C&P#9: FDA & CBD + cannabinoids for neurodegeneration + a bounty of preclinical research
Lex Pelger
'Cannabinoids & the People' newsletter on Substack + canna-edu vids on YT @cannabinoidsandthepeople + the Moby Dick pot books (graphic novels on cannabis)
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This week saw a number of indicative legal changes at the state level, the FDA admitting their slowness on CBD & in science news, I don’t remember the last time I had so many papers to process.
Besides advances in using cannabinoids for neurodegeneration & a study of the causes of the vaping crisis, in preclinical research, there’s a host of fascinating experiments in animal & cellular models. It looks like the Federation of American Societies for Experimental Biology hosted their annual conference & they released about 3 dozen papers & abstracts in one day that covers a variety of domains. It’s a great look at how the preclinical works confirms & advances what we already know about how the cannabinoids work in humans. Check out this week’s preclinical section to get a sense of how much of human ingenuity is being applied to the complex problem of how cannabinoids cause their host of actions.
Plus, this week has more jokes than normal about my ‘neural ocean’ metaphor. Check out the Living Glossary at the bottom for more.
My ad: Cannabis counseling sessions for the brave of heart
My cannabis counseling sessions are not for those afraid to do the hard work of experimenting on themselves & figuring out what works. The cannabinoids are powerful medicines for pain, neurodegeneration, autism, insomnia & anxiety/depression – but everyone’s endocannabinoid system is different & only you can find what works for you. We have many tools – CBD, THC, PEA, OEA & CBDA – but finding the solution that helps serious conditions is not easy. So if you know anyone – especially folks dealing with aging – who are ready to do the hard work to find health, tell them to sign up for an individualized 1-on-1 session : Cannabinoid Education Sessions.
This newsletter is a free offering from my company White Whale Creations. We produce educational content for cannabis & psychedelic companies & have sponsorship opportunities for The Lex Files podcast. #opentowork
Best of cannabinoid science...
In Parkinson’s patients, nabilone (a pharmaceutical THC analog) had beneficial effects on sleep outcomes
Effects of nabilone on sleep outcomes in patients with Parkinson's disease: a post-hoc analysis of NMS-Nab study
If you know anyone with a neurodegenerative disorder, they should be trying cannabinoids. See my advice here.
The great Appendino with a takedown on how much CBD actually gets produced in Nature outside the cannabis plant
Cannabidiol (CBD) From Non-Cannabis Plants: Myth or Reality?
A chemical study of the vaping crisis of 2019 & how Vitamin E Acetate in illegal vape pens caused that rash of severe lung injuries
Vaping Aerosols from Vitamin E Acetate and Tetrahydrocannabinol Oil: Chemistry and Composition
Some of the best reporting on how that went down comes from Marissa Wenzke & David Downs on Leafly:
A patent dispute over the terpene source of the “skunky” smell of cannabis
“Skunky” Cannabis: Environmental Odor Troubleshooting and the “Need-for-Speed”
In male mice, low doses of CBD increases social interaction
Acute Low Dose Cannabidiol Treatment Boosts Social Interaction Preference in Male Mice
In mice with chronic pain from the chemotherapy drug cisplatin, CBD helped with their pain & this seems to be mediated by the CB1 & CB2 receptors working via the TRPV1 receptors & in females only, a serotonin receptors
The Role of Cannabidiol (CBD) in a Cisplatin-Induced Model of Chronic Neuropathic Pain
In a rat model of obesity, synthetic CBD reduced body weight & fat levels but not blood pressure
Synthetic Cannabidiol Reduced Body Mass and Visceral Adiposity but Not Blood Pressure in Rats With Advanced Metabolic Syndrome
In mice, CBG lowers blood pressure
Acute Cannabigerol Administration Lowers Blood Pressure in Mice
A review of cannabinoids for addiction
Cannabinoids as Potential Molecules for Addiction Disorders
A review of using the cannabinoids for pain
Cannabis, cannabinoids, and cannabis-based medicines: future research directions for analgesia
This computer simulation study looked at the ability of THC, CBD, AEA & 2-AG to bind to the endoplasmic reticulum (final processing center for proteins) & how this helps to increase the breakdown of misfolded proteins
Promising action of cannabinoids on ER stress mediated neurodegeneration: An In Silico Investigation
A big problem in neurodegenerative diseases is misfolded proteins. All proteins have their 2D sequence of amino acids – but then they have to fold into their 3D shape. If that 3D shape is wrong, it can create toxic effects. Imagine that a city suddenly started producing garbage trucks with no brakes. You can bet that wouldn’t be good for the upkeep of the city.
