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From MMJ to Special K

Brain & Ketamine

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.

Ketamine’s efficacy against pain is attributed to the drug’s ability to induce a dissociative state. At high doses ketamine produces anesthesia; at lower doses, it relieves pain and causes hallucinations. “Special K” acquired a reputation as a party drug in the 1970s due to its psychedelic and mood-altering effects. Favored by fashionistas and Silicon Valley bros, it’s still part of the recreational drug scene.

At high doses ketamine produces anesthesia; at lower doses, it relieves pain and causes hallucinations.

Some have attributed Elon Musk’s erratic behavior of late to ketamine benders at parties. (He says he uses it to relieve depression — proof that money can’t buy everything.) Although ketamine is potentially addictive and excessive use can cause liver damage, renal failure, and psychotic episodes, it’s classified as a Schedule III controlled substance (along with anabolic steroids and some acetaminophen-codeine combinations), indicating a relatively low risk for abuse.

Unlike LSD and psilocybin, ketamine has no natural source. Lysergic acid is present in ergot (rye fungus), psilocybin is a magic mushroom compound, mescaline comes from the peyote cactus, and for MDMA (“ecstasy”) there’s sassafras. But there’s no natural correlate for synthetic ketamine, which works through different molecular pathways than the classic, naturally sourced psychedelics. Acid and ‘shrooms deliver a full-blown psychedelic experience by binding to the 5-HT2A serotonin receptor, whereas ketamine confers its powerful dissociative and psychedelic effects by blocking the N-methyl-d-aspartate (NMDA) receptor, a glutamate ion channel that manages the ebb and flow of calcium inside the cell.

Fertilizer for the Brain

By inhibiting the NMDA receptor, ketamine triggers the production of a chemical known as brain-derived neurotrophic factor (BDNF), which has been likened to “fertilizer of the brain.” The role of BDNF in adult neurogenesis (the creation of new brain cells) and neuroplasticity (the ability to reorganize neural networks and synaptic connections in response to injury and lived experience) is the subject of many scientific papers.

According to a 2012 study by University of Bonn scientist Andras Bilkei-Gorzo: “On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis.” Subsequent reports by Brazilian investigators established that ketamine’s central and peripheral painkilling effects are mediated by the endocannabinoid system. When scientists blocked the CB1 cannabinoid receptor, ketamine did not prevent pain. The same group of researchers also found that ketamine caused anandamide (one of two major endocannabinoids) to be released in certain brain areas. And when anandamide levels increased, so did ketamine’s analgesic effect.

“CBD significantly augmented the activating effects of ketamine.”

Plant cannabinoids have also been shown to potentiate ketamine’s painkilling properties. A 2011 report on “The interplay of cannabinoid and NMDA glutamate receptor systems” examined “the interactive effects of cannabidiol and ketamine in healthy human subjects.” The report concluded that “CBD significantly augmented the activating effects of ketamine.” Other studies have noted that CBD boosts endocannabinoid levels and CB1 receptor signaling by delaying the metabolic breakdown and reuptake of anandamide.

CBD and ketamine are both neurogenic compounds, and this may factor into how they confer antidepressant effects. Impaired neurogenesis has been linked to clinical depression, substance abuse, and other mental health conditions. Ketamine’s rapid antidepressant effects involve enhanced BDNF-induced (and cannabinoid-regulated) neurogenesis and neuroplasticity. The drug is currently being administered off-label for refractory depression at numerous ketamine clinics around the country.

Common Biological Mechanisms

“Pain and depression share common biological mechanisms,” explains Dr. Michelle Weiner, a double board-certified physician who specializes in interventional pain medicine, physical medicine, and rehabilitation. In addition to her clinical practice at five locations in southern Florida, Dr. Weiner is an Assistant Professor at Nova Southeastern University College of Osteopathic Medicine.

Take a spin on her website and you’ll find a group photo picturing Dr. Weiner and her team of practitioners, a bevy of Florida beauties who look as though they could’ve been cast as the Real Housewives of Miami. There’s a lot going on behind the glamor. When interviewed by Project CBD, Dr. Weiner’s enthusiasm for her calling is obvious, her expertise backed by years of on-the-ground research and a vast knowledge rooted in pain studies and cutting-edge neuroscience.

While building her practice, Dr. Weiner grew increasingly frustrated with the limited tools available beyond conventional pain pills and injections. When medical cannabis was legalized in Florida in 2016, she became one of the first licensed physicians to include it in her treatment plans. She found that cannabis was an effective therapeutic option for helping chronic pain patients, especially seniors, decrease their dependence on opioids.

“It really changed my practice,” says Weiner, who is a member of Florida’s Medical Cannabis Advisory Committee. Weiner’s experience as a cannabis clinician encouraged her to explore other mind-body healing modalities, including psychedelic drugs. Today she is vice president of Mr. Psychedelic Law, a not-for-profit that advocates for responsible legal reform of psilocybin prohibition in the Sunshine State.

Teaching Resilience

Dr. Weiner’s interest in ketamine began during a residency and training fellowship at the University of Miami. “Back then we used ketamine differently than we do now,” she says. “We’d give patients a benzodiazepine sedative beforehand to tone down the hallucinatory experiences common with ketamine.” But after learning of ketamine’s potential as treatment for anxiety, depression, and PTSD, she changed her approach to encompass a dual-pronged focus on pain and mental health.

“Eighty-five percent of chronic pain patients also suffer from depression,” says Dr. Weiner. “You can’t successfully treat pain without concurrently treating mental health.” From her perspective, it’s all interconnected: chronic pain adversely impacts how the brain functions, causing maladaptive changes in the central nervous system and weakening synaptic circuitry between brain regions — and these changes often lead to depression, according to a 2017 study published in the journal Neural Plasticity. Not only does it offer rapid relief from both depression and pain, ketamine also appears to refresh and reset neural circuitry.

But the benefits of a single ketamine treatment are often short-lived (seven days on average for depression), and the drug may be contraindicated for certain conditions. Some people can’t tolerate ketamine’s intense hallucinogenic effects. Another major drawback: MediCare and health insurance companies don’t cover ketamine treatments, so patients must pay out of pocket. For those who can’t afford it, there are DIY at-home ketamine kits with medicine procured from less-than-reliable online sources, which is problematic.

“When used mindfully, ketamine, through its dissociative effects, allows patients a time-out from their pain.”

Ketamine treatment needs to be monitored by an experienced practitioner, says Dr. Weiner. Most of her patients come into the clinic once or twice a week for at least a month to receive ketamine by intramuscular or intravenous infusion, along with therapy sessions and lifestyle counseling for a better long-term outcome. Treatment is tapered off over time, and the benefits are maintained with occasional ketamine “boosters,” an approach backed by research. The goal is to relieve pain while helping patients learn new strategies for how to live with it.

“When used mindfully,” says Dr. Weiner, “ketamine, through its dissociative effects, allows patients a time-out from their pain. Yes, it’s temporary, but being able to take a break from intense pain also gives them a chance to see it from a different perspective. It’s not who they are. It’s not their identity. Ketamine disrupts the static and unproductive patterns with which patients deal with their pain and encourages the development of better life strategies. What we’re really doing is teaching them resilience.”

A Remarkable Drug

Unlike Dr. Weiner’s other patients, Irv Rosenfeld has her blessing to treat himself orally with ketamine at his own home. The fact that she makes an exception in Irv’s case is a testament to her admiration and respect for Rosenfeld, who has been under Dr. Weiner’s pain management care for many years.

