent on the leaves, cannabinoid acids such as THCA and CBDA offer a robust cornucopia of health benefits without any intoxicating effect. What’s more, cannabinoid acids are more easily absorbed than their decarbed versions.

Pain, anxiety, and sleep are major drivers of medical cannabis use. But gastrointestinal symptoms, such as nausea and upset stomach, aren’t far behind.1 Even small doses of cannabis can soothe the stomach and stimulate the appetite. In fact, of the four cannabis-derived drugs approved so far by the U.S. Food and Drug Administration, three are prescribed for the treatment of chemotherapy-induced nausea and vomiting.

One gastrointestinal condition long associated with self-medication through cannabis is inflammatory bowel disease (IBD). A flurry of recent research bears this out. In a newly published survey of 162 IBD patients in Puerto Rico, where medical cannabis is legal but recreational use is punishable with prison time, about 25% anonymously reported using cannabis to treat their symptoms. Among these, nearly all said it offered relief.

Findings from another recent survey of New York and Minnesota medical cannabis dispensary patients were similar. And two new reviews aimed at physicians and researchers concur that while further study is needed, the evidence to date leaves little doubt that IBD patients are helped by cannabis.

ECS & the Gut

On a molecular level, this all makes sense. The endocannabinoid system is widely distributed throughout the gastrointestinal system, including not only CB1 and CB2 cannabinoid receptors but also other cannabinoid targets like PPARs, GPR55, and TRPV1. The job of the endocannabinoid system here, as everywhere, is to maintain order and balance, and the endogenous compounds (ligands) that interact with these receptors can be supported in this task by cannabis-derived and synthetic cannabinoids.

(The concentration of cannabinoid receptors in the gut also helps to explain cannabis hyperemesis syndrome, in which an overabundance of exogenous cannabinoids, particularly THC, triggers debilitating nausea, vomiting, and pain that typically resolves when cannabis use stops.)

Cannabis is supposed to be relaxing and fun. What’s not to like about giggles, munchies, and a brief break from the mundane? Unfortunately, the news from California’s Emerald Triangle is anything but upbeat these days.

Report after report portends doom with headlines like “the world’s largest legal weed market is going up in smoke” (The Economist), “California pot industry facing ‘extinction event‘” (SF Gate), and “Despair in Emerald Triangle as CA legal cannabis collapses” (CalMatters).

Is It Really That Bad?

Yeah, it is.

Legal sales have been on a downward slide for over two years with no signs of relief on the horizon. At its roots, the main cause appears to be the overwhelming dominance of the illicit market, which is estimated to be twice the size of the regulated market (Politico).

The result: Cascading business failures across the industry.

Project CBD recently reported on studies indicating that cannabis terpenes — the compounds that give the plant its robust and distinctive smell — activate the CB1 cannabinoid receptor. What’s more, in the presence of THC (also a CB1 agonist), terpenes appear to modulate cannabinoid activity in varied and interesting ways.1,2 Today we focus on spicy-peppery beta-caryophyllene (BCP), one of the most common cannabis terpenes, which acts on several targets that impact the endocannabinoid system, not just CB1.

BCP is also a component of black pepper, basil, oregano, cinnamon, hops, rosemary, cloves, and citrus, as well as many leafy greens. Approved by the United States Food and Drug Administration for use as a flavoring and fragrance agent in food, this powerhouse sesquiterpene has been the subject of considerable medical-science research. Recent papers explore the potential role of BCP in treating a wide range of conditions including non-alcoholic fatty liver disease, chronic pain, and substance abuse.

A “Dietary Cannabinoid”

Beta-caryophyllene, a weak CB1 agonist, is what scientists refer to as a “full agonist” at the CB2 cannabinoid receptor, which plays an important role in regulation of immune function and inflammation. Its presence in many foods and spices and its strong affinity for CB2 has earned BCP recognition as the first known “dietary cannabinoid.”