In fact, there’s a theory that Alzheimer’s disease is a disease of prions. Prions are misfolded proteins that propagate themselves, the most famous being mad cow disease. It’s remarkable that simply the introduction of a protein of the wrong shape causes other proteins of that type to do the same. It sounds like fascist memes or Vonnegut’s ice-9. Anyway, the prion theory of Alzheimer’s seems to be gaining ground (though despite the conviction of this article, in general when I read papers on the cause of Alzheimer’s, probably only half of them even mention this theory). If true, the problem is that misfolded proteins are incredibly hard to prevent from spreading. The normal hospital procedures for sterilizing & autoclaving surgical equipment would not get rid of them.
The ability of the cannabinoids to help the neurons to cleanse themselves of these prions might be part of the reason that we see such strong preclinical & anecdotal evidence for neurodegenerative disorders. As I said above, if you know of anyone struggling with neurodegenerative diseases, here’s my advice on how they can experiment with harnessing the power of the cannabinoids.
An evergreen note on reading restricted paper:
First stop for seeing if there’s a free version of a paper, use the Google Scholar Chrome extension (Mac version) or Google Scholar itself.
For the infamous backdoor, use Sci-Hub – the pirated papers repository (Chrome extension here). This works better for older paper than the stuff that just came out.
Finally, email the author. They’re almost always happy to oblige because, thanks to the predatory academic publishing system, they don’t make a dollar off of their papers.
Popular science articles & videos
Alice Moon will be talking at a free UCLA virtual event on cannabinoid hyperemesis syndrome (the dreaded cyclical vomiting that occurs in some long term cannabis users)
Otherside Farms on THC-O – a more potent THC analog rising in popularity
the Headlines & Fav Articles
WHY WE’RE DOING THIS: thanks to medical cannabis, Charlie has been (almost) seizure free for 100 days
Also, this is a great account to follow for more on medical cannabis in the UK.
The head of the FDA admits they’ve been slow to regulate CBD
Slow? <shakes head> My first kid was born when the Farm Bill passed. So in the time that the FDA has failed to do anything meaningful on CBD, my kid has learned to walk, talk & memorize dozens of characters from Tin Tin, Asterix & Norse mythology. And in that time, you couldn’t complete a basic safety outline on hemp extracts like the one that Australia finished years ago?
The Minority Cannabis Business Association releases their review of state equity programs & it’s as disappointing as you would imagine it would be
Not even half of the 36 cannabis states have any kind of social equity program to make up for the blatant racism of the War on Drugs. Few of the equity programs that do exist provide any funding or expedited processing times. Perhaps most wrong, the vast majority of states maintain a ban on participation for individuals with past cannabis convictions. #ironyofirony
The Eu officially recognizes its first CBG-rich hemp variety
There’s a reason CBG is rising in popularity so quickly: it works. And it works in quite a different way than CBD. If you want to find CBG in the wild, it tends to occur the most in the Durban varieties of cannabis that hail from southern Africa.
Best psychoactive TikTok of the week:
Grandma Glam: “I’m sorry. You can’t expect me to work well with others & pass a drug test. It’s one or the other.”
Law & Business
The FDA warns about copycat foods leading to people (& kids) accidentally ingesting THC
Relatedly, a review of what happens when kids accidentally ingest cannabis
Acute pediatric cannabis intoxication: A scoping review
Delaware is being celebrated for removing penalties for adult cannabis possession – but stops short of establishing regulated sales
There’s an unfortunate trend of ‘legalization’ creating more penalties surrounding cannabis, not less. With possession limits, cultivation limits & other commercial restrictions, we’re still far from treating cannabis like a tomato plant, like in Ed Rosenthal’s vision. Even in this case of Delaware, you’re still in trouble if you possess more than an ounce.
For instance, in Oklahoma, a new cannabis policy reform bill signed by the governor increases the penalties for patients who resell their medical cannabis to non-cardholders
Meanwhile in California, the state issued its first ever street fair cannabis consumption permit & the governor proposed eliminating the tax on cannabis growing to allow the licit market a better chance to compete with the illicit market (which still dominates the state)
Washington State Supreme Court reinforced the state's stoned driving laws & reaffirmed the validity of blood THC concentration limits at the time of testing
This is lousy & unscientific news. And the problem is all in the lead money quote from the judge: the “limit may not be perfect in terms of identifying the degree of impairment for all individuals, [but] it is reasonably and substantially related to recent consumption, which is related to impairment.”
Those last two phrases are simply wrong. THC levels in the blood are not nearly correlated to consumption times or impairment to be used as a viable test for handing out the extremely punitive charge of a DUI. THC blood levels ≠ impairment
This being said, stoned driving is not a good thing & it’s reasonable to want to stop it. But currently, there are no good tests for cannabis impairment. It’s quite the conundrum.
In related news, Sen Blumenauer told the Department of Transportation to stop drug testing of truck drivers for off-duty use
But as we know, there’s no way to be sure if someone is impaired or not.