Every five days or so, when the pain in his bones gets really bad, Irv texts his wife Debbie before he drives home from work: I’m doing ketamine tonight. Debbie knows to stay close by yet out of his way. In order to “do ketamine,” Rosenfeld needs complete isolation and quiet. Once at his house in Fort Lauderdale, he will put on some classical music. Then he’ll place one-and-a-half sublingual tablets containing a total of 300 milligrams of ketamine between his cheek and gum, sit down in a comfortable armchair, and wait for the portal to open. His flight from pain is about to take off.

About an hour passes before Rosenfeld notices any effects. When they arrive, the feelings are both physical and emotional. He can see “the pain flow out and float far away,” he tells Project CBD. Under the influence of “forgetamine,” existential agony and exhaustion are replaced by euphoric hallucinations lasting several hours with his eyes closed.

Rosenfeld accepts that the relief he gets from ketamine won’t last beyond his solitary, three-to-four-hour sit-down sessions. But the knowledge that he can occasionally be whisked away from the Land of Pain is in and of itself transformative, nourishing his innate resilience and helping him tackle life’s daily challenges.

“It’s a remarkable drug,” he says with an obvious tone of gratitude. Just as pain has influenced the course of Rosenfeld’s life, so has his outspoken activism, his efforts to get the word out about the therapeutic benefits of cannabis before most people knew much about it. And now he’s also singing the praises of ketamine. Listening to him talk is uplifting, like getting a dose of medicine you really need.

Melinda Misuraca is a Project CBD contributing writer with a past life as an old-school cannabis farmer specializing in CBD-rich cultivars. Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

Sources

  • Bilkei-Gorzo A. The endocannabinoid system in normal and pathological brain ageing. Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3326-41. doi: 10.1098/rstb.2011.0388. PMID: 23108550; PMCID: PMC3481530.
  • Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depresson: new insights from stress and rapid-acting antidepressants. Nat Med [Internet]. 2016;22(3):238–49.
  • Ferreira RCM, Castor MGM, Piscitelli F, Di Marzo V, Duarte IDG, Romero TRL. The Involvement of the Endocannabinoid System in the Peripheral Antinociceptive Action of Ketamine. J Pain. 2018 May;19(5):487-495. doi: 10.1016/j.jpain.2017.12.002. Epub 2017 Dec 13. PMID: 29247851.
  • Hallak JE, Dursun SM, Bosi DC, de Macedo LR, Machado-de-Sousa JP, Abrão J, Crippa JA, McGuire P, Krystal JH, Baker GB, Zuardi AW. The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):198-202. doi: 10.1016/j.pnpbp.2010.11.002. Epub 2010 Nov 7. PMID: 21062637.
  • Khakpai F, Ebrahimi-Ghiri M, Alijanpour S, Zarrindast MR. Ketamine-induced antidepressant like effects in mice: A possible involvement of cannabinoid system. Biomed Pharmacother. 2019 Apr;112:108717. doi: 10.1016/j.biopha.2019.108717. Epub 2019 Feb 28. PMID: 30970516.
  • Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins KA, Mathew SJ, Charney DS, Iosifescu DV. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013 Aug 15;74(4):250-6. doi: 10.1016/j.biopsych.2012.06.022. Epub 2012 Jul 27. PMID: 22840761; PMCID: PMC3725185.
  • Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu Rev Pharmacol Toxicol. 2014;54:119-39. doi: 10.1146/annurev-pharmtox-011613-135950. PMID: 24392693; PMCID: PMC4089991.
  • Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69 Suppl E1:4-7. PMID: 18494537.
  • Pacheco DDF, Romero TRL, Duarte IDG. Ketamine induces central antinociception mediated by endogenous cannabinoids and activation of CB1 receptors. Neurosci Lett. 2019 Apr 23;699:140-144. doi: 10.1016/j.neulet.2019.01.059. Epub 2019 Feb 1. PMID: 30716423.
  • Pourmand A, Mazer-Amirshahi M, Royall C, Alhawas R, Shesser R. Low dose ketamine use in the emergency department, a new direction in pain management. Am J Emerg Med. 2017 Jun;35(6):918-921. doi: 10.1016/j.ajem.2017.03.005. Epub 2017 Mar 2. PMID: 28285863.
  • Riccardi A, Guarino M, Serra S, Spampinato MD, Vanni S, Shiffer D, Voza A, Fabbri A, De Iaco F; Study and Research Center of the Italian Society of Emergency Medicine. Narrative Review: Low-Dose Ketamine for Pain Management. J Clin Med. 2023 May 2;12(9):3256. doi: 10.3390/jcm12093256. PMID: 37176696; PMCID: PMC10179418.
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Three Delicious Raw Cannabis Smoothie Recipes

smoothie

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.

Several studies have shown that THCA, a neuroprotectant, has immunomodulatory, anti-inflammatory, antiseizure, and antineoplastic activity, while CBDA is a potent antiemetic and anticonvulsant. Dr. Dustin Sulak, an integrative physician and medical cannabis expert based in Maine, observes that “CBDA is stronger and more potent than CBD, not just because it’s getting absorbed better but because it is acting more powerfully.”

Beyond the Bud

Each part of the cannabis plant contains its own distinctive chemistries, and these may interact synergistically, increasing the therapeutic potential of the whole plant beyond the benefits of a single compound or botanical constituent. That includes all the components of raw cannabis — not just the flowers:

  • Cannabis shade leaves. Although they generally possess little cannabinoid content, cannabis leaves contain other beneficial compounds, including alkaloids, flavonoids, resins, and terpenes. Plentiful and relatively easy to obtain, shade leaves are also high in chlorophyll, which has an array of useful properties that promote wound and skin healing and help to detoxify the body from heavy metals. Many so-called folk remedies involve the use of raw cannabis leaves to treat various conditions. A study in the African Journal of Traditional, Alternative and Complementary Medicine mentions an effective traditional treatment for tuberculosis using cannabis leaf macerated in warm water, as administered by Bapedi healers of Limpopo province, South Africa.
  • Cannabis roots. Cannabis roots contain no phytocannabinoids, but they produce triterpenoids such as friedelin, which has anti-inflammatory, antipyretic, anticarcinogenic, and antimicrobial effects. And epifriedelanol, another triterpenoid found in cannabis roots, has anticancer and cytoprotective properties that could be useful in treating aging-related diseases, according to a review by Ethan Russo and Jahan Marcu in Advanced Pharmacology.
  • Cannabis and hemp seeds. Raw cannabis and hemp seeds have a mild, nutty flavor and are among the world’s most nutritious foods. An article by Jace Calloway in Euphytica reports that these nutrient-packed seeds have potent anti-inflammatory properties. Hemp seeds are rich in essential fatty acids that are metabolized into building blocks of the endocannabinoid system. Add hemp hearts (hulled hemp seeds) to your smoothie or sprinkle some on salads and vegetable dishes. You can also sprout cannabis seeds just as you would wheatgrass or other greens and juice them. Cannabis sprout juice is especially high in beneficial compounds. Cut the sprouts when they are four-to-five inches tall and juice away.

Fresh From the Garden

Where can you get fresh cannabis? The most obvious answer is to grow your own (if you live in a US state that allows this) or ask a grower friend for some trimmings. While the plant is still in the ground you may want to preserve the flowering colas for a ripe final product. Trimming some of the smaller buds for juicing won’t interfere with this and can actually increase the size and potency of the colas, so consider trimming from the lower branches.

(Many thanks to Cora Genetics for generously donating fresh cannabis so Project CBD could develop several smoothie recipes.)

When juicing or adding fresh cannabis in smoothies, make sure to use organic, unsprayed, freshly picked and washed flowers and leaves. The best flowers for juicing have sticky, resin-rich trichomes that have ripened to a milky or cloudy color. Leaves should be deep green and healthy looking. Roots should be washed and scrubbed well. Seeds generally don’t need washing but should be unsprayed, clean, and sorted.

