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Get High and Lose Weight?

cannabis for weight loss

Evidence shows marijuana users are much less likely to develop metabolic syndrome, a significant risk factor for obesity, diabetes, and heart disease.
By Martin A. Lee On January 03, 2018

Marijuana Use Associated with Decreased Chance of Developing Metabolic Syndrome

First the bad news: The United States is facing epidemic levels of obesity, diabetes, and cardiovascular disease.

Now the good news if you are a cannabis consumer: According to a study published in the American Journal of Medicine, marijuana users are much less likely than non-users to develop metabolic syndrome, which is a significant risk factor for obesity, type II diabetes, and heart disease.

Conducted by scientists at the University of Miami in Florida, this study examined the relationship between cannabis consumption and the individual components of metabolic syndrome, such as high blood pressure, increased abdominal fat, elevated blood sugar, and unhealthy cholesterol levels.

Nearly 8,500 people from age 20 to 59 provided survey data for the study. Participants were separated into three categories—current marijuana users, past users, and those who had never smoked the herb. Whereas metabolic syndrome afflicts 22 percent of the U.S. adult population, less than 14 percent of current cannabis-using adults in this study had metabolic syndrome.

Among young adults, cannabis consumers are 54 percent less likely than non-consumers to present with metabolic syndrome. Past marijuana use is associated with lower odds of metabolic syndrome among middle-aged adults. And seniors who medicate with cannabis tend to be slimmer and less insulin-resistant than seniors who just say no.

The Munchies Receptor

The results of the study, entitled “Metabolic Syndrome among Marijuana Users in the United States,” may seem counterintuitive given marijuana’s notorious appetite-stimulating effects, jocularly known as “the munchies.” Under the influence of marijuana, flavors seem to jump right out of food. That’s because tetrahydrocannabinol (THC) activates CB1 cannabinoid receptors in the brain that rouse one’s appetite and heighten one’s sense of smell.

The munchies are a scientifically proven phenomenon. THC is a CB1 “agonist” that turns on the appetite receptor and causes it to signal. An “antagonist” will block the receptor and prevent it from signaling. Tetrahydrocannabivarin (THCV), a minor but medically significant component of the cannabis plant, is a neutral CB1 receptor antagonist.

Scientists have also synthesized “inverse agonists” that can activate a cannabinoid receptor and cause it to signal in the opposite manner from how it functions naturally. A CB1 inverse agonist will curb appetite and reduce food intake by binding to CB1 receptors, whereas THC boosts appetite and food intake by binding to CB1.

One could reasonably assume, given what we know about the munchies, that increased use of marijuana will result in greater caloric consumption with consequent adverse metabolic outcomes, including obesity. However, the results of this study and other reports indicate that such is not the case. Indeed, the opposite appears to be true.

In addition to underscoring potential health benefits of herbal cannabis, these findings highlight the discrepancy between human research that links marijuana use to lower rates of obesity compared to preclinical studies involving synthetic isolates in which CB1 antagonism (blocking the munchies receptor) and CB1 inverse agonism (flipping the anti-munchies switch) are shown to prevent obesity.

How is it possible that marijuana consumption, which activates CB1, is associated with preventing obesity in humans, while blocking or reversing the CB1 receptor via a synthetic, single-molecule compound results in weight-loss in animal models and human trials? What can explain this apparent contradiction? It may have something to do with the complementary, yet opposing functions of two different sets of cannabinoid receptors.

CB2 Receptor Activation

Australian scientists recently examined the role of the cannabinoid CB2 receptor “in modulating energy homeostasis and obesity-associated metabolic pathologies.” The CB2 receptors are concentrated in the peripheral nervous system, immune cells, and in metabolically active tissue. The Australian researchers found that CB2 receptor activation by JWH-015, a “selective CB2 receptor agonist,” reduces food intake in mice and prevents the build-up of body fat.

THC, a non-selective, plant-derived agonist, binds to both the CB1 receptor and the CB2 receptor. The fact that THC and other cannabis components (including the aforementioned THCV) activate CB2 receptor signaling may explain why marijuana users are less likely to develop metabolic syndrome than marijuana abstainers. Metabolic syndrome is a generalized, low-grade inflammatory condition, and the THC-sensitive CB2 receptor regulates immune function and inflammation.

CB2 receptor activation—through healthy diet and cannabis-enabled stress reduction—may prove to be a better strategy for preventing and treating metabolic syndrome than the misguided attempt by French pharmaceutical giant Sanofi-Aventis to market Rimonabant, a synthetic CB1 inverse agonist as an appetite suppressant. Promoted as a blockbuster diet drug in 2006, Rimonabant was soon recalled in Europe because of severe side effects, including neurological deficits, depression, and suicide. The anti-munchies pill was never approved for sale in the United States.

Sorry Big Pharma, but when it comes to preventing or mitigating metabolic dysfunction, synthetic isolates are much less effective than whole plant cannabis with its synergistic treasure trove of natural medicinal components that enhance and balance each other’s effects.