Asa Waldstein’s 3 part series on how hemp/CBD companies can stay compliant
Asa is a great resource if this issue if of interest to you. Friendly too…
The War on Drugs & Harm Reduction
In pregnant women, urine drug screenings were most commonly ordered for women who were young, Black & on public insurance, sometimes triggering a “a downstream cascade of stigmatized legal consequences”
Urine Drug Screening for a History of Isolated Marijuana Use: Is Our Help Hurting?
Rhode Island’s first safe consumption site is moving forward!
If there’s anything we believe in around here, it’s safe injection facilities (SIFs). I had long known that the science supporting SIFs was there - but after touring InSite in Vancouver ten years ago, I saw how vital these hubs of safety are for a community.
If you have any extra bread, donate to Insite now!
The effects of Prohibition: China banned any synthetic cannabinoids based on 7 general core scaffolds – and thus, the gray market shifted to a new core called OXIZID
Cannabinoid receptor activation potential of the next generation, generic ban evading OXIZID synthetic cannabinoid receptor agonists
Medical Cannabis & Culture
The new High Times WEIRDOS section devoted to community voices kicks off with a Jon Cappetta piece about not buying cannabis based on its THC percentage
In a surprise to no one, cannabis videos on TikTok tend to show the plant in a positive light
I thought about starting a cannabis education channel there – but TikTok is notoriously puritanical & censorious about drugs, so instead I made a channel devoted to my favorite books. If you wanted to give me some likes, watches & comments, it’d be appreciated. It’s my main artistic output during these days filled with baby care & lack of sleep.
The Plant & the History
An attempt at using hemp concrete for passive energy storage in buildings
Investigation of a novel bio-based phase change material hemp concrete for passive energy storage in buildings
According to our Resident Construction Skeptic Ned Pelger, “Scientific masturbation. A phase change of 5°C as a best case won't be practical for anything.”
He continues, “This is fun, being like one of the old guys on the Muppets who are always negative about everything.”
On using hemp to make concrete self-curing
Self-Curing Concrete Made By Using Hemp: A Review
Ned Pelger deadpans, “All concrete is self-curing.”
Science
Clinical Studies & Surveys
In humans, 8 weeks of CBD had no negative effects on the levels of blood immune cells or natural killer cells
Eight Weeks of Daily Cannabidiol Ingestion Does Not Alter Peripheral Blood Mononuclear Cell Profile or Natural Killer Cell Cytotoxicity
In humans exposed to a threat, their blood levels of anandamide & 2-AG increased
Acquisition of threat responses are associated with elevated plasma concentration of endocannabinoids in male humans
We know that endocannabinoid levels in the blood rise to help us stop responding to a threat – but now it appears that they also help us to learn to respond to a threat.
In depressed females, they had higher plasma levels of anandamide – but for the most part did not find a relationship between depression & the immunoregulatory markers analyzed
Circulating inflammatory markers, cell-free mitochondrial DNA, cortisol, endocannabinoids, and N-acylethanolamines in female depressed outpatients
In human hearts, CBD did not alter heart rate, blood pressure or heart rate variability but it did increase standard deviation of interbeat intervals & root mean square of successive differences, indicating an activation of the parasympathetic nervous system
The Effects of Acute Cannabidiol on Autonomic Balance
Also, apparently in the state of Vermont, a third of the state’s population have tried hemp extracts. Green Mountains indeed…
In a study surprising no one, the combination of alcohol & cannabis created an additive effect for both of their acute negative effects such as verbal recall, reaction times & mood
Separate and combined effects of alcohol and cannabis on mood, subjective experience, cognition and psychomotor performance: A randomized trial
“Cannabis appeared to affect mood and subjective experience, with minimal impact on cognitive performance. Alcohol appeared to impair cognitive and psychomotor performance, with minimal impact on mood and subjective experience.”
In a clinical trial of topical CBD for psoriasis, I have no idea what happened
Topical cannabidiol-based treatment for psoriasis: A dual-centre randomized placebo-controlled study
It’s $25 to even glance at the abstract.
Harms & No Help
An analysis suggests that in COVID-19 patients, the ability of cannabinoids to alter the immune system may be a negative for alleviating the cytokine storms
Substance abuse and the risk of severe COVID-19: Mendelian randomization confirms the causal role of opioids but hints a negative causal effect for cannabinoids
Using statistical analyses of state-level data of congenital birth anomalies, these researchers implicate the cannabinoids in a diverse spectrum of heritable congenital anomalies (hattip to Stuart Tomc)
Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001-2015
However, as one toxicology expert pointed out privately, the money quote comes on page 52 where they refer to the study’s methods as “introductory and pathfinding”. These statistical techniques “are not widely deployed across the published literature of the clinical teratological [abnormal growth] disciplines”.
While I think that with the widespread nature of cannabinoid receptors in the placenta & developing human brain that moderate negatives could occur from cannabinoids, this study presents the worst case scenario that I recall seeing so far & should be taken with a grain of salt.
As Alex Tabarrok says, “trust literatures, not papers”.