It’s best to use your raw cannabis plant material soon after picking. If you don’t use it right away, keep it in an airtight bag in the fridge for a week or two. You can also freeze raw cannabis for later use. Note that the leaves and flowers will turn a darker color, but the compounds will stay fresh for several months in a well-sealed container. Another option is to juice or puree fresh cannabis and freeze it in ice-cube trays; just pop a few into a beverage. Cannabis puree can also be added to pesto!

Straight Shots & Mocktails

You can drink straight “shots” of fresh cannabis juice or add the freshly pressed juice to a smoothie or other drink. Even a mocktail can be doctored up with a jigger of C-juice. If you want a smooth, pulp-free juice, use a cold-process juicer such as a Champion or another type that removes the fiber.

If you aren’t afraid of a little texture, add whole, raw flowers, leaves, or a piece of cannabis root to your smoothie and you’ll gain all the benefits plus a fiber boost. It won’t feel like you’re gulping down a mouthful of grass clippings if you use a good-quality, high-speed blender that can pulverize the plant fiber to a fine, smooth consistency. (Note: stick or immersion blenders generally don’t work for this purpose.)

If you haven’t consumed raw cannabis before, it’s best to start slow. It won’t make you feel intoxicated, but some people may be allergic or extra sensitive to raw cannabis. Discontinue using if you have an adverse reaction. And keep in mind, if you are preparing a recipe with cannabinoid acid-rich flowers and decide to heat it, you will end up decarboxylating the cannabinoids and the THCA will turn into THC, “the High Causer.”

There’s no better way to level up on your micronutrients than with a swig of cold, freshly pressed cannabis juice or a raw cannabis smoothie. Project CBD has developed three, dare I say, delicious cannabis smoothie recipes for you to try. Give them a go, and let us know what you think!

Recipe: Virgin Mary Jane

Perfect for a warm afternoon, this ice-cold, zesty, savory beverage is chock full of veggies and spices that jive perfectly with fresh cannabis. Dial up the veggies if you want a thicker, gazpacho-like texture, or add more chili if you like it extra spicy. For a delicious mocktail, add a splash of lime-flavored kombucha or non-alcoholic beer and you’ve got yourself a virgin Red Eye. With so much flavor, it’ll feel like you’re getting away with something. Serves two.

Ingredients:

  • 1 packed cup or more of fresh cannabis, torn into rough pieces: flowers, leaves, or a mix
  • I stalk of celery, including leaves, diced, plus two stalks for serving
  • 1 Roma tomato, seeded and diced
  • ½ bell pepper, seeded and diced
  • 2 sprigs cilantro, leaves and stem, roughly chopped, plus some extra sprigs for serving
  • 1 teaspoon prepared horseradish
  • 1/2 teaspoon diced shallot or red onion
  • 1-2 cloves garlic, peeled (optional)
  • ½ to 1 japapeño or serrano chili, seeded and diced (optional)
  • Dash Worcestershire sauce
  • 1/2 teaspoon celery salt or ground celery seed
  • Kosher salt to taste
  • Black pepper to taste
  • Hot sauce to taste (Tabasco or other)
  • 1 lime, juiced
  • 16 ounces of low-sodium tomato juice

Directions: Blend all ingredients in a blender, adjusting seasonings and adding more juice if needed. Serve over ice in tall glasses with a celery stalk and a sprig or two of cilantro.

Recipe: Berry Cannalicious

Dark-colored berries are packed with antioxidants and flavonoids, and studies have shown that regular intake of flavonoids reduces the rate of cognitive decline in older adults, making this the perfect anti-aging smoothie. A splash of cherry or pomegranate juice, or hibiscus tea, adds even more flavor, color, and nutrients. You can tailor this smoothie to your sweetness quotient and sprinkle in some medicinal mushroom powder for more brain boost. Drink this smoothie and you just might live forever. And it tastes amazing! Serves two.

Ingredients:

  • 1 packed cup or more of fresh cannabis, torn into rough pieces: flowers, leaves, or a mix
  • 1 ½ to 2 cups mixed frozen berries: blueberries, raspberries, blackberries, strawberries, and/or cherries
  • ¾ cup of dark cherry or pomegranate juice, or cold, unsweetened hibiscus tea (you can find dried hibiscus flowers at your local Mexican market)
  • Juice of one lemon
  • ¾ cup unsweetened almond, cashew, soy, rice or other plant-based milk
  • Honey, 2-3 pitted medjool dates, or stevia to taste
  • Optional: Two teaspoons of mixed dried medicinal mushroom powder

Directions: Blend all ingredients in a blender until smooth, adding more liquid as needed. Serve in tall glasses.

Recipe: Tropic of Canna

This creamy smoothie is a beautiful, bright green color, and full of the tropical fruit flavors of mango, papaya, and pineapple. Throw in some hemp seeds for a fatty acid boost, or strawberries and mint to your liking. Guaranteed to transport you to a tropical island with the best waves for mind/body surfing. Serves two.

Ingredients:

  • 1 packed cup or more of fresh cannabis, torn into rough pieces: flowers, leaves, or a mix
  • 2 cups mixed frozen mango, pineapple, papaya, and/or strawberry
  • 1-inch piece of fresh, raw ginger root, diced
  • 2 cups or more of coconut water, plant-based milk or water
  • 2-3 tablespoons raw hemp seeds, optional
  • Honey, 2-3 pitted medjool dates, or stevia to taste
  • Couple of mint leaves for flavor and/or garnish (optional)

Directions: Blend all ingredients until smooth, adding more liquid or fruit to get the desired consistency. Serve in tall glasses with optional mint garnish.

Melinda Misuraca is a Project CBD contributing writer with a past life as an old-school cannabis farmer specializing in CBD-rich cultivars. © Copyright, Project CBD. May not be reprinted without permission.

References

  • Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M, Stott CG, Javid FA, Parker LA, Pertwee RG. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behavior in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013 Mar;168(6):1456-70.
  • B.S. Audu, P.C. Ofojekwu, A. Ujah, M.N.O. Ajima. Phytochemical, proximate composition, amino acid profile and characterization of Marijuana (Cannabis sativa L.) The Journal of Phytopharmacology. 2014 3(1): 35-43.
  • Callaway, J. Hempseed as a nutritional resource: An overview. Euphytica. 2004 140. 65-72.
  • Dawidowicz AL, Olszowy-Tomczyk M, Typek R. CBG, CBD, Δ9-THC, CBN, CBGA, CBDA and Δ9-THCA as antioxidant agents and their intervention abilities in antioxidant action. Fitoterapia. 2021 Jul;152:104915.
  • Devore EE, Kang JH, Breteler MM, Grodstein F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol. 2012 Jul;72(1):135-43.
  • Pellesi L, Licata M, Verri P, Vandelli D, Palazzoli F, Marchesi F, Cainazzo MM, Pini LA, Guerzoni S. Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)-a pilot study. Eur J Clin Pharmacol. 2018 Nov;74(11):1427-1436.
  • Russo EB, Marcu J. Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Advanced Pharmacology. 2017 80:67-134.
  • Semenya SS, Maroyi A. Medicinal plants used for the treatment of tuberculosis by Bapedi traditional healers in three districts of the Limpopo Province, South Africa. Afr J Tradit Complement Altern Med. 2012 Dec 31;10(2):316-23.
  • Takeda S, Okajima S, Miyoshi H, Yoshida K, Okamoto Y, Okada T, Amamoto T, Watanabe K, Omiecinski CJ, Aramaki H. Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett. 2012 Nov 15;214(3):314-9.
  • Yang HH, Son JK, Jung B, Zheng M, Kim JR. Epifriedelanol from the root bark of Ulmus davidiana inhibits cellular senescence in human primary cells. Planta Med. 2011 Mar;77(5):441-9. https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/chlorophyll-metallo-chlorophyll-derivatives#supplements

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Gut Feeling

Gut microorganism

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.)