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

Copyright, Project CBD. May not be reprinted without permission.


  • Englund A, et al. “The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial.” Journal of Psychopharmacology. 2015 Nov 17.
  • Karlsson C et al, “Baseline anandamide levels and body weight impact the weight loss effect of CB1 receptor antagonism in male rats,” Endocrinology, 2015 April.
  • Verty, AN, et al. “Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice. PLoS One. 2015 Nov 20.
  • Vidot DC, Prad G, Hlaing WM, Arheart KL, Messiah SE. “Metabolic Syndrome among Marijuana Users in the United States: An Analysis of National Health and Nutrition Examination Survey Data.” American Journal of Medicine. 2015.
  • Yale University press release, “Mulling the marijuana munchies: How the brain flips the hunger switch,” 18-Feb-2015.

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New Oregon Cannabis Rules: Part One – Marijuana Promotional Events

Change is the only constant in cannabis regulation.

On December 22, the Oregon Liquor Control Commission (OLCC) adopted a large packet of rules amendments that incorporate the many cannabis bills signed by Oregon Governor Kate Brown this year, as well as “technical amendments [made] in response to market realities.” These changes, effective December 28, 2017, include:

  • implementation of mandatory seed-to-sale tracking for medical cannabis;
  • a new regulatory regime for hemp and hemp products that allows hemp products into Oregon’s recreational cannabis supply chain;
  • new rules governing Marijuana Promotional Events;
  • new canopy limits for growing immature plants outside of the standard canopy areas;
  • an exception to the retailers-must-be-1,000-ft-from-a-school rule if there is a physical or geographical barrier between the retail site and the school that prevents children from traveling to the retailer, such as a river;
  • new certifications for recreational wholesalers that can now trim cannabis, and can offer mobile for-hire trimming services;
  • some minor changes to transportation rules;
  • a small change to the definition of “financial interest” that will have a big impact on what investors must be pre-approved by the OLCC;
  • a new prohibition on sales through walk-up windows to complement the existing prohibition on drive-thru sales (Makes you wonder who came up with the work-around that led to this rule change); and
  • micro-tier producers can now do some processing of cannabis concentrates.

Because the changes cover quite a bit of ground, we’ll dig into several of these in more detail in future installments in this series. For now, we will focus on the new Marijuana Promotional Events, governed by OAR 845-025-1335. This new administrative rule allows recreational licensees to display their products at trade shows, which is something many of our clients have been eager to do for a while.

Under the new rules, trade shows or similar events will be organized by a single licensee or “Event Organizer”, that will be the primary contact with the OLCC. The Event Organizer must submit an application to the OLCC at least 28 days before the event that will include the names and signatures of any participating licensees, the amount and type of cannabis items that will be on display, and a control plan that explains how the participating licensees will prevent violations.

Assuming the OLCC approves an application, the participating licensees may bring and display marijuana and marijuana products from their inventory (sorry, no hemp). All of the marijuana must be returned to the licensee’s premises at the end of the event. Thus, these trade shows are not an opportunity to sell or otherwise distribute any cannabis products. Even samples are prohibited.

The ban on samples will probably dissuade some members of the public from attending, but that rule is no different than the ban on samples from licensed dispensaries generally. On the licensee side, trade shows may prove invaluable for smaller industry players hoping to distinguish themselves in a very competitive market. The other possibility, of course, is that licensees may find the regulations too strict, and decline to participate.

Check back soon for another dive into the new rules governing Oregon’s cannabis market. And Happy New Year!

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Oregon Cannabis: State of the State (Part Two)

Interesting times for Beaver State cannabis.

A little over a year ago, I put together a State of the State blog post on Oregon cannabis. At that time, the rules were rolling out in a business-friendly manner, many of our clients were proceeding toward licensure, and the market did not feel saturated. Today, the first two items remain true, but the Oregon market has become fuller and more competitive. Part of this has to do with the state’s lack of residency requirements, part has to do with how easy it is to acquire an Oregon marijuana license, and part is just standard free market dynamics. All of this has been a long time coming.

As of the Oregon Liquor Control Commission’s (OLCC) December 19 report, there were 877 licensed marijuana producers in Oregon, with nearly another 1,000 applications pending. Much of the massive Croptober harvest is drying out and finding its way to the market, and prices for outdoor cannabis seem to be falling fast: in some cases, flower is dropping below $400 per pound. It’s hard to know where bottom is. Program architects may not put the brakes on this anytime soon: the legislature won’t meet again until February (and may not take up the issue at all); and, in the interim, OLCC has no authority to cap the number of licenses awarded. Instead, the agency can only reduce canopy sizes (which it has no plans to do, according to our recent conversations).

Today’s market dynamics were somewhat predictable: given the state of the rules and Oregon’s unique accessibility, we predicted a lot of “triage, consolidation, litigation, guesswork, and general ups and downs” as far back as early 2016. Some of this was almost certainly by design: in the Cannabis Law & Policy class I teach we do a deep dive on markets, and we talk about the general desire for states to allow the price of state-sanctioned pot to stay low, so as to undercut the black market. The countervailing consideration, of course, is the state’s desire to create tax revenues. In an excise tax program like Oregon’s, those revenues are higher when prices hold up at retail.