In pregnant women, cannabis use is a predictor of excessive gestational weight gain
Tobacco and Marijuana Use and Effect on Gestational Weight Gain
In patients with agoraphobia, a combination of exposure therapy with 300 mg of isolated CBD showed no greater efficacy with the CBD than the exposure therapy alone
Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial
In humans with dyspepsia (indigestion) but normal gastric emptying, 4 weeks of CBD treatment showed little significant help
CANNABIDIOL FOR FUNCTIONAL DYSPEPSIA WITH NORMAL GASTRIC EMPTYING: A RANDOMIZED, CONTROLLED TRIAL
In obese men, one 30 mg dose of CBD did not alter the thermic effects of feeding & the energy expenditure of digestion
Acute Cannabidiol Administration Does Not Increase the Thermic Effect of Feeding in Men with Overweight and Obesity
This case study show the danger of synthetic cannabinoids getting contaminated with superwarfarins (toxic derivatives of coumarin that cause a loss of the blood’s ability to clot) in a young man with a significant deficiency of clotting factors
Factor-guided diagnosis of coagulopathy associated with coumarin-contaminated synthetic cannabinoids: A case report
In a mouse model of sepsis, activating the CB2 receptor “with HU308 led to decreased survival rates and more severe lung injury in septic mice” via the inhibition of production of the anti-inflammatory cytokine IL-10
Activation of CD4 + T Cell-Derived Cannabinoid Receptor 2 Signaling Exacerbates Sepsis via Inhibiting IL-10
Cancer
A review of the supportive role of cannabis for cancer therapy
Do We Have Structure, Process and Outcomes to Support Cannabis as Supportive Therapy in Cancer?
In bone cancer cells, THC analogs combined well with the component of tea called epigallocatechin gallate to lower proliferation
Synthesis of A Tetrahydrocannabinol (THC) Analog For Analyzing Cellular Proliferation in Concert With Epigallocatechin Gallate (EGCG) on A Bone-like Cancer Cell Line (UMR 106-01 BSP)
In neuroendocrine neoplasms (tumors of the neuroendocrine cells), extracts that activated the CB1 receptor decreased their viability & increased their apoptosis (cellular suicide) as well as demonstrating synergistic effects with the treatment drug everolimus
Engaging the Endocannabinoid System in Neuroendocrine Neoplasms (NENs) potentiates treatment outcomes and null drug resistance
Recent Reviews
A review of 27 studies finds that people use medical cannabis as a substitute for pharmaceuticals – but most of the data comes from observational studies
Medical Cannabis as a Substitute for Prescription Agents: A Systematic Review and Meta-analysis
A review of cannabis & its effects on anesthesia & your surgical operations
Cannabis and Cannabinoids in the Perioperative Period
If you’re using cannabis before a surgery, tell your doctor! In general, it makes you more resistant to anesthesia. And you don’t want to be waking up during your operation.
A review of 7 studies on sickle cell anemia found that the use of cannabis “either worsened their painful crises or offered little to no help compared to opioids or hydroxyurea usage”
The Efficacy of Marijuana Use for Pain Relief in Adults With Sickle Cell Disease: A Systematic Review
That being said, there is not much evidence here to draw on – and while cannabis is obviously not a wonder cure for sickle cell anemia, you certainly hear underground anecdotal reports about it being a useful tool in the arsenal.
A new book on cannabis for healthcare
Cannabis/Marijuana for Healthcare
A book chapter I can’t access on CBD in the ‘Handbook of Substance Misuse & Addictions’ that appears to have the most negative of slants
Over-The-Counter Cannabidiol (CBD)
And a chapter on the impact of parental cannabis that appears to mostly say that we don’t have any idea (scientifically)
Impact of Parental Cannabis
Preclinical Research
In a complex study of acute & chronic CBD treatment as well as prenatal exposure in mice, the CBD helped male mice (but not female mice) to be less obsessive, it helped both sexes to be less anxious (with lower doses needed for females) & worryingly, the CBD-treated pups had a lower survival rate
Acute, Chronic, and Prenatal Exposure to Cannabidiol (CBD) Differentially Affects Anxiety and Successful Birthrate in Mice
In a rat stressed out by the smell of a predator, CBD helped to lower unconditioned – but not conditioned - fear
The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats
In the fat cells of rats, cannabis extract caused changes in genetic expression leading to more signals for apoptosis (cellular suicide)
The Effect of Cannabis Extract on the Expression of Bax and Bcl-2 Genes in Adipose Tissue Cells in Adult Male Rats
In fat cells, CBD caused less proliferation at some levels & time-points
Effects of physiological and supraphysiological concentrations of cannabidiol on pre-adipocyte proliferation
A look at the breakdown products of CBD & how the liver enzymes convert it from 7-OH-CBD to 7-COOH-CBD
Formation of the Major Circulating Metabolite of Cannabidiol by Non-P450, Cytosolic Enzymes
In different strains of mice, sometimes the males are more sensitive to the painkilling effects of cannabinoids & sometimes not
Sex-Differences in Acute Cannabinoid Response and Tolerance as a Function of Mouse Strain
This is noteworthy because in humans, females tend to be more sensitive to the painkilling effects of the cannabinoids than males.