Even small doses of cannabis can soothe the stomach and stimulate the appetite.

Inflammatory bowel disease is an umbrella term for two chronic disorders of the gut: Crohn’s disease, characterized by inflammation of the lining of the digestive tract; and ulcerative colitis, which involves inflammation and sores along the lining of the large intestine (colon) and rectum. Symptoms of both include diarrhea, fatigue, abdominal pain, reduced appetite, and weight loss.

IBD in Puerto Rico

In 2016, the government of Puerto Rico legalized medicinal cannabis for a relatively short list of specific conditions, including Crohn’s disease. Only non-smokable preparations are permitted, and all unauthorized cannabis use and possession remains illegal. As of March 2022, approximately 120,000 patients were registered in the program.

The recent survey was conducted through a clinic at the University of Puerto Rico Center for Inflammatory Bowel Diseases with around 900 patients. Ultimately 162 adults (85 males) completed the 27-item questionnaire. Among these, 60 (37%) reported current or past cannabis use, of which 39 used it to treat abdominal pain, 25 to treat weight loss, and 10 to treat diarrhea, among other symptoms.

But the most telling findings involve these patients’ perceptions of cannabis use as a treatment for IBD. The vast majority of current and past users noted that cannabis was beneficial for their health (94%), that it offered an improvement in their quality of life (84%), and that they would recommend it to other patients (86%). The study was published in March 2023 in the International Journal of Environmental Research and Public Health.2

Fewer ER Visits in New York & Minnesota

When researchers with Stony Brook University Hospital, Northwestern University, and Albert Einstein College of Medicine surveyed IBD patients in New York and Minnesota about their cannabis use, both states only allowed medical use. This study was conducted at medical cannabis dispensaries and relied on self-reported IBD diagnoses. Generally speaking, the 236 eligible respondents reported mild-to-moderate IBD disease activity. Most used cannabis at least once a week, primarily through high-THC vape pens and cartridges.

Euphoria was by far the most common side effect reported.

Again, the most notable findings reveal just how helpful these patients found cannabis in managing inflammatory bowel disease. Respondents reported fewer IBD-related emergency-room visits (a common concern across the patient population) in the year after they began using cannabis. They also saw a reduced impact of symptoms on their daily life. Euphoria was by far the most common side effect (75.4%), with drowsiness, memory lapses, dry mouth, anxiety, and paranoia all reported in low-single-digit percentages. The results appeared in the Journal of Clinical Gastroenterology in October 2022.3

Rave Reviews

Scientific review papers are typically circumspect in tone, more inclined to highlight evidence gaps than to draw grand conclusions. But two recently published reviews are clear when it comes to the benefits of cannabis for inflammatory bowel disease patients.

“Cannabinoid usage in IBD treatment comes with promising results as reported in the majority of the selected studies,” reads a systemic review of the literature from 2012 to 2022 published in the journal Cureus. “The selected studies’ point of convergence is that they confirmed the promising role of cannabinoids in steering improvements in IBD treatment through some objective clinical rating scales such as weight gain, Harvey-Bradshaw Index, Mayo score, CDAI score, and general well-being.” The main caveats? Heterogeneous study designs and a dearth of high-quality evidence for ideal dosage and mode of administration.

The second new review, set to be published in July in Current Opinion in Gastroenterology,4 similarly concludes that “there is a considerable amount of patient-reported outcome data that is significant in supporting the use of cannabis to provide symptom relief and overall increase in quality of life in patients with IBD.”

The authors do make an important distinction between symptoms and underlying conditions, however, by noting that existing evidence addresses the former, not the latter: “There are no data that cannabis has any benefit in decreasing the inflammation/fibrosis that continues to affect patients with IBD.”

This doesn’t mean that cannabinoids have been proven ineffective in addressing the root cause of IBD, just that there’s no evidence yet establishing that they do. “The most important point is that gastroenterologists need to ask their patients about their [cannabinoid] use, including discussion of the benefits and risks of using them,” the authors conclude.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Leung, Janni et al. “Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada.” Psychopharmacology vol. 239,5 (2022): 1509-1519. doi:10.1007/s00213-021-06047-8
  2. Velez-Santiago, Alondra et al. “A Survey of Cannabis Use among Patients with Inflammatory Bowel Disease (IBD).” International journal of environmental research and public health vol. 20,6 5129. 15 Mar. 2023, doi:10.3390/ijerph20065129
  3. Greywoode, Ruby et al. “Medical Cannabis Use Patterns and Adverse Effects in Inflammatory Bowel Disease.” Journal of clinical gastroenterology, 10.1097/MCG.0000000000001782. 14 Oct. 2022, doi:10.1097/MCG.0000000000001782
  4. Saidman, Jakob et al. “Inflammatory bowel disease and cannabis: key counseling strategies.” Current opinion in gastroenterology vol. 39,4 (2023): 301-307. doi:10.1097/MOG.0000000000000946

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Beta-Caryophyllene: Terpene Powerhouse

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

Because of its presence in many foods and spices and its strong affinity for the CB2 receptor, beta-caryophyllene is known as a “dietary cannabinoid.”

Writing in the International Journal of Molecular Sciences in March 2023,4 the researchers note that not only did they observe improvements in diseased liver cells, but they also confirmed through the use of specific receptor antagonists that these changes were indeed mediated by CB2 and two PPAR receptor types: PPAR-alpha and PPAR-gamma.

(Interestingly, multiple large epidemiological studies5 — including one published in May 2023 in the journal PLoS One6 — have linked cannabis use with reduced risk of fatty liver disease. This new evidence out of Italy suggests that activation of CB2 and PPAR receptors may be at least partly responsible.)

Alzheimer’s & Substance Abuse

Other studies in recent years have added to our understanding of beta-caryophyllene’s myriad potential health benefits and multiple methods of action. In 2014, for example, Chinese researchers at Chongqing Medical University reported that BCP prevented cognitive impairment in a mouse model of Alzheimer’s. This positive cognitive outcome “was associated with reduced beta-amyloid burden in both the hippocampus and the cerebral cortex,” according to their paper in the journal Pharmacology,7 which identified CB2 receptor activation and the PPAR-gamma pathway as mediators of BCP’s neuroprotective effects.

More recently, a July 2022 paper in BioFactors8 by Iranian scientists reviewed the antioxidant and immunomodulatory effects of beta-caryophyllene, which was shown to reduce relevant proinflammatory cytokines while increasing anti-inflammatory cytokines. CB2 and PPAR-gamma, among other cellular pathways, were cited as key mechanisms of action.

And a December 2022 article in Current Neuropharmacology,9by researchers in Brazil, investigated BCP’s potential “as a new drug for the treatment of substance use disorders.” The authors reviewed previous preclinical studies using animal models of addiction to cocaine, nicotine, alcohol, and methamphetamine. “Remarkably,” they concluded, the terpene “prevented or reversed behavioral changes resulting from drug exposure,” with evidence again pointing to the involvement of both CB2 and PPAR-gamma.

Painkiller

Finally, a paper by scientists with an Indian company called Vidya Herbs, which produces a black-pepper-seed extract called Viphyllin, suggests that beta-caryophyllene can reduce pain in mice primarily via activation of CB2, PPAR-alpha, and a third pathway also shared with cannabidiol: the TRPV1 (pronounced trip-vee-one) ion channel.