Multiple studies have shown that beta-caryophyllene also interacts with peroxisome proliferator-activated receptors (PPARs, pronounced pee-parrs) located on the surface of the cell’s nucleus. CBD also activates these receptors, which regulate metabolism and energy homeostasis.

Given the role of PPARs and the endocannabinoid system in modulating metabolic processes, a group of researchers based in Turin, Italy, wanted to see if BCP was effective in a cellular model of non-alcoholic fatty liver disease, the most common chronic liver disorder worldwide with a global prevalence of more than 30%.3

Biblical scholars have written about the role of cannabis as a sacrament in the ancient Near East and Middle East. Archeological evidence confirms the use of the plant in fumigation rituals in ancient Israel. Scriptural references indicate that cannabis was a key ingredient in the holy anointing oil employed in religious rites. But Yahweh, the Almighty Jealous God, frowned upon the idolatrous use of cannabis, the polytheistic drug of choice. The Old Testament chronicles the embrace of One God instead of many, a major shift that coincided with the displacement of cannabis as a ceremonial substance, as Chris Bennett reports in his latest book, Cannabis: Lost Sacrament of the Ancient World.

Humankind’s connection to cannabis reaches back tens of thousands of years. The role of cannabis in the ancient world was manifold: with its nutritious seeds, an important food; with its long, pliable strong stalks an important fiber; as well as an early medicine from its leaves and flowers; and then there are its psychoactive effects . . .

Due to its usefulness, cannabis has a very long history of human cultivation. How long, exactly, remains unknown. “No other plant has been with humans as long as hemp,” says ethnobotanist Christian Rätsch. “It is most certainly one of humanity’s oldest cultural objects. Wherever it was known, it was considered a functional, healing, inebriating, and aphrodisiac plant. Through the centuries, myths have arisen about this mysterious plant and its divine powers. Entire generations have revered it as sacred . . . . The power of hemp has been praised in hymns and prayers.”

The Great Leap Forward

There has been interesting scientific speculation that the psychoactive properties of cannabis played a role as a catalyst in the “Great Leap Forward,” a period of rapid advancement for prehistoric humanity, which started about 50,000 to 65,000 years ago. In their fascinating paper, “The Evolution of Cannabis and Coevolution with the Cannabinoid Receptor — A Hypothesis,” Dr. John M. McPartland and Geoffrey W. Guy explain how ingestion of this plant may have aided prehistoric humans. “In a hunter-gatherer society,” they write, “the ability of phytocannabinoids to improve smell, night vision, discern edge and enhance perception of color would improve evolutionary fitness of our species. Evolutionary fitness essentially mirrors reproductive success, and phytocannabinoids enhance the sensation of touch and the sense of rhythm, two sensual responses that may lead to increased replication rates.”

The authors postulate that plant compounds, which interact with the human body’s endocannabinoid system, “may exert sufficient selection pressure to maintain the gene for a receptor in an animal. If the plant ligand [plant-based cannabinoid] improves the fitness of the receptor by serving as a ‘proto-medicine’ or a performance-enhancing substance, the ligand-receptor association could be evolutionarily conserved.” In essence they are suggesting that there’s a coevolutionary relationship between “Man and Marijuana” — and that somehow as we have cultivated cannabis, it may have cultivated us, as well.

Ten years ago, most cannabis consumers couldn’t tell a terpene from a cannabinoid. But today things are different. Cannabis flower is categorized according to terpene profile. Product manufacturers add terp blends back into edibles and concentrates. Limonene is practically a household name.

And for good reason. Terpenes impart desirable flavors and aromas. And they appear to be good for the body, as well.1 Now it turns out that some terpenes also may contribute to the cannabis high.

A 2021 study2 by University of Arizona scientists concluded that certain terpenes are “cannabimimetic” (in a mouse model of cannabis intoxication) and can selectively enhance cannabinoid activity.

And this month comes a brand-new paper in the journal Biochemical Pharmacology3 by Israeli researchers who report that three cannabis terpenes — at concentrations similar to those found in actual cannabis plants — significantly boost THC signaling at the CB1 receptor.