In a rat model of pain, ?-caryophyllene (a predominant terpene in cannabis & an activator of the CB2 receptor) seems to cause its pain-relieving effects at least partially via the opioid receptors
Contribution Of Opioid Receptors To Antinociception Produced By ?-Caryophyllene
In mice with scarring of the heart from diabetes, 12 weeks of oral β-caryophyllene “significantly decreased the levels of blood glucose, serum lipids, while increased serum insulin level with improving the insulin resistance” as well as improved the heart’s functioning & protecting it from abnormal morphological changes via the TGF-β/SMAD signaling pathway
β-Caryophyllene, a dietary CB2 receptor selective cannabinoid mitigates myocardial fibrosis in a mice model of diabetic cardiomyopathy
In a mouse model of diabetes, the CB1 receptors of the plasma membrane seem to operate in a Yin-Yang balance with the CB1 receptors of the mitochondria (powerhouse of the cell) to control glucose homeostasis & mitochondrial function
Glucose-dependent insulin secretion is regulated by mitochondrial-associated cannabinoid receptor type 1 (mtCB1)
I love love love seeing Yin & Yang in scientific papers. Especially because the epitome of the endocannabinoid system is balance.
The breakdown of the benzodiazepine oxazepam may be inhibited by the major cannabinoids & be a potential drug-drug interaction
Inhibitory Effects of Major Cannabinoids and their Metabolites on Oxazepam Metabolism
These binding studies look at how the major cannabinoids inhibit the breakdown of morphine
Inhibition of Morphine Metabolism by Major Cannabinoids and their Metabolites
In monkeys with free access to fentanyl, THC & CBD, alone or in combination, did “not enhance or diminish the rewarding effects of fentanyl”, suggesting them as a safe way to enhance the painkilling power of fentanyl
Effects of cannabidiol (CBD), ?9-tetrahydrocannabinol (THC), and CBD/THC mixtures on fentanyl self-administration in a food drug choice procedure in rhesus monkeys
In mice that are trained to detect fentanyl, drugs that activate the CB1 receptor show some overlap with fentanyl detection & neutral antagonists of the CB1 receptor (molecules that block other molecules from binding to the receptor) show promise as a treatment for the abuse of opioids
Effects of Cannabinoid Agonists and Antagonists in Rats Discriminating Fentanyl
In a mouse model of alcoholism, one dose of JZL184 (an inhibitor of MAGL that would raise 2-AG levels) caused helpful effects during the withdrawal period
Endocannabinoid regulation of behavior in response to negative affective states associated with alcohol abstinence
And in another experiment, JZL184 caused anti-anxiety effects & thus might be helpful for treating PTSD
Effects of Increasing Endocannabinoid 2-AG Tone on Sensorimotor Gating and Anxiety-like behavior
In placentas, a look at how THC crosses the placental barrier
Mechanisms of Transplacental Transfer of (-)-? 9-Tetrahydrocannabinol (THC) in the Human Dual Cotyledon, Dual Perfusion, Placenta Model
And a study of how two cellular drug transporters (P-glycoprotein (P-gp) & breast cancer resistance protein (BCRP)) did not alter fetal exposure to THC but did alter maternal brain exposure
P-gp and Bcrp Exert Differential Impacts on Maternal and Fetal Exposure to Tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice
In a cellular model of arthritis, THC caused both pro- & anti-inflammatory effects depending on the dosage
Impact of Δ9-Tetrahydrocannabinol on Rheumatoid Arthritis Synovial Fibroblasts Alone and in Co-Culture with Peripheral Blood Mononuclear Cells
Those cannabinoids. In the scientific dictionary, you can see their picture right next to the word ‘biphasic’: a little bit is good, a lot can be not so good.