Published in the Journal of Pain Research10 in February 2022, the study involved administration of both 90% pure beta-caryophyllene and the black-pepper extract Viphyllin, which contains at least 30% beta-caryophyllene alongside lesser quantities of limonene, beta-pinene, and sabinene (three terpenes that can also be found in various cannabis strains).

Medical scientists are studying beta-caryophyllene as a treatment for non-alcoholic fatty liver disease, chronic pain, and substance abuse.

When Viphyllin was given at about three times the dose of pure BCP, the two treatments proved to be similarly effective at reducing pain in all four behavioral models employed.

In three of these tests, the researchers also used blockers of CB1, CB2, TRPV1, and PPAR-alphato evaluate how Viphyllin worked on the molecular level. They found that CB2, PPAR-alpha, and TRPV1 were most responsible for conveying the black pepper extract’s analgesic effect, but that the common terpene target CB1 may have played a role, as well.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Raz, Noa et al. “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.” Biochemical pharmacology vol. 212 (2023): 115548. doi:10.1016/j.bcp.2023.115548
  2. LaVigne, Justin E et al. “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.” Scientific reports vol. 11,1 8232. 15 Apr. 2021, doi:10.1038/s41598-021-87740-8
  3. Younossi, Zobair M et al. “The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.” Hepatology (Baltimore, Md.) vol. 77,4 (2023): 1335-1347. doi:10.1097/HEP.0000000000000004
  4. Scandiffio, Rosaria et al. “Beta-Caryophyllene Modifies Intracellular Lipid Composition in a Cell Model of Hepatic Steatosis by Acting through CB2 and PPAR Receptors.” International journal of molecular sciences vol. 24,7 6060. 23 Mar. 2023, doi:10.3390/ijms24076060
  5. Kim, Donghee et al. “Inverse association of marijuana use with nonalcoholic fatty liver disease among adults in the United States.” PloS one vol. 12,10 e0186702. 19 Oct. 2017, doi:10.1371/journal.pone.0186702
  6. Du, Rui et al. “Marijuana use is inversely associated with liver steatosis detected by transient elastography in the general United States population in NHANES 2017-2018: A cross-sectional study.” PloS one vol. 18,5 e0284859. 18 May. 2023, doi:10.1371/journal.pone.0284859
  7. Cheng, Yujie et al. “β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway.” Pharmacology vol. 94,1-2 (2014): 1-12. doi:10.1159/000362689
  8. Baradaran Rahimi, Vafa, and Vahid Reza Askari. “A mechanistic review on immunomodulatory effects of selective type two cannabinoid receptor β-caryophyllene.” BioFactors (Oxford, England) vol. 48,4 (2022): 857-882. doi:10.1002/biof.1869
  9. Asth, Laila et al. “Effects of β -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction.” Current neuropharmacology vol. 21,2 (2023): 213-218. doi:10.2174/1570159X20666220927115811
  10. Venkatakrishna, Karempudi et al. “ViphyllinTM, a Standardized Black Pepper Seed Extract Exerts Antinociceptive Effects in Murine Pain Models via Activation of Cannabinoid Receptor CB2, Peroxisome Proliferator-Activated Receptor-Alpha and TRPV1 Ion Channels.” Journal of pain research vol. 15 355-366. 5 Feb. 2022, doi:10.2147/JPR.S351513

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Getting to Know Cannabigerol with Bonni Goldstein, MD

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.

CannMed: For what conditions do you think CBG has the most promise? What are you most interested in?

Dr. Goldstein: I think CBG holds a lot of promise for people who struggle with inflammation, pain, and mood disorders, like anxiety or depression. Ethan Russo, along with other researchers, recently did a survey of CBG users. About 70 percent of people said CBG was superior to their conventional medication. It was highly rated for anxiety, pain, depression, and sleep problems. I don’t know that it’s a direct sleep agent, but when you are having less anxiety and less pain you likely will fall asleep a little bit easier and maybe sleep better. It’s noteworthy that much of this anecdotal data is supported by findings from preclinical research.

CBG holds a lot of promise for people who struggle with inflammation, pain, and mood disorders, like anxiety or depression.

CannMed: In the survey you mentioned, was that CBG being taken by itself or in combination with other cannabinoids?

Dr. Goldstein: In the survey, I think they tried to sort that out, and it was people taking plant CBG that they buy in the hemp market because most CBG products that are on the market do not contain a significant amount of THC. They are coming from hemp plants, so they are readily available on the hemp market. I’ve seen it as flower, I’ve seen it as topical, which has anti-bacterial and anti-psoriatic effects. Psoriasis is a well-known condition where people get not only joint pain but they also get these thick red patches and scales on their skin. It can be a very difficult condition. And CBG has been found to have anti-psoriatic properties. It acts on the skin cells themselves and inhibits the build-up of those scaly patches. I think this just goes to show that the applications of cannabinoids are truly wide-ranging. People often ask: How is it possible that these compounds can do so many things? Well, they have multiple targets in the brain and body and that’s what makes them so amazing. Remember, the pharmaceutical model is “this medicine addresses this specific target.” Whereas cannabinoids are what we call promiscuous – they go to a lot of targets.

CannMed: How does CBG differ in its targets from other plant cannabinoids? Does it work on the same receptors with similar mechanisms of action?

Dr. Goldstein: There’s overlap with some of the actions of THC and CBD, for example. But then there are also some opposite reactions. CBD and CBG have opposite reactions at a specific serotonin receptor — 5HT1A — where CBD binds to it and CBG blocks it. They both act at that receptor, but in different ways. CBG also overlaps with CBD by binding to what we call PPAR receptors [on the surface of the cell’s nucleus]. And both of these plant cannabinoids interact with TRP [ion] channels to help with inflammation and pain.

CBG is the only cannabinoid that has been found to work at the alpha-adrenergic receptor, which mediates pain perception and inflammation. There are pharmaceuticals for ADHD or behavioral issues, for example, which target this receptor. CBG is always a compound I consider when treating children who have either behavior or other types of difficulties. I have used it in some of my patients with autism. Some families report their child is calmer, has better focus, even speech is improving in some of the children with autism who are non-verbal. But other parents report that CBG makes their child way too hyper. That may be a dosing issue. Why not try it? We know that it’s safe. And it’s under medical supervision. We start with very low doses so that we can control what’s going on and of course there’s a lot of oversight. The parents are watching, I’m watching. We’re just trying to make sure that we do no harm. Thus far, I’d say about 60 percent of kids that try CBG seem to get some benefit from it.

CannMed: I’m glad you brought up ADHD. Full disclosure: my son has been diagnosed with ADHD. I was surprised to learn that CBG might be helpful for that.

Dr. Goldstein: We don’t have clinical trials to say, yes this is definitively beneficial or detrimental for children. But we may be on the cusp of having those trials, which would be very exciting. In my practice, which is in California, I am allowed to work with parents to try different cannabinoids to see what might help. We do it very methodically. As I discuss in my book, we have a saying, ‘Rule it in or rule it out’. We start low dose, and we titrate up. We focus on one compound to see if there are benefits. And remember, too, that sometimes when we’re seeing a benefit it may be because the child is also on CBD — and maybe that combination is working well. If you add a compound and see enhanced benefits, you don’t know if it’s working because of that particular compound or the combination of the two if they’re already on something else. There’s a lot of trial and error involved, and it takes time to sort it out. I always tell families when I first meet them that we’re going to be working together for quite some time. It’s not like we just pick something and it immediately works great. We might get lucky. That happens, but that’s not the usual case.

CannMed: Another thing that stood out to me was this idea of CBG enhancing the body’s function. I was wondering if you could speak a bit to that.