CB1 Activation

Using an in vitro cellular model, the Israeli team compared CB1 receptor activation by 16 different cannabis terpenes to that of THC alone and to THC-terpene blends with a botanically relevant ratio of 10:1.

Special glands protruding from cannabis flowers express a series of unique molecules. Cannabinoids, as they are known, exist in cannabis.  But it turns out that identical molecules are present in non-cannabis plants, as well.  Researchers from Israel’s Weizmann Institute recently reported that they found cannabigerolic acid (CBGA) and other rare cannabinoids in Helichrysum umbraculigerum, a perennial shrub informally known as the woolly umbrella.1

A South African Botanical

Ferdinand Bohlmann and Evelyn Hoffman first discussed the chemical irregularity of Helichrysum. In a 1979 paper published in Phytochemistry2, they analyzed the South African species H. umbraculigerum, native to the eastern part of the country, where it was used in traditional medicine and fumigation rituals.

Bohlmann and Hoffman asserted that the plant’s tops — both leaves and flowers — produce cannabis-specific compounds. But a follow-up study conducted by Italian researchers in 2017 failed to find CBG or its acidic precursor in H. umbraculigerum flowers. They did, however, identify an analog of CBG known as Heli-CBG (also present in some fiber hemp varietals), which binds to the CB2 cannabinoid receptor.3,4

In a May 2023 article in Nature Plants, Weissman Institute scientists confirmed that woolly umbrella produces CBGA in trichomes on its leaves, but hardly any CBGA was present on its flowers. That’s different from cannabis, where CBGA and other cannabinoids are concentrated in trichomes on flower tops.1

Trichomes found on cannabis inflorescence (flowers) have a special cellular build, according to a 2022 study by University of British Columbia researchers in Current Biology. The gland’s bulbous head holds large porous cells that let acidic cannabinoids (CBGA, CBDA, THCA, etc.) move through the trichome.5 The Weizmann Institute team reported that H. umbraculigerum produces a similar cannabinoid transport network on its leaves.1

Recently I was chatting with a friend who is casually interested in psychedelic science. He told me he hadn’t read as much coverage of psychedelics in popular magazines and other mainstream outlets lately, and asked whether research has slowed. My response? Not at all.

According to Pubmed, the online repository of the National Library of Medicine, last year saw far more papers published on psychedelics than ever before — about 33% more than in 2021, which itself was a 19% increase over 2020. And this year is well on pace to surpass 2022.

Every day another email arrives in my inbox with word about the latest papers, many of which address the promise of psychedelic-assisted therapy for depression, addiction, PTSD, and other mental health disorders.

But dig deep into the scientific literature and you’ll find plenty of outliers and oddities that have nothing to do with therapy per se, covering fascinating subjects like psychedelics for headaches or color-blindness; “entity” encounters; and the still-mysterious question of what, exactly, these compounds do to the brain.

Mood-Elevating Microdosing

Whether microdosing psychedelics can help people in meaningful ways independent of the placebo effect continues to be a subject of debate. A March 2023 paper in the journal Biological Psychiatry1 adds to the discourse by reporting that in a placebo-controlled study of 40 healthy male volunteers, microdosing LSD improved self-reported ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days relative to non-dose days. However, microdosing was not sufficient to promote enduring changes to overall mood or cognition. Nor was it entirely harmless. Seven of the 40 participants reported treatment-related anxiety, and four dropped out as a result.

This transcript is adapted from CannMed’s weekly podcast, hosted by Ben Amirault, who recently interviewed Bonni Goldstein, MD, one of the country’s most respected and experienced medical cannabis physicians. Dr. Goldstein has treated thousands of patients with medical cannabis. She is the medical director of Canna-Centers Wellness & Education and the clinical advisor to Cannformatics. She is also the author of Cannabis is Medicine: How Medical Cannabis and CBD are Healing Everything from Anxiety to Chronic Pain. Dr. Goldstein will be leading the Medical Practicum at CannMed 2023 (May 15-17), where she will also be speaking about CBG and other minor cannabinoids during the main session.