All of this said, we still think Oregon is a great state for marijuana entrepreneurs, even as the market settles out. Here are three interesting trends we are seeing today:

Consolidation. The Oregon merger and acquisition market is in full swing for cannabis, and our well positioned clients are expanding by acquiring competitive and complementary businesses, up and down the supply chain. Other clients are selling, with the belief that prices are still reasonable, but may crater down the line. In the past week alone, we commenced five different purchase and sale transactions, and we don’t expect a lull in this type of activity any time soon. Interestingly, prices and valuation of these businesses are all over the board. For some basics on buying and selling Oregon pot businesses, see our series here:

Litigation. Unfortunately, when pot businesses fail, litigation sometimes follows. We have seen an uptick in Oregon pot litigation as of late, particularly partnership beefs and creditor actions. We do not expect the dispute dynamic to change anytime soon. For this reason, we have been staffing up with litigators in the Portland office, we and are even putting on a free litigation webinar next month to more fully discuss this topic. (Join us!)

Hemp? Lately, more and more of our clients have shown an interest in growing hemp under licensure by the Oregon Department of Agriculture. Some of these clients are pursuing hemp-derived cannabidiol (CBD) sales in interstate commerce, which the ODA program does not prohibit. Others are preparing to sell CBD into the OLCC stream of commerce, which is finally allowed under Senate Bill 1015 (new rules take effect next week). As to interstate CBD sales, federal law is a cluster, but that hasn’t stopped many big box retailers from trading in this area. Right now, a wave of Oregon cannabis growers are going there, too.

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Treasure Hunt

Nine ways that scientists are targeting the endocannabinoid system with synthetic drugs and isolates
By Martin A. Lee On December 13, 2017

In recent years, cannabis has been at the center of one of the most important developments in modern science, which has significantly advanced our understanding of health and disease.

Research on marijuana’s effects led directly to the discovery of a major biochemical signaling system in the human body – the endocannabinoid system – which plays a pivotal role in regulating a wide range of physiological processes that affect our mood, our blood pressure, our bone density, our metabolism, our intestinal fortitude, our energy level, how we experience pain, stress, hunger, and much more.

“By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance,” says Israeli scientist Raphael Mechoulam. “We wouldn’t have been able to get there if we had not looked at the plant.”

Described by Mechoulam as “a medicinal treasure trove,” cannabis contains more than 100 unique biologically active compounds known as “cannabinoids,” including tetrahydrocannabinol (THC) and cannabidiol (CBD). THC causes the high that cannabis is famous for, CBD does not; both have important therapeutic attributes.

In addition to phytocannabinoids produced by the plant, there are endogenous cannabinoids – marijuana-like molecules – that occur naturally in the human brain and body. And there are also synthetic cannabinoids created by pharmaceutical researchers, who are developing new medicines that target the endocannabinoid system for therapeutic benefit.

Some of these novel synthetic compounds activate the same cannabinoid receptors – CB1 and CB2 – in the brain and body that respond pharmacologically to THC and other cannabis components.1

Medical scientists are also experimenting with synthetic drugs designed to improve “endocannabinoid tone” without binding directly to cannabinoid receptors.

Here are nine strategies that scientists are currently pursuing in an effort to harness the healing potential of the endocannabinoid system:



1. Single-molecule plant cannabinoids

Dronabinol, marketed in pill form as Marinol, is a single-molecule THC extract combined with sesame oil. It got fast-tracked for approval by the Food and Drug Administration in 1985 in response to rising patient demand for medical marijuana.

Other THC preparations are also on the FDA‘s radar, including Syndros, a liquid THC drug produced by Insys. But patented single-molecule THC is a poor substitute for whole plant cannabis.

Even though it is highly psychoactive and potentially dysphoric, pharmaceutical THC is legally accessible in all 50 states as a prescription medication.

Cannabidiol, unlike pure THC, is not yet legal in all 50 states. But CBD will soon become a legal pharmaceutical, as the FDA is poised to approve Epidiolex, a botanically derived anti-seizure medication produced by GW Pharmaceuticals. Epidiolex is pure CBD with a dash of cannabidivarin (CBDV), a “minor” cannabinoid that also has potent anti-epileptic properties.

Along with the imminent advent of pharmaceutical CBD, several R&D firms have begun to harvest single-molecule cannabinoids, such as CBDV, from a yeast substrate. As this biotechnology improves, drug developers and pharmacists will have access to numerous single-molecule cannabis compounds.


Image Credit: Bryan Satalino

2. Synthetic cannabinoid analogs

Scientists have created synthetic analogs of plant cannabinoids for research purposes and for commercial sale and distribution. Nabilone, a synthetic THC analog, was developed by Eli Lilly and Co. as a treatment for chemotherapy-induced nausea and vomiting.