In rats, activating the CB1 receptor help to reduce inflammation via the release of GABA (the primary inhibitory neurotransmitter of the brain)
Persistent Inflammation Induces Desensitization of the Presynaptic Cannabinoid 1 Receptor in the Ventrolateral Periaqueductal Gray
In a mouse model of kidney disease, inhibiting the FAAH enzyme (thus raising the anandamide levels, similar to CBD) mediates the protection against kidney scar formation
Fatty acid amide hydrolase (FAAH) inhibition mitigates TGF-β1-induced fibrogenesis via the anandamide-COX-2-dependent pathway
And in a mouse model of kidney damage from the chemotherapy drug cisplatin, the mice with no FAAH enzymes saw less kidney damage & demonstrate that targeting the FAAH enzymes may be helpful to protect the kidneys during cancer treatment
Knockout of fatty acid amide hydrolase (FAAH) gene attenuates cisplatin-induced nephrotoxicity in mice
And here’s a look at where the CB1 receptor tends to be found in the human kidney
Localization and Functional Characterization of the Cannabinoid Receptor Type 1 (CB1R) in the Kidney
In a cellular model of stroke, the FAAH inhibitor URB597 (which, similar to CBD, would lead to higher levels of anandamide) combines with the Chinese herbal ingredient andrographolide to cause anti-inflammatory effects, antioxidation, protection of the mitochondria (powerhouse of the cells) & less cellular suicide
URB597 and Andrographolide Improve Brain Microvascular Endothelial Cell Permeability and Apoptosis by Reducing Oxidative Stress and Inflammation Associated with Activation of Nrf2 Signaling in Oxygen-Glucose Deprivation
The cannabinoids work in our olfactory (smell) neurons via retrograde signaling & the release of GABA (the brain’s primary inhibitory neurotransmitter)
Cannabinoid Receptor-Mediated Synaptic Signaling and Neural Plasticity in Central Olfactory Neurons
The endocannabinoid-like molecule oleoylethanolamide appears to be the native binding ligand for hypoxia-inducible factors 3α (HIF-3α, a cellular transcription factor that helps a cell respond to low oxygen conditions)
Identification of oleoylethanolamide as an endogenous ligand for HIF-3α
The CB1 receptor works with the CRIP1a protein that acts as a carrier of downstream signals into the cell via the messenger G proteins
Giα and β Proteins Associate in a Complex with Cannabinoid Receptor Interacting Protein 1a (CRIP1a)
In our neural ocean metaphor, if the CB1 receptor is a saloon built into the wall surrounding the cellular city, then CRIP1a is some kind of barrel fish that listens to the whalish cannabinoids coming in ?from outside the cell & then helps to carry their messages into the cell’s interior via Western Union G telegrams.
(you can see why I want to illustrate these concepts in a graphic novel instead of just using clunky old words…)
Cannabinoid Chemistry & Technology
A look at how novel FAAH inhibitors work & how this might be a novel approach to treating pain
Shut the F(AAH) Up: Inhibiting Fatty Acid Amide Hydrolase as a Novel Approach to Pain
In surveys of why people use CBD (a FAAH inhibitor), pain is always in the top three reasons (along with sleep & anxiety). Here’s my advice on how to explore using the cannabinoids for pain.
A new monitoring system for looking at the levels of 2-AG in rats being deprived of sleep
An innovative electrochemical immuno-platform towards ultra-sensitive monitoring of 2-arachidonoyl glycerol in samples from rats with sleep deprivation: bioanalysis of endogenous cannabinoids using biosensor technology
Real-time monitoring of endocannabinoid levels is a tough nut to crack & there’s a lot of people working on it. One hard part is that endocannabinoids tend to be produced “on demand” – so their levels rise & fall quickly, and often act quite locally. Sometimes the blood levels correlate to something meaningful – and sometimes not.
New derivatives of Rimonabant – a classic pharmaceutical drug that acts at the CB1 receptor as an inverse agonist (a drug that binds to a receptor but causes the opposite effect - as well as blocking access to that receptor for other molecules)
Experimental and computational studies of 1,5-diphenyl-pyrazole-3-carboxamide compounds as potential Cannabinoid receptor type 1
Rimonabant was the first great failure of the synthetic cannabinoid pharma game. Approved in the UK (but not the US) for obesity, it did help people to lose weight. But it also increased suicidal ideation & had to be pulled off the market.
However, with the power of CB1 inverse agonism to help for a number of diseases, the hunt continues for a safer alternative, perhaps one that doesn’t penetrate into the brain but does its work only in the body.
A cool fluorescent probe of brain activity by the enzyme DAGL (2-AG synthesis) that can be activated
An activatable fluorescence probe for visualization of DAGL activity in hippocampal tissue of brain-injured mice
The neat part of an activatable probe is that you can just turn it on & then see what happens. In this case, it’s a powerful tool for finding out what more 2-AG does to help in an injured brain.
How to synthesize cannabidibutol (cannabidiol-C4) – a cannabinoid found at low concentrations in the plant
Total Synthesis of (-)-Cannabidiol-C4
In our elephant metaphor for phytocannabinoids, CBD-C4 is just CBD with a slightly shorter tail (one carbon shorter to be exact).
For more on the sartorial & physiological differences of cannabinoid elephants, see my Chapter 25: THE CROWN.
Plant Medicines & Psychoactives
Dr. Mona Sobhani on seeing entities in the psychedelic space
3 psychedelic documentaries available on YouTube:
?
Shayla Love: ‘Psychedelic Patents are Broken Because the Patent System Is Broken’
For more on the insidious history of the US patent system, see my friend Alexander Zaitchik’s ‘Owning the Sun: A People's History of Monopoly Medicine from Aspirin to COVID-19 Vaccines’. Excellent writing paired with deep research on how the patent system has stifled innovation & led to the rise of industrial monopolies.