Dr. Goldstein: A number of endocannabinoids, including CBD and CBG, delay the breakdown of our endocannabinoids. Remember, our endocannabinoids are our inner cannabis-like compounds, which our body releases on demand in response to a trigger, usually something that is stressing us, whether it be an illness or a traumatic insult or an infection of some sort. Your body cranks out these endocannabinoids to help maintain balance among all the various messages that our cells are constantly sending and receiving. The endocannabinoid system is a physiological regulator, and it’s helping you stay in balance. We can enhance our own natural endocannabinoid system with plant cannabinoids, which delay the breakdown of endogenous cannabinoids so that they last longer. It’s kind of like the way some anti-depressants work by increasing how long serotonin is hanging around.

We can enhance our own natural endocannabinoid system with plant cannabinoids.

CannMed: Now correct me if I’m wrong, but physical exercise is another way to spur your body into creating endocannabinoids?

Dr. Goldstein: Yes.

CannMed: Would supplementing with CBD or CBG be an effective way to keep anandamide in the system and get more benefits from our natural cannabinoids?

Dr. Goldstein: Theoretically you could look at it that way. I don’t know that there’s a direct correlation, as in take a dose and now you have extra anandamide. But I do think the literature supports this whole idea of cannabinoids being anti-inflammatory, antioxidant, neuroprotective — and one dose is not going to do the trick. It’s helpful to think in terms of a wellness regimen that includes cannabinoids, of course, in addition to other healthy things that you should be doing to enhance your endocannabinoid system – healthy diet, exercise, good sleep, really trying to control your stress.

CannMed: Could you speak to how CBG might enhance the effects of other cannabinoids or situations where you think the combination is useful?

Dr. Goldstein: There’s a 2019 animal study that showed the combination of CBD and CBG decreased neuroinflammation. They were looking specifically at neurodegenerative disorders with dementia, what we call Lou Gehrig’s Disease or ALS. And it showed in this preclinical study that CBD and CBG worked together and gave better results for protecting against neuroinflammation. This ties into the concept of the entourage effect, whereby combinations of cannabinoids and terpenes appear to enhance the benefits, the positive results. Another recent study showed that CBG in addition to THC and/or CBD has anti-cancer effects in test tube experiment looking at certain brain tumor cells. When some of my cancer patients come to me with advanced cancer, very poor prognosis — and I’ve been doing this now for a number of years — I add CBG into the mix. To me there is no harm in doing so. It doesn’t cause the impairment that anti-cancer doses of THC can sometimes cause.

CannMed: What other scenarios or situations do you encounter where you think CBG is either the right tool or might be a good companion if you have already started a cannabis regimen and you’re not getting the right results?

Dr. Goldstein: I think that if you’re trying to treat anxiety, pain, inflammation, and you are not getting great results with either THC and/or CBD, which, of course, are the two most common cannabinoids being used right now, then certainly the addition of CBG is worth a try. Remember too, that when you combine cannabinoids sometimes you can get away with a lower dose of either or both, while getting an enhanced effect from that entourage. Because there are studies that show sub-therapeutic doses of cannabinoids — meaning doses not expected to do anything clinically — when combined will work better. For a lot of people high, high doses are just not financially feasible. And sometimes that combination of small amounts of two compounds actually is more effective. As for what I would recommend CBG for — anxiety, pain, psoriasis, I use it in my patients with autism, I use it in my patients with cancer. Because it’s safe, and if somebody’s struggling and conventional medicine is not helping them or it is only helping to a point, I don’t see any reason, especially under medical supervision, not to try CBG and other cannabinoids when there’s compelling preclinical research that begs for clinical trials.

CBG is always a compound I consider when treating children who have behavior or other types of difficulties.

CannMed: It seems like CBG is very well tolerated by patients, but are there adverse reactions that you’ve run into?

Dr. Goldstein: I haven’t really seen a lot of adverse reactions, except for a few specific ones related to the population of children that I take care of. In some kids with autism, it’s just too overstimulating. It makes behavior go off the charts. So, I warn the families about this before we get started. It may be a dosage thing. Dosing is very, very important. Lower doses may be overstimulating. If that’s the case, we might try higher doses. But that’s specifically related to a certain population. I have not observed or heard of too many side effects from adults taking CBG. Some patients say that CBG is somewhat alerting, meaning it feels a little up. So, you would not want to take CBG right before bedtime. You figure out how you respond to it, and then don’t use it at night if that’s the effect you get. On the other hand, some people say it helps with sleep. Maybe it’s helping with sleep because it’s calming and decreases anxiety. When a doctor hands you an antidepressant or an opioid, nobody knows how you’re going to respond if you’ve not taken that before. It’s the same thing with CBG. There is always a chance when you take a new medication that you may be the person who doesn’t respond very well. Or you might be the person who gets a great result.

CannMed: CBG is still one of the lesser-known cannabinoids. How easy is it to access CBG products?

Dr. Goldstein: In the video that I put up on YouTube, there’s a slide that shows some of the CBG products. You can get it as flower if you want to vaporize it. You can get it as a topical, as I’ve mentioned. Mostly I’ve seen it in tincture form, which means an extract in a bottle where you have a little eyedropper or syringe and you measure out your dose and squirt it under the tongue. I don’t endorse any company, but certainly a quick Google search will lead you to where you can find CBG. And of course, always, always before you purchase anything, you want to make sure you get a Certificate of Analysis (CoA) so you see what is supposed to be in that bottle before you buy it. And if a CoA isn’t available or not readily transparent, move on to the next product.

CannMed: We actually did a podcast with a laboratory professional who was talking about how some manufacturers will even falsify their CoA’s. She had some good tips for being able to spot the real ones and the less scrupulous ones. So, Bonni, before I let you go, I want to thank you so much for talking about CBG with us. I look forward to hearing your talk on some of the other cannabinoids at CannMed 2023, where you’re also going to be leading our Medical Practicum, along with Dustin Sulak, Kevin Spelman, and Eloise Thiessen. Could you give us a sneak quick preview of what people can expect at the Practicum and why you believe it’s important to have events like this to educate clinicians and laypersons about cannabis medicine.

Dr. Goldstein: It’s important because for health care professionals there is no full board training program, no residency or internship that focuses on cannabis therapeutics. The feedback we’ve gotten is it’s very helpful to hear directly from clinicians who are actually practicing this type of specialty and who are exploring the nuances of cannabis medicine. The practicum is a full day of education. We start off with endocannabinoid system physiology, the physiology of the cannabinoids and other constituents of the plant. Dr Kevin Spelman, who’s a brilliant botanist and herbalist with many years of experience, is one of the teachers. His lectures are amazing. Especially coming from my world as an MD, an allopathic world, it was a big change for me to understand botanical medicine. Having him on board really helps bridge that gap for those of us who are coming from the allopathic field. During the practicum, we also go through clinical applications for cannabis, special considerations for geriatric patients, chronic pain treatment. I’ll be talking about pediatrics, my area of specialty. And then there will be practical panels where we’ll be giving case reports and advice on how to help your patients pick the right medicine. It’s really a full day with lots of information for anyone who wants to advance their knowledge. I really enjoy it. It’s great to be around like-minded people, and it’s great to hear about other people’s experiences. I always learn something from my colleagues at CannMed, from people in the audience, and from the other speakers.

For more information on Dr. Goldstein, visit her YouTube channel Bonni Goldstein MD. She occasionally posts on Instagram, and she is also on LinkedIn. To hear the full CannMed podcast with Dr. Bonni Goldstein, go here.

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Project CBD Launches New Website Developed in Collaboration with Blue Dream

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.

We look forward to an ongoing partnership with Blue Dream, as we expand our reporting on cannabis science, plant medicine, psychedelics, regenerative farming, and the social dimensions of health and drug policy.