Marketed under the trade name Cesamet, this synthetic cannabinoid is used as an adjunct therapy for chronic pain management in Canada and other countries. Clinical trials of Nabilone have indicated some effectiveness for fibromyalgia, Parkinson’s, PTSD-related nightmares, irritable bowel disease, and multiple sclerosis.

Researchers are using various synthetic analogs to investigate the biochemical pathways and molecular mechanisms of the endocannabinoid system. Some of these compounds (such as WIN55,212-2 and CP55,940) bind to both cannabinoid receptors – CB1 and CB2 – much like THC. Other experimental drugs target only one type of cannabinoid receptor and not the other. 2

A cannabinoid agonist binds to a cell receptor and causes it to initiate a signaling cascade that modulates various physiological processes and protects neurons against toxic insults. A cannabinoid antagonist binds to a cell receptor and prevents it from signaling.


Image Credit: Bryan Satalino

3. Synthetic cannabinoid antagonists

Cannabinoid CB1 receptors, which mediate the psychoactive effects of THC, are concentrated in the brain and central nervous system. When THC binds to CB1, it can make a person feel stoned – and hungry. The “munchies,” scientists confirmed, are linked to stimulation of CB1 receptors in areas of the brain that regulate hunger and satiety. If activated, CB1 receptors induce appetite; if blocked, they reduce it.

SR141716,” a synthetic CB1 antagonist developed by the French pharmaceutical giant Sanofi-Aventis, was initially utilized as a research tool: By blocking CB1 and monitoring which functions were altered, scientists advanced their understanding of the endocannabinoid system.

Sanofi strategists believed they had invented the perfect diet pill, and they promoted SR141716 as an appetite suppressant in Europe. But the diet drug, sold as “Rimonabant,” proved to be too blunt an instrument. Before long, the synthetic CB1 antagonist was pulled from circulation because of dangerous side effects – high blood pressure, nausea, vomiting, anxiety, mood swings, depression, headaches, seizures, sleep disorders, and a heightened risk of suicide.

If nothing else, the CB1 antagonist debacle provided vivid evidence that a well-functioning endocannabinoid system is essential for good health.3


4. Peripherally restricted CB1 agonists

Cannabinoid CB1 receptors, the most prevalent protein receptors in the human brain, influence many neurological functions, including marijuana’s mood-altering effects. CB1 receptors are also expressed in the enteric nervous system (the gut), the liver, kidneys, heart and other peripheral organs.

Stimulating CB1 receptors can deliver significant therapeutic benefits, but THC‘s psychoactivity limits its medical utility, according to Big Pharma catechism, which defines the CB1-mediated marijuana “high” as an adverse side effect that drug designers should avoid if they hope to win regulatory approval of their patented synthetic novelties.

So pharmaceutical researchers have created peripherally-restricted CB1 agonists (such as AZ11713908) that only activate CB1 receptors outside the central nervous system, but don’t cross the blood-brain barrier.

A peripherally restricted CB1 agonist won’t cause side effects such as disconcerting dysphoria or useless euphoria. But such a compound has never been approved for therapeutic use by the FDA.


Researchers studying impact on CB2 receptors in animals

5. Selective CB2 agonists

Scientists have been hot on the trail of another type of synthetic cannabinoid – a “selective CB2 agonist” – that will bypass the brain while acting on the peripheral nervous system, where CB2 receptors are concentrated. CB2 receptors regulate immune function, pain perception, and inflammation.

Tinkering with synthetic compounds (such as HU 308 and JWH 133) that selectively stimulate CB2 receptors raises the prospect of healing without the high because CB2 receptors are localized primarily outside the brain and thus do not induce psychoactivity.

Cannabinoid researchers have their eyes on the ultimate prize, the pharmaceutical Holy Grail – a non-addictive painkiller bereft of adverse side effects. Animal experiments focusing on the CB2 receptor initially showed promise.

Thus far, however, drug companies have not been able to synthesize clinically effective CB2-selective compounds, though not for lack of trying. “If drug discovery is a sea, then CB2 is a rock that is surrounded by shipwrecked-projects,” remarked Italian scientist Giovanni Appendino.



6. Water-soluble cannabinoids

In their natural form, plant cannabinoids and endocannabinoids are oily, hydrophobic substances that don’t dissolve in water. But these lipid molecules can be structurally altered so that they become water soluble without diminishing their therapeutic attributes.

Scientists have developed several ways of synthesizing water-compatible derivatives of THC and other cannabinoids that are more bioavailable and thus potentially more potent than their oily, naturally-occurring counterparts.

The first water-soluble version of THC was created in 1972. Subsequent research found that water-friendly cannabinoid derivatives can lower intraocular pressure in rabbits. A water-soluble cannabinoid ester, “O-1057,” exhibited stronger analgesic properties than THC in preclinical experimentation.

Internet retailers are claiming to sell water-soluble CBD formulated as a nanoemulsion. Pure CBD delivered via nanotechnology is supposed to provide exceptionally high bioavailability and remedial effect compared to a hydrophobic CBD oil extract.