Ben Amirault, CannMed: I wanted to discuss one of the so-called minor compounds that you’ll be covering during your talk at CannMed this month. You have said that cannabigerol, or CBG, is one of your favorite cannabinoids. Why?

Dr. Goldstein: It appears that CBG does a lot of things that THC does and a lot of things that CBD does — but maybe even a little bit better. It’s kind of a bridge between THC and CBD. CBG is not intoxicating or impairing. It seems to be effective at lower doses compared to CBD. And it does appear to address some of the main issues that people turn to cannabis for — inflammation, pain, anxiety, sleep problems, depression, and cancer. So, like it checks all the boxes, especially for people who don’t want to get high and who don’t have the ability to pay for very high doses of CBD.

CannMed: It’s interesting that you say CBG is a bridge between THC and CBD. Is that because CBG is a precursor for the other plant cannabinoids?

Dr. Goldstein: CBG’s parent compound, cannabigerolic acid (CBGA), is kind of known as the mother of all the cannabinoids in that it’s the compound that’s found in immature cannabis flower. And then, based on the genetics of the plant and the enzymes that it’s exposed to, CBGA changes into CBDA and/or THCA, which turn into CBD and THCA when heated. CBGA hasn’t really been studied very much. I would say it is highly understudied. But I suspect that we will eventually find out that CBGA has some very interesting anti-inflammatory and anti-cancer properties. We don’t know really know yet. But at least CBG is being studied. I constantly look at the scientific literature, and just this year there’s a study published from Israel on how CBG may be helpful for multiple sclerosis. And there’s another study that looked at CBG’s mechanism of action in terms of how it works for pain and inflammation. So, there’s a lot of interest in CBG, which is really exciting.

In 2013, Noriko Shinjyo, Ph.D., a Research Associate at Chiba University in Japan, coauthored a study with Italian scientist Vincenzo Di Marzo on cannabichromene (CBC), a phytocannabinoid that exerts profound effects on the nervous system.1

Published in Neurochemistry International, their paper probed how CBC influences the fate of adult neural stem progenitor cells, which are described as “an essential component of brain function in health as well as in pathology.” As stem cells mature, they change and differentiate into new neurons and other cells. CBC was shown to have a positive effect on neural stem progenitor cells during their maturation phase, according to in vitro research.

Recently a different group of scientists has followed up on this decade-old discovery by delineating seven mechanisms through which CBC is able to protect and regenerate the nervous system. They reported their findings in Life, a Swiss scientific journal, noting that CBC, a “neurogenesis enhancer,” enables stem cells “to sustain their viability and differentiation.”2

What Are Neural Stem Cells?

Scientists have identified specific areas of the brain — the hippocampus and the lateral ventricles — where neural stem cells are created. These cells undergo a maturation process, known as differentiation, which is an important stage for young cells located in the spinal cord, brainstem, and brain regions programmed for muscle control. Young stem cells evolve into new neurons, but they can also form cells that comprise the protective sheath surrounding nerves.

Some neural stem cells differentiate into astroglial cells, also known as astrocytes. These abundant star-shaped cells populate the grey and white matter of the brain, where they regulate cerebral blood flow and the transmission of electrical impulses. They also play a crucial role in maintaining the blood-brain barrier and repairing the brain and spinal cord following an infection or a traumatic injury.

If you’ve been to our website before, you’ll see it’s much easier to navigate now, thanks to the talented folks at Blue Dream, Ganjapreneur’s in-house creative agency.

You’ll also see that we have significantly increased our medical conditions-related content.

“The new Project CBD website is designed to make their educational content more accessible and discoverable,” explained Noel Abbott, CEO of Ganjapreneur and strategic advisor for Blue Dream. “It also includes an updated marketplace for ethical CBD brands to showcase their products.”