Project CBD & Blue Dream/Ganjapreneur

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THC & CBD-Rich Cannabis for Fibromyalgia

For all modern medicine can do, many mysteries remain unsolved. What is long COVID? Is there really such thing as a “cure” for cancer? And how to explain the surprisingly high prevalence of fibromyalgia, a debilitating, lifelong disorder of the central nervous system without a known cause that affects between 2 and 4 percent of adults worldwide?

In the absence of an answer — or a cure — treatment is the name of the game for fibromyalgia. No single drug yet exists to address all of the disease’s effects on the body, which can include widespread aches and pains, sleeplessness, fatigue, anxiety, and depression. Instead, patients turn to a mix of whatever individual medications, therapies, and lifestyle changes (especially exercise) help ease symptoms and improve quality of life.

On the drug front, anti-depressants, analgesics, and muscle relaxants might be prescribed. But there’s another option that can address mood, pain, and more at once, all with fewer side effects: cannabis.

It’s not a new idea. Researchers have been investigating the use of cannabis to treat fibromyalgia’s constellation of symptoms for decades, with early clinical trials in the 2000s1-4 suggesting a possible benefit of both pure THC and flower in managing the disease. Nor is it necessarily surprising, given the ability of cannabis to target the ubiquitous, homeostasis-seeking endocannabinoid system.

Recently published papers — a series of reviews, two human studies, and an animal study — only bolster the case that cannabis can help those suffering from this confounding condition. Still more may be forthcoming, including through a newly announced randomized controlled trial in the Netherlands that will compare cannabis, oxycodone, and a combination of the two for pain relief in 60 fibromyalgia patients.5

Solid Evidence Base

Over the last few months a number of reviews have helped refine our understanding of the relationship between cannabis, the endocannabinoid system (ECS), and fibromyalgia symptoms. In November 2022, a paper in the journal Pain Reports6 provided the first systematic review and meta-analysis of previous studies measuring levels of circulating endocannabinoids and other fatty acid derivatives in patients with both fibromyalgia and chronic widespread pain.

Across the eight studies they analyzed, the Australia-based authors identified increased levels of oleoylethanolamide and stearoylethanolamide (endocannabinoid-like molecules called N-Acylethanolamines that don’t bind with the cannabinoid receptors) in patients with these conditions compared to controls. There were no differences observed in levels of the endocannabinoids anandamide and 2-AG.

“Available data strongly support the use of cannabinoids in treating fibromyalgia pain” due to “overwhelmingly positive treatment results.”

Still, the authors caution that “most studies did not account for variables that may influence ECS function, including cannabis use, concomitant medication, comorbidities, physical activity, stress levels, circadian rhythm, sleep quality, and dietary factors.” They call for additional study in this area and, more broadly, seek to “highlight the importance of investigating endocannabinoid activity in chronic widespread pain and fibromyalgia because it will underpin future translational research in the area.”

Other recent papers summarize the state of the science:

  • A review of clinical and preclinical research into cannabinoids, the ECS, and fibromyalgia in Pharmacology & Therapeutics7 (December 2022) agreed that “there is evidence for alterations in the endocannabinoid system in patients with fibromyalgia.”
  • A systematic review and meta-analysis of eight studies investigating the benefits of cannabinoids for chronic pain in Pain and Therapy8 (December 2022) reported that “cannabinoids might improve pain and quality of life in patients with fibromyalgia.”
  • And a narrative review also in Pain and Therapy9 (January 2023) on the efficacy, risks, and benefits of cannabinoids in the treatment of various pain subtypes concluded that “available data strongly support the use of cannabinoids in treating fibromyalgia pain” due to “overwhelmingly positive treatment results.”

Mice Respond to Cannabis Oil

Unlike some other areas of cannabinoid science, fibromyalgia research is not dominated by preclinical laboratory studies. But an October 2022 paper in Biomedicine and Pharmacotherapy10 offers an interesting parallel to previous human studies through the use of a well-established mouse model of fibromyalgia induced by reserpine, a drug that acts on the central nervous system (and is sometimes used to treat high blood pressure in humans).

The Italy- and Brazil-based authors sought to evaluate the effect of a “broad-spectrum” 11:1 CBD:THC cannabis oil in mice with reserpine-induced fibromylagia. They report that oral feeding of a single dose of cannabis oil was enough to mitigate some hallmarks of the condition in mice. Better yet, repeated administration over the course of two weeks reversed reserpine-induced mechanical and thermal sensitivity, and also reduced depressive-like behavior.

While the implications of these findings for human physiology and disease are perhaps unclear — given that we still don’t fully understand the etiology of fibromyalgia — they appear to lend yet more credibility to cannabis.

Cannabis Helps “Treatment-Resistant” Patients

Two new prospective cohort studies build upon this work with additional real-world data that may well wind up in future reviews. A November 2022 article in the journal Pain Practice11 covers a clinical trial in which 30 women suffering from fibromyalgia symptoms resistant to traditional pharmacological treatments were provided medicinal cannabis. That seemed to make all the difference. Comparing the women’s scores on the World Health Organization Quality of Life questionnaire before and after a month of cannabis use revealed “a marked improvement in general quality of life, general health, physical health, and psychological domain.”

And a similar, earlier study by researchers in Canada — with 323 fibromyalgia patients followed for 12 months — also found through quarterly physician assessments that initiating cannabis use was associated with improvements on a variety of fronts. As the authors report in the journal Arthritis Care & Research,12 observed reductions in pain intensity appeared to be partly explained by concurrent benefits to both sleep and mood.

“With suboptimal response to current medications, many patients with fibromyalgia seek … cannabis,” the authors conclude. “Medical cannabis may present a useful treatment strategy for patients with fibromyalgia in light of an effect on the triad of symptoms of pain, negative affect, and sleep disturbances.”

Nate Seltenrich, an independent science journalist based in the San Francisco Bay Area, covers a wide range of subjects including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Schley, Marcus et al. “Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief.” Current medical research and opinion vol. 22,7 (2006): 1269-76. doi:10.1185/030079906×112651
  2. Skrabek, Ryan Quinlan et al. “Nabilone for the treatment of pain in fibromyalgia.” The journal of pain vol. 9,2 (2008): 164-73. doi:10.1016/j.jpain.2007.09.002
  3. Ware, Mark A et al. “The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial.” Anesthesia and analgesia vol. 110,2 (2010): 604-10. doi:10.1213/ANE.0b013e3181c76f70
  4. Fiz, Jimena et al. “Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life.” PloS one vol. 6,4 e18440. 21 Apr. 2011, doi:10.1371/journal.pone.0018440
  5. van Dam, Cornelis Jan et al. “Cannabis-opioid interaction in the treatment of fibromyalgia pain: an open-label, proof of concept study with randomization between treatment groups: cannabis, oxycodone or cannabis/oxycodone combination-the SPIRAL study.” Trials vol. 24,1 64. 27 Jan. 2023, doi:10.1186/s13063-023-07078-6
  6. Kurlyandchik, Inna et al. “Plasma and interstitial levels of endocannabinoids and N-acylethanolamines in patients with chronic widespread pain and fibromyalgia: a systematic review and meta-analysis.” Pain reports vol. 7,6 e1045. 7 Nov. 2022, doi:10.1097/PR9.0000000000001045
  7. Bourke, Stephanie L et al. “Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research.” Pharmacology & therapeutics vol. 240 (2022): 108216. doi:10.1016/j.pharmthera.2022.108216
  8. Giossi, Riccardo et al. “Systematic Review and Meta-analysis Seem to Indicate that Cannabinoids for Chronic Primary Pain Treatment Have Limited Benefit.” Pain and therapy vol. 11,4 (2022): 1341-1358. doi:10.1007/s40122-022-00434-5
  9. Ang, Samuel P et al. “Cannabinoids as a Potential Alternative to Opioids in the Management of Various Pain Subtypes: Benefits, Limitations, and Risks.” Pain and therapy, 10.1007/s40122-022-00465-y. 13 Jan. 2023, doi:10.1007/s40122-022-00465-y
  10. Ferrarini, Eduarda Gomes et al. “Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 154 (2022): 113552. doi:10.1016/j.biopha.2022.113552
  11. Hershkovich, Oded et al. “The role of cannabis in treatment-resistant fibromyalgia women.” Pain practice : the official journal of World Institute of Pain vol. 23,2 (2023): 180-184. doi:10.1111/papr.13179
  12. Sotoodeh, Romina et al. “Predictors of Pain Reduction Among Fibromyalgia Patients Using Medical Cannabis: A Long-Term Prospective Cohort Study.” Arthritis care & research, 10.1002/acr.24985. 25 Jul. 2022, doi:10.1002/acr.24985

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Cannabinoids for Tinnitus?