But a CBD isolate typically requires a much higher dose for therapeutic efficacy than a whole plant CBD-rich concentrate – and this factor may cancel out the alleged advantages of nanoemulsified single-molecule CBD.


ZCZ011 {Image source Wikipedia}

7. Allosteric cannabinoid receptor modulators

Because direct, full-on stimulation of cannabinoid receptors in the brain may trigger undesirable psychoactive effects, scientists have developed synthetic compounds that change the shape of the CB1 receptor and influence how it signals without causing a THC-like high. These compounds, known as allosteric modulators, can either amplify or decrease a receptor’s ability to transmit a signal.

A “positive allosteric modulator” increases the potency and/or efficacy of CB1 receptor activation by anandamide and 2AG (the two main endogenous cannabinoids), thereby boosting the protective effects of the endocannabinoid system.

Scientists at the University of Aberdeen in Scotland have synthesized a positive allosteric modulator of CB1 to treat pain and neurological disorders. When researchers at Virginia Commonwealth University tested this experimental drug (“ZCZ011”) on mice, it reduced inflammatory pain by magnifying the CB1 receptor’s response to anandamide.

But allosteric effects are rarely consistent across species, which significantly impedes drug development in this area.4


The brain on cannabis

8. Inhibitors of endocannabinoid metabolizing enzymes

Medical scientists are experimenting with synthetic designer drugs to enhance endocannabinoid tone without binding directly (or allosterically) to cannabinoid receptors.

Pharmacological augmentation of endocannabinoid signaling can be achieved by inhibiting fatty acid amide hydrolase (FAAH) and/or monoglycerol lipase (MAGL), the catabolic enzymes that break down the brain’s own marijuana-like molecules, anandamide and 2AG, respectively.

Simply put, less FAAH and MAGL means more anandamide and 2AG, resulting in greater cannabinoid receptor activity throughout the body. Drugs that suppress endocannabinoid-metabolizing enzymes indirectly boost cannabinoid receptor signaling, causing a natural high without the vivid psychoactive effects associated with synthetic and plant-based CB1 agonists.

Preclinical research suggests that indirect modulation of endocannabinoid signaling could become a treatment option for various inflammatory conditions and stress-related disorders. FAAH and MAGL inhibition have been shown to ease pain, anxiety, colitis, hypertension, opiate withdrawal, diarrhea and arthritis in animal models.

While drug developers investigate synthetic FAAH-inhibitors (such as URB597) and MAGL-inhibitors (such as JZL 184), one need look no further than the kitchen spice rack for phytonutrients that regulate endocannabinoid tone by inhibiting the same catabolic enzymes. Nutmeg, one of many culinary spices that interact with the endocannabinoid system, inhibits the breakdown of both anandamide and 2AG, the brain’s own marijuana.


AM404 {Image source Wikipedia}

9. Endocannabinoid reuptake inhibitors

Another way to augment endocannabinoid tone entails delaying the reuptake of anandamide and 2AG. Scientists have synthesized reuptake inhibitors (such as AM404) that target transport molecules known as fatty acid binding proteins. These membrane-penetrating fatty acid binding proteins facilitate the intracellular transport and reuptake of endogenous cannabinoids.

By blocking access to these critical transport molecules, synthetic reuptake inhibitors increase endocannabinoid levels in the brain’s synapses. This results in heightened cannabinoid receptor signaling and endocannabinoid-induced protective effects.

THC and CBD also inhibit endocannabinoid reuptake. Enhancing endocannabinoid tone via reuptake inhibition may be a key mechanism whereby plant cannabinoids confer protective effects against seizures and neurodegeneration, as well as many other health benefits.

Fool’s gold?

Despite repeated setbacks, the possibility of healing without the high persists as an idée fixe among cannabinoid scientists and pharmaceutical researchers.

The lack of success with selective CB2 agonists, peripherally restricted CB1 agonists, allosteric modulators, CB1 antagonists and other non-euphoric cannabinoids underscores the challenges and limitations of synthetic, monomolecular medicine that targets a single protein receptor while forsaking whole plant synergies.

Synthetic CBD analogs are also in development. By tweaking the mother molecule and removing, adding or editing a molecular side chain, pharmaceutical researchers hope to create a marketable compound that is more potent and more effective than botanical CBD.

But a CBD isolate is not inherently superior to a whole plant CBD-rich extract. Preclinical studies that compare the efficacy of single-molecule CBD and full spectrum CBD-rich oil concentrates indicate that CBD solo is effective only at precise, high doses – whereas whole plant CBD-rich extracts have a much wider and safer therapeutic window and are effective at significantly lower doses. Problematic drug interactions are also much likelier with high dose single-molecule CBD.

Regulatory policy should not privilege single-molecule meds over full spectrum cannabis remedies. Patients are best served by having access to a wide range of cannabinoid-based therapeutic options, including artisanal whole plant preparations and synthetic isolates, if and when they become available.