A book chapter on why psychedelics make sense for headaches & chronic pain disorders
Psychedelics in the Treatment of Headache and Chronic Pain Disorders
If you know someone with cluster headaches, it’s crazy for them to not try LSD (see Clusterbusters). And for many other pain conditions, we may look back on these as the Dark Ages where we ignored the power of psychedelics for physical pain.
In a review of studies on psilocybin for depression, it showed statistical significance in reducing depression & anxiety
The efficacy of psilocybin in the treatment of depression and anxiety: A meta-analysis
NYTimes on psychedelic therapy for female veterans
An article on the MAPS MDMA trials suggest that patients at different trial centers had different experiences
Marc Gunther on a pharma company looking to use mescaline to treat alcoholism
The mental health startup Cerebral is under DOJ & DEA investigation for, among other things, using telehealth to overprescribe stimulants & this may have implications for all those new businesses sending ketamine through the mail
Thanks.
?- lex
PS: For this week’s seductive tunes, Anouar Brahem’s ‘The Astounding Eyes Of Rita’. A Tunisian master of the oud, he combines jazz, folk & Arab classical music. Accomplished as a soloist who can make the oud sing but also an “exceptional … improviser”, Brahem also often plays in small groups of 3 or 4 other musicians – such as the quartet in this album with bass clarinetist Klaus Gesing, double bassist Bj?rn Meyer & Khaled Yassine on darbouka & bendir.
The Living Glossary
Here’s a running glossary of the basic cannabinoid terms. This will also function as the legend for the ‘neural ocean’ metaphor that I’m using in my graphic novel series on the endocannabinoid system based on Moby-Dick. You can watch a lecture laying out the full idea here, but basically, we treat the human brain like the ocean: both deep, mysterious & chockablock with fish & feedback systems that we don’t understand.
Endocannabinoids are whales. Phytocannabinoids are elephants (because what is an elephant but a whale of the land). And neurons are complex underwater cities where hundreds of fish interact.
Endocannabinoids
The cannabinoids found inside all mammals & almost every other form of life besides insects
The Endocannabinoids System (ECS)
One of the most widespread signaling systems in the human body & brain - but only first discovered in the early ‘90s. Unlike most of the classical neurotransmitters, endocannabinoid are lipids, or fats. This makes them slippery, hard to study & a supremely sensitive signaling system because of the ability of cells to detect minute changes in lipid levels & act accordingly. Intimately connected to the immune system, the neuronal system & the hormonal system, as one old scientist said to me in his cups, “If you told me that the endocannabinoid system is where the body meets the soul, I’d believe you.”
Anandamide (AEA) [Our Great White Whale]
The first endocannabinoid neurotransmitter ever discovered. Widespread in the human brain & produced ‘on-demand’ when needed. Appears quickly, broken down quickly. Often called the neurotransmitter of balance.
[in our neural ocean metaphor, the sperm whale]
FAAH (fatty acid amide hydrolase)
The enzyme that breaks down anandamide & a frequent target of drug discovery for modulating the endocannabinoid system. If you inhibit the FAAH enzyme, it does less breaking down of AEA, and your AEA levels rise. More balance.
[the giant squid that slices sperm whales in half]
CB1
The first endocannabinoid receptor discovered. Mediates the psychoactivity (getting high feeling of THC). Most importantly, it’s the most widespread receptor of its class in the human brain.
[the bar in the membrane wall of the neuronal city where endocannabinoid whales meet with messenger fish to pass on their messages into the interior of the cellular city]
2-AG
The second endocannabinoid neurotransmitter discovered. Only 2-AG & AEA have been well studied (thousands of research papers)
[blue whale]
MGL (monoacylglycerol lipase - also sometimes abbreviated as MAGL)
The enzyme that breaks down 2-AG. Another frequent target of drug discovery because inhibiting MGL raises 2-AG levels
[a giant octopus that eats blue whales]
CB2
The second endocannabinoid receptor discovered. Found in almost every organ of the body & closely connected to our immune system. The CB2 occurs at low levels in the brain where it responds to neural insults.
[a gay bar in the membrane wall of the neuronal city]
Palmitoylethanolamide (PEA)
An endogenous fatty acid amide whose only reason for not being labeled as a classic endocannabinoid is because it doesn’t bind to the CB1 or CB2 receptor - but it’s a hugely important neurotransmitter found in every cell of the body. A long body of work stretching back to World War 2 has found it to be an amazingly safe & effective drug for a number of things related to the immune system. Available as a dietary supplement, this is one of the best-studied cannabinoids in humans. Highly recommended.