Recently my wife returned from a night out with a ringing in one ear and significantly diminished hearing. It was a sure sign of injury caused by standing too close to a speaker. She was upset with herself for being so careless and concerned that the condition would persist. For the next couple days, she got extra sleep to aid recovery, and for good measure took an extra dose or two of CBD.

For many other people of all ages, tinnitus is indeed a chronic condition that has nothing to do with loud ‘80s cover bands in small clubs. Risk factors span a wide range of physical and psychological conditions including concussion, smoking, certain medications, ear infection, high blood pressure, anxiety, depression, and, most commonly, age-related hearing loss.

And it’s not just ringing. Technically, tinnitus (pronounced tih-NITE-us or TIN-ih-tus) is the perception of sound originating from within the nervous system that’s unrelated to external stimulation. Tinnitus can also be experienced as buzzing, whirring, humming, whooshing, clicking, and hissing. Whatever the precise nature of the phantom sound, it often comes with a constellation of symptoms related to the disruption such a condition can bring: sleep problems, difficulty concentrating, low mood, etc. Estimates vary, but tens of millions of people in the United States alone likely suffer from chronic tinnitus.

My wife’s ringing tinnitus did fade, and her hearing gradually improved over the course of a few days. The CBD she took may or may not have helped, but according to a recent survey of tinnitus patients, she wasn’t alone in trying — or at least in being interested in cannabis as a potential remedy.

Auditory & Other Symptoms

The survey, whose findings were published in February 2023 in the Journal of Otolaryngology – Head & Neck Surgery1evaluated cannabis perceptions and consumption among 45 adult tinnitus patients randomly selected and recruited from an outpatient ear, nose, and throat clinic in Ontario, Canada.

Among the 45 respondents, median age 55, only 10 said they were current cannabis users (19 had never used, and 16 had used in the past). But of the 10 current users, eight reported that cannabis did help with some of their tinnitus-related symptoms — if not necessarily the sound itself. Seven of the eight found it helpful for sleep disturbances, seven for pain, six for emotional complaints, four for functional difficulties, and three for dizziness symptoms. Only three of the ten found cannabis helpful for the actual auditory symptoms characterizing tinnitus.

But many more patients were willing to try, perhaps as an indication of the intractability of chronic tinnitus. All but two of the 45 respondents said they’d consider cannabis as a treatment, with 29 seeking help for sleep disturbances, 27 for emotional complaints, 25 for functional disturbances, and nine for pain. Of note, however, 41 of the 45 said they’d turn to cannabis for auditory symptoms — the primary concern for most tinnitus patients yet the least improved by cannabis according to the survey’s 10 current users.

Interestingly, and perhaps unfortunately for patients, previous reviews in 2020 and 20192 also concluded there was insufficient evidence that cannabis can diminish chronic tinnitus.

Mixed Findings

A December 2020 review in the journal Laryngoscope Investigative Otolaryngology3 by researchers at Yale University and nearby University of Connecticut tackles the question head-on. Its title: “Does cannabis alleviate tinnitus? A review of the current literature.”

And its conclusion? “While animal studies have revealed that cannabinoid receptors likely have a role in modulating auditory signaling, there is no compelling data either from animal or human studies for the use of cannabinoids to alleviate tinnitus.”

There could be a role for cannabinoids in the management of tinnitus through their anticonvulsant effects.

In fact, there’s some evidence from animal research that cannabinoid administration may actually induce or exacerbate tinnitus. That’s what appeared to happen in rats injected with the synthetic CB1 agonists WIN55,212‐2 and CP55,940 in a 2010 study4 and THC and CBD in a 1:1 ratio in a 2011 follow-up study.5

As far as human studies, the review authors also summarize two previous surveys in 2010 and 2019, a 1975 clinical trial and a 2006 case study — whose cumulative findings are, at best, entirely unclear.

Despite all this, there is a potential biological rationale for the treatment of tinnitus with cannabinoids, the authors explain. Other animal studies have suggested that cannabinoid receptor expression in the cochlear nucleus may vary with tinnitus symptomatology. And since the most widely accepted hypothesis for the pathophysiology of tinnitus relates to something called “neuronal hyperexcitability” — a mechanism that has also been observed in epilepsy, they note — “there is a potential role of cannabinoids in the management of tinnitus through its anticonvulsant effects.”

Cannabinoid Receptors Influence Hearing

Finally, a November 2020 review in Frontiers in Neurology6 adds more complexity and subtlety to the issue. The article wisely notes that animal studies showing cannabinoids to potentially worsen tinnitus have focused on CB1 agonists. This excludes compounds that target, among others:

  • CB2 receptors, which influence immune function and are “increasingly recognized as essential in understanding nervous system pathological responses”
  • and “non-classical” cannabinoid targets like TRP (“trip”) channels, which mediate processes including vision, taste, olfaction, touch and hearing.

While the collective evidence to date is mixed and inconclusive, it’s also incomplete. The potential is huge for new animal studies using cannabinoids other than CB1 agonists, and for more robust human studies (indeed any clinical trial at all) to contribute fresh insights to this burning, buzzing question.

Nate Seltenrich, an independent science journalist based in the San Francisco Bay Area, covers a wide range of subjects including environmental health, neuroscience, and pharmacology. Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Mavedatnia, Dorsa et al. “Cannabis use amongst tinnitus patients: consumption patterns and attitudes.” Journal of otolaryngology – head & neck surgery vol. 52,1 19. 24 Feb. 2023, doi:10.1186/s40463-022-00603-8
  2. Zheng, Yiwen, and Paul F Smith. “Cannabinoid drugs: will they relieve or exacerbate tinnitus?.” Current opinion in neurology vol. 32,1 (2019): 131-136. doi:10.1097/WCO.0000000000000631
  3. Narwani, Vishal et al. “Does cannabis alleviate tinnitus? A review of the current literature.” Laryngoscope investigative otolaryngology vol. 5,6 1147-1155. 30 Oct. 2020, doi:10.1002/lio2.479
  4. Zheng, Yiwen et al. “The effects of the synthetic cannabinoid receptor agonists, WIN55,212-2 and CP55,940, on salicylate-induced tinnitus in rats.” Hearing research vol. 268,1-2 (2010): 145-50. doi:10.1016/j.heares.2010.05.015
  5. Zheng, Y et al. “Acoustic trauma that can cause tinnitus impairs impulsive control but not performance accuracy in the 5-choice serial reaction time task in rats.” Neuroscience vol. 180 (2011): 75-84. doi:10.1016/j.neuroscience.2011.02.040
  6. Perin, Paola et al. “Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective.” Frontiers in neurology vol. 11 505995. 23 Nov. 2020, doi:10.3389/fneur.2020.505995

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