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


  1. Only four cannabis compounds bind directly to either one or both cannabinoid receptors. THC activates CB1 and CB2. Cannabinol (CBN), a THC breakdown component, activates the CB1 receptor, though with less potency than THC. Tetrahydracannabivarin (THCV), the propyl variant of THC, binds to both cannabinoid receptors, activating CB2 while blocking CB1. And beta caryophyllene, an aromatic terpene found in many cannabis strains, green leafy vegetables, and common kitchen spices, activates CB2. Other cannabinoids, including CBD, interact with the endocannabinoid system indirectly without binding like lock and key to a cannabinoid receptor.
  2. Developed as a research tool to study that endocannabinoid system, JWH-018 is a synthetic cannabinoid compound that activates the CB1 receptor but not CB2. After the formula for this potent CB1 agonist was published in the scientific literature, JWH-018 surfaced as a street drug known as “Spice” or “K2.” Media accounts typically mischaracterize Spice as “synthetic marijuana.”
  3. U.S. government scientists have not given up entirely on Rimonabant. The fact that this compound blocks the euphoric effects of cannabis is a big plus to the National Institute on Drug Abuse, which has sponsored research on utilizing CB1 blockers to treat various addictions, including “cannabis dependence.”
  4. Canadian scientists have identified CBD as a “negative allosteric modulator” of the CB1 receptor based on in vitro research. This means that CBD, when administered in combination with THC, will alter the shape of the CB1 receptor in a way that weakens its binding affinity for THC. As a negative allosteric modulator of CB1, CBD lowers the ceiling on THC‘s psychoactivity, which might be why people don’t feel as high when using CBD-rich cannabis as compared to a THC-infused product.


• Han S, Thatte J, Buzard DJ, Jones RM. Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists. J Med Chem. 2013 Nov 14;56(21):8224-56. PubMed PMID: 23865723.
• Ignatowska-Jankowska BM, Baillie GL, Kinsey S, Crowe M, Ghosh S, et al. A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects. Neuropsychopharmacology. 2015 Dec;40(13):2948-59. PubMed PMID: 26052038; PubMed Central PMCID: PMC4864630.
• Mitjavila J, Yin D, Kulkarni PM, Zanato C, Thakur GA, et al. Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons. Pharmacol Res. 2017 Nov 20;PubMed PMID: 29158048.
O’Hearn S, Diaz P, Wan BA, DeAngelis C, Lao N, et al. Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017 Aug 31;PubMed PMID: 29156899.
• Pertwee RG, Gibson TM, Stevenson LA, Ross RA, Banner WK, et al. O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. Br J Pharmacol. 2000 Apr;129(8):1577-84. PubMed PMID: 10780961; PubMed Central PMCID: PMC1572002.
• Schindler CW, Scherma M, Redhi GH, Vadivel SK, Makriyannis A, et al. Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology (Berl). 2016 May;233(10):1867-77. PubMed PMID: 26803499; NIHMSID: NIHMS754451; PubMed Central PMCID: PMC4846479.
• Wasilewski A, Misicka A, Sacharczuk M, Fichna J. Modulation of the endocannabinoid system by the fatty acid amide hydrolase, monoacylglycerol and diacylglycerol lipase inhibitors as an attractive target for secretory diarrhoea therapy. J Physiol Pharmacol. 2017 Aug;68(4):591-596. PubMed PMID: 29151076.
• Yu XH, Cao CQ, Martino G, Puma C, Morinville A, et al. A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain. 2010 Nov;151(2):337-44. PubMed PMID: 20696525.

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Epilepsy, Endocannabinoids and Phytocannabinoids

There's promise in the use of cannabis to manage epilepsy

Cannabidiol and several other cannabis components can help patients with seizure disorders, and sometimes it’s best to combine CBD with conventional anti-epileptic meds.
By Stacey Kerr, M.D. On November 25, 2017


• More than 5 million Americans suffer from epilepsy.
CBD is helping many patients, including children with seizure disorders.
THCA, the unheated form of THC, and linalool, an aromatic terpene present in many varieties of cannabis, are potent anticonvulsant compounds.
• Oftentimes, patients must experiment with different cannabis products to find the best remedy for their condition.

“David,” a 10 year old boy, had his first seizure at 2 months of age. The convulsions were photosensitive generalized tonic-clonic seizures that occurred 1-4 times each day. These events were occurring daily, even though he was being treated with two anti-seizure medications – lamotrigine (Lamictal) and valproic acid. But they had already tried carbamazepine, phenobarbital, zonisamide and levetiracetam (Keppra) without success.

On the recommendation of his physician, THCA was added to his medication at 0.05mg/kg/day and his parents immediately noticed a reduction in seizure frequency. They then increased the THCA dosage to 2.2mg/kg/day, and even though there was no benefit noted to this increased dosage, the parents continued at this higher amount. After three months of THCA treatment, his parents reported to his physician a 40% reduction in seizure activity, shorter seizures, and the ability to discontinue the anti-seizure medication Diastat, which they had been using for seizure rescue. Hoping for even more control, they began a formula that contained THC at a THCA:THC ratio of 4:1. This caused transient side effects of somnolence but did nothing to improve the frequency of seizures.