Migrating from another content management system and rebuilding our entire website was a huge job, encompassing our Japanese and Spanish language platforms, as well as more than 750 original articles in English.

The Project CBD team knows a lot about the cannabis plant but very little about website design and search engine optimization. The Blue Dream team has been a fantastic partner with much-needed expertise in those areas. 

Cannabinoid receptors CB1 and CB2 are the definitive and best-known targets of endogenous and plant-derived cannabinoids, but they’re far from the only ones.

Several phytocannabinoids, including cannabidiol (CBD), for example, and the two primary endocannabinoids — anandamide and 2-AG — have been shown to interact with peroxisome proliferator-activated receptors, or PPARs1 (pronounced pee-parrs), which are found on the surface of the cell’s nucleus. This may help to explain how CBD, which has little affinity for either CB1 or CB2, can do so much.

Get to Know the PPARs

PPARs are a group of nuclear receptors that play important roles in regulating metabolism, inflammation, and gene expression. Triggered by hormones, endocannabinoids, and other fatty acid derivatives, and various nutritional compounds,2 PPARs are expressed in different parts of the body:

PPAR-a (PPAR-alpha) is found in the liver, kidney, heart, and skeletal muscle, as well as adipose (fat) tissue and the intestinal tract;PPAR-b (PPAR-delta) is expressed in adipose tissue, skeletal muscle, heart, and liver; andPPAR-y (PPAR-gamma), which comes in two forms, is expressed in almost all tissues of the body including the colon, the cardiovascular system, and immune cells.

The first evidence of an endocannabinoid interacting with PPARs came in 2002, when a research team in Tennessee showed that a metabolite of 2-AG activated PPAR-a.3 Since then many more breakthroughs have been made, and peroxisome proliferator-activated receptors are now viewed as an extension of the classic endocannabinoid system (ECS).

PPARs are now viewed as an extension of the classic endocannabinoid system.

It has long been known that resinous cannabis flower tops are infused with robust therapeutic properties. But there are also pharmacologically active components in other parts of the plant that shouldn’t be ignored when assessing the health benefits of cannabis.

The earliest reference to the therapeutic use of cannabis dates back to 2700 BC in ancient China, “the land of hemp and mulberry.” Cannabis (“Ma”) was subsequently included in the Shennong Ben Cao Jing, humankind’s first pharmacopeia, which had been assembled by Emperor Shen Nung, the legendary father of traditional Chinese medicine, who is credited with introducing the custom of drinking tea. Ma was recommended for more than a hundred ailments, including gout, rheumatism, malaria, constipation, beri-beri, and absent-mindedness.

The Shennong Ben Cao Jing called Ma one of the “Supreme Elixirs of Immortality.” It was said to confer longevity and good health. If consumed over a long period of time, Ma could “enable one to communicate with the spirit light and make the body light. It mainly supplements the center and boosts the qi [chi]. Protracted taking may make one fat, strong, and never senile.”1

When consumed in excess, however, “it may make one behold ghosts and frenetically run about.”

Seeds of Health

In traditional Chinese medicine, protein-rich cannabis seeds figured prominently both as a food source and a remedy — apparently more so than resinous cannabis flower tops. The seeds don’t contain CBD, THC, or any other cannabinoids. But modern science confirms that cannabis seeds are an excellent source of omega 3 fatty acids, which are indispensable biochemical building blocks for a healthy endocannabinoid system.

This is first of an occasional column that updates developments pertaining to articles previously published by Project CBD. We start with some positive news from the Golden State. Then a follow-up on our investigative report about Curaleaf, the world’s biggest cannabis company. And freedom of expression takes a hit when it comes to cannabis advocacy in the Czech Republic.