[North Atlantic Right whale of course. Just look at that grin…]
Oleamide (OEA)
An endocannabinoid related to sleep. They discovered it by keeping cats awake for 3 days & then analyzing their spinal fluid. You can buy it on Amazon. 2 scoops helps you to sleep while 6 scoops is a very pleasant psychoactive experience (Hamilton Morris has called it his favorite way to get high - which is saying something)
[Humpback whale, because it sings hippies to sleep]
Oleoylethanolamide (unfortunately, also abbreviated as OEA sometimes)
An analog of anandamide, this lipid acts via the peroxisome proliferator-activated receptor alpha (PPAR-α) receptors on the cell’s nucleus. These alter genetic transcription, a powerful method of cellular control. In animal models, oleoylethanolamide causes them to eat less food & drink less alcohol. In roundworms, it causes them to live longer. For the orphaned GPR119 receptor (a receptor that might one day be officially designated as a cannabinoid receptor), it may be the native ligand (the thing that binds to it). It’s already identified as the native ligand for hypoxia-inducible factor 3α (HIF-3α). OEA also interact with our histamines.
[Pygmy sperm whale. Not well known, a smaller cousin to the sperm whale]
Fatty acid-binding proteins (FABPs)
These transport proteins move fatty lipids such as the endocannabinoids around the body. While still mysterious, they’re thought to move anandamide between membranes as well as transporting it to be broken down by the enzyme FAAH. Several types of FABPs exist in humans. THC & CBD bind to some of them. This may explain why endocannabinoid levels tend to increase after consuming cannabinoids. As the brain ages, the levels of FABPs decrease.
Phytocannabinoids
The cannabinoids produced by the cannabis plant.
THC (delta-9-tetrahydrocannabinol or Δ9-THC)
The well-known & well-studied molecule in cannabis that gets you high - and helps in a number of other fascinating ways.
[African elephant. Powerful, unpredictable, beautiful]
CBD (cannabidiol)
The cousin of THC that does not get you high but does a lot of the heavy lifting in why hemp has been such a staple of medicine since before recorded history. In most plants outside those bred for the recreational market, CBD is the most common cannabinoid. It binds to a wide swathe of receptors outside the endocannabinoid system including three serotonin receptors, two opioid receptors, a dopamine receptor as well as glutamate & GABA (the two most widespread neurotransmitters, the basic neuronal signals for excitation & inhibition, respectively)
[Indian elephant. sweet, gentle, you can work with it]
CBC (cannabichromene)
The third most common cannabinoid in the plant, it’s not well studied in humans despite a number of intriguing preclinical studies, especially as an anti-inflammatory and for pain. Nonpsychoactive, it interferes with the breakdown of AEA & 2-AG (leading to a rise in their levels) as well as interacting with the vanilloid receptors.
[Sri Lankan elephant. Little, sweet, not as well known as it should be]
CBDV (cannabidivarin)
CBDV is like CBD with a shortened tail (side chain). Also nonpsychoactive, it tends to occur at low levels in most cannabis cultivars. It’s known to be an anticonvulsant & is suggested for treating autism in humans & in animal models. The cannabinoid pharmaceutical company GW has it in their developmental pipeline as GWP42006.
[An Asian elephant with a short trunk]
Δ8-THC (delta-8-tetrahydrocannabinol or THC8)
A more rare cannabinoid in the plant – but one with psychoactive effects. At the moment, the ability to source Δ8-THC from hemp makes it a ‘legal high’ that’s become a hot seller across the US. Of course, the usual legislative & regulatory backlashes are following. It’s been studied as a treatment for glaucoma, eye injuries & the nausea of chemotherapy. Most people describe it as a nice mellow way to get high.
[The forest species of the African elephant – smaller & more elusive]
Beta-caryophyllene (BCP)
A terpene that’s also a cannabinoid.
The terpenes of cannabis give the plant its smell. Also found in oregano, black pepper, lavender & hops, beta-caryophyllene has a spicy sweet woody smell. But unique among terpenes, this one also binds to the CB2 receptor, making it a dietary cannabinoid. It shows a potential for treating inflammation, pain, anxiety & seizures. The FDA has designated it to be GRAS (generally regarded as safe) & thus it can be safely used as a food additive.
[a terpene/cannabinoid that travels through the air? That could only be a flying elephant]
Pharmaceutical cannabinoids
Nabiximols (ie Sativex?)
A pharmaceutical 1:1 CBD:THC spray produced by GW Pharmaceuticals. One of the first cannabinoid pharmaceuticals on the market, Sativex is an approved treatment for neuropathic pain, spasticity, overactive bladder & the symptoms of multiple sclerosis.
Epidiolex? (in the UK, Epidyolex?)
An isolated CBD formulation approved for treating the severe seizures of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex. Produced by GW Pharmaceuticals, the doses tend to be incredibly high – hundreds or thousands of milligrams of CBD every day in young children. But even with that, the side effects tend to only be lethargy & stomach upset.
Dronabinol (ie Marinol? and Syndros?)
A synthetic form of THC for the treatment of anorexia