Even if it did not completely resolve his seizure disorder, the phytocannabinoid THCA was able to make a significant difference in David’s quality of life. He is not alone. Cannabis holds hope for many, like David, who suffer from seizure disorders.

Epilepsy is a complex medical, economic, and social issue that affects at least 5.1 million of the US population by 2013 population reports. In Hawaii, there are an estimated 15,000 patients with seizure disorders. The total indirect and direct cost of epilepsy in the United States is estimated to be $15.5 billion yearly. 1, 2 For the individuals and families of those patients with seizure disorders, life can be limited and extremely complicated depending on the type and frequency of seizures and on the effects of anti-seizure medications, both therapeutic and undesirable.

Seizures occur when a part of the brain becomes overly excited or when nerves in the brain begin to fire in an abnormal way. An abrupt imbalance between the triggers of excitatory signals and inhibitory signals causes the excitatory forces to take over. This excitation then spreads to surrounding cells which all start firing in the same abnormal way. Increased excitation of nerve cells, or decreased inhibition of nerve cells due to a variety of potential insults can lead to a seizure. Balance, or homeostasis, is disrupted.

Most epileptics have no known cause for their seizures. The minority have numerous identified causes that include trauma, infections, inborn metabolic errors, drugs (or withdrawal from drugs), and inherited conditions.

Conventional treatment

There are no treatments for the underlying causes of seizures, and no treatments to reliably prevent the development of seizures after head traumas. There are only medications to limit the seizure intensity or frequency, and these medications are not always effective. In fact, a third of epileptic patients fail to become seizure free even after trying and tolerating two or more appropriately prescribed anti-epileptic drugs (AEDs).3

More than 20 new seizure medications have been developed over the past few decades, but the percentage of patients with uncontrolled seizures has not changed as much as we would hope or expect. Patients who are resistant to AEDs have a higher risk of complications and sudden death due to epilepsy. The need for multiple AEDs also increases the occurrence of significant side effects. The need for better, safer, and more effective treatment is clear.

Safety profile

Cannabis is a safe medication with no incidence of fatalities due to the lack of cannabinoid receptors in the brainstem. The most common side effects reported among patients using cannabis for seizure control are fatigue, decreased appetite, and somnolence, all of which resolve when cannabis is discontinued. AEDs can have significant side effects, and contrary to cannabis some of these can be fatal.

It is important to note that there are some drug-drug interactions when using cannabis with AEDs because cannabinoids are primarily metabolized by the Cytochrome P-450 system in the liver. Competition for these enzymes can affect the serum levels of AEDs, so patients using cannabis in addition to prescribed AEDs should be monitored, and dosage adjustments may be needed.

The endocannabinoid system in epilepsy

The job of the endocannabinoid system is to maintain homeostasis, so it is no surprise that cannabis has been used to help control seizures for centuries. Well-designed studies on rats have shown that the endocannabinoid system is a significant part of the brain’s response to seizure disorders.

We know that cannabinoid receptors are particularly dense in the central nervous system, and while we do not yet completely understand all the mechanisms that explain the anti-seizure effects of cannabis, we do have theories.

There are cannabinoid receptors in the hippocampus, that part of the brain that handles emotions and memory encoding. Abnormal changes in cells in the hippocampus are a cause of medial temporal lobe epilepsy, which is one of the most common forms. In this type of epilepsy, hippocampal cells create an excitatory feedback loop that causes seizures. Animal and human studies show that cannabinoids seem to be protective of the normal hippocampal cells, and may make the abnormal cells less active.4

In acutely seizing animals, the endocannabinoid 2-AG was significantly increased compared to controls. By testing the levels of both anandamide and 2-AG we have seen that both are synthesized on demand when seizures occur, thus activating the CB1 receptors. It also appears that there is a significant increase in CB1 receptor expression in epileptic animals, a receptor increase that is prolonged and probably permanent.

In studies done on rats with refractory seizures, it was noted that THC completely terminated those seizures without causing sedation, while maximal levels of phenobarbital or phenytoin were unable to do the same. This indicates that phytocannabinoids may offer advantages in treating refractory seizures compared to currently prescribed anti-convulsants.5

In more recent years research on animal models and human clinical observations have rekindled interest in using cannabis to control epilepsy. Cannabinoids decrease glutamate synthesis throughout the central nervous system, which in turn decreases inflammation and seizure activity.6 Regardless of the mechanism, human clinical observations are promising for the use of cannabis as an anti-epileptic medication, either alone or as adjunctive therapy.

Specific cannabinoids as medicine

The evidence continues to indicate that whole-plant usage is more effective than any single isolated constituent, perhaps due to the entourage effect. Cannabis contains many cannabinoids, THC and CBD being only two of over 80 possibles. In addition, the plant contains terpenes which are medically active chemicals that give the plant its fragrance. Combining these constituents can decrease side effects from any single cannabinoid and together, and may be more effective in controlling seizures. 7 We do not yet know what the best combination is for any specific type of seizure but the evidence is strong enough to encourage more research efforts for answers.