Plastic Pollution in California

Inspired by Project CBD’s exposé, “Bag the Tags” (June 29, 2022), California state senator Ben Allen has introduced a bill to end the onerous requirement to apply a plastic tag to every cannabis plant grown by licensed cultivators, as is currently mandated under the state’s track-and-trace program. Sponsored by CannaCraft, Inc., a major cannabis producer (and longtime friend of Project CBD), and supported by several organizations including the National Product Stewardship Council and the California Cannabis Industry Association, Senate Bill 622 seeks to mitigate unnecessary labor and operational costs for cannabis cultivators, while eliminating the creation of millions of pounds of plastic waste that can’t be recycled.

As Project CBD reported last year: “With over 2,000 acres licensed to grow cannabis, California cannabis farmers put between 30 and 55 million plants in the ground every year. The tags are the definition of ‘single use’ – they can only be used on one plant and never re-used during subsequent growing seasons. That’s a lot of plastic tags for an industry with green pretensions.”

The ostensible purpose of imposing the tag rule was to monitor cannabis grown in California to make sure that it would not end up in the illicit market within or outside the state. But the factsheet summarizing SB 622 emphasizes that “individual plant tags are completely ineffective in preventing diversion.” Why? Because cannabis can’t be diverted until the plants are harvested! And the tags are removed and discarded after they are pulled from the ground.

The SB 622 factsheet asserts: “In a state that prides itself on championing environmentally sensitive initiatives designed to stop climate change and improve the environment, it is antithetical and irresponsible to continue to mandate plastic plant tagging, which does nothing to prevent diversion.”

In the first part of this series, we reviewed recent research into the role of the CB2 cannabinoid receptor in cancer proliferation. This week we turn our attention to another fascinating aspect of CB2 function: its impact on psychiatric and mood disorders despite not being concentrated in the central nervous system (CNS).

After all, the CNS is the domain of its sibling, the CB1 cannabinoid receptor — the primary target of THC and the mediator of cannabis’ intoxicating effects. CB2, by contrast, is more prominently expressed in the peripheral nervous system, where it regulates inflammation, pain, and neuroprotection. CB2 is found to a much lesser extent in the brain, where it modulates dopamine signaling, neuroinflammation, and neurogenesis.

The CB2 receptor was of particular interest to visionary cannabinoid scientist Raphael Mechoulam. In the year prior to his recent passing at age 92, Mechoulam was still actively involved in research investigating CB2 in a variety of disease models. Here we look at a couple of his final papers on CB2 and mental health, as well as two related reviews published in the same timeframe.

CB2 & Schizophrenia

First comes a paper on CB2’s role in schizophrenia, a condition related to psychosis whose symptoms include hallucinations, delusions, disorganized thinking, social withdrawal, decreased emotional expression, and apathy. Coauthored by Brazilian scientists affiliated with the University of São Paulo, it appeared in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry1 in July 2022.

“The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients,” the authors explain. That much is clear. Given this, they wanted to know, how might “HU-910,” a synthetic research compound that selectively activates the CB2 receptor, affect behavior in a rodent model of the disease?

The cannabinoid receptor CB1, primary target of THC in the brain, is known for mediating the cannabis high. And its counterpart CB2, mainly expressed in immune cells throughout the body, is understood to play an important role in inflammatory processes. These abstractions are accurate as far as they go, but as with anything related to the endocannabinoid system, reality is far more complex.

Project CBD’s recent article on the passing of Raphael Mechoulam noted that the esteemed scientist believed CB2 should be a focus of future cannabinoid science. The CB2 receptor interacts with THC, CBD, endocannabinoids, and other compounds in a multitude of organs including skin and bone.

Recent research — including papers co-authored by Mechoulam well into his 80s — has confirmed that aberrant CB2 signaling is implicated in a raft of autoimmune, neurodegenerative, metabolic, and psychiatric disorders. CB2 is also an increasingly hot topic in cancer research.

In this two-part series, Project CBD will explore some of the latest studies and what they reveal about what we know — and still don’t know — about this ubiquitous, somewhat mysterious cell receptor.

This week: cancer. Next week: cognitive and mood disorders, including some of Mechoulam’s final work before his death in March at the age of 92.