CBD: Is CBD the primary cannabinoid that treats seizure disorders? It seems so if you consider the recent reports of use in severely affected children. CBD is certainly a major player, but not the only one. CBD has been clinically proven as an anticonvulsant for many and at worst, for a minority of patients with epilepsy, it gave no benefit. Its anti-convulsive effects are probably due to a combination of beneficial activities. CBD blocks NMDA receptors (similar to the AED Felbamate) and enhances GABA receptors (similar to phenobarbital and Depakote). It stabilizes ion channels (similar to Dilantin and Keppra), acts as an anti-inflammatory, and also as a neuroprotectant.8

THC: In some study models, THC reduced seizure frequency and intensity, but in others there was no effect. Some patients treated with THC had increased seizure activity.6

THCA: THCA, the acidic raw form of THC is non-psychoactive and also appears to have anti-seizure qualities.9

CBDV: Cannabidivarin or CBDV, is a non-intoxicating cannabinoid that also has significant anti-convulsant properties which were even more effective when combined with CBD.6,10

Alpha-linalool: The terpene alpha-linalool has been shown to have anti-seizure activity in pre-clinical models, especially when combined with cannabinoids.7,9


Cannabis has a biphasic dose-response, meaning that more is not always better or more effective. This is more prevalent in THC than in CBD but patients and clinicians are cautioned to avoid the assumption that if a dose is not working, it should be increased. It very well may need to be decreased, especially if THC is part of the preparation.

Dosing for adults has been noted at amounts as small as .02 mg cannabinoids/kg/day, but the clinical trials done on Epidiolex (a purified CBD product made by GW Pharmaceuticals) tested a range of 2-50mg/kg/day. While dosing cannabis for seizures is still an evolving science, an experienced physician treating children for intractable seizures shares the following guidelines. First, an EEG is recorded prior to starting CBD oil and then repeated at 1-3 months if the child is showing improvement. Oral or sublingual dosing of a quality-controlled, lab-analyzed CBD oil with a ratio of at least 10:1 CBD:THC is started at 1mg/kg/day divided into every 8 hour doses. These doses are increased every 1-2 weeks depending on the child’s results. She notes that the therapeutic range for many patients appears to be between 4-9 mg/kg/day. As the seizures decrease in frequency, it is possible that the AEDs can be slowly weaned.10

The latest publication on the use of cannabis for the treatment of epilepsy comes from three physicians with experience in the states of Maine, Washington, and California. Of their 272 combined patients, fourteen percent found cannabis to be ineffective at reducing seizures, fifteen percent experienced a 1-25% reduction in seizures, twenty-eight percent experienced a 76-99% reduction, and ten percent had a complete clinical response.

CBD made the difference

When Sam was 4, he had his first myoclonic seizure, and those progressed to myoclonic absence seizures. Sam did not fall to the floor and twitch. Instead, sometimes 100 times a day, he lost consciousness for 20-30 seconds at a time. He stopped, stared vacantly, his head bobbed rhythmically and then it would all be over. He didn’t even notice these seizures, only that when he would come to, everything around him had shifted slightly. But it kept him from a normal life: having full conversations, from learning in school, and from participating in sports.

Sam had tried almost two-dozen treatments including intravenous immunoglobulin and a ketogenic diet. Few of these were effective, and those that were either had worrisome side effects (hand tremors, hives, zombie consciousness, etc.) or they quit working after a short while. By the time he was 11, he was on massive doses of corticosteroids – the only thing they’d found that made any difference – but the side effects were devastating. He’d been hospitalized twice and seen six neurologists in three states.

Then, as a last resort, his parents decided to try CBD. The effects were profound, but the road was “not a straight line,” to quote his father. CBD had immediately helped – dropping the seizure rate from 68 on a Thursday to 6 on the following Monday. A few years after starting the CBD, Sam was down to between 0 and 5 seizures a day on 1000mg of CBD and taking no other seizure medications. Then, he had his first-ever generalized tonic-clonic seizure. Three weeks later he had another, so Depakote was added to his regimen. The Depakote worked.

Sam is now 15 years old and has had 15 months without a seizure. To his parents, this is a relief and a miracle. He is taking 875mg of Depakote a day, and 250mg of CBD twice a day. Now active in sports, fly fishing and rock climbing, Sam gets to be a normal boy.

Clearly, there is promise in the use of cannabis to manage epilepsy and still much to learn.

Stacey Kerr MD is a teacher, physician, and author living and working in Northern California. Dr. Kerr was in private practice until she decided to write and educate full-time. After several years working with the Society of Cannabis Clinicians, and co-developing the first comprehensive online course in cannabinoid medicine, she is now serving as the Medical Director for Hawaiian Ethos, an evidence-based cannabis company on the Big Island of Hawaii.

This article was reprinted by Project CBD with permission. It may not be reproduced in any form without approval from the source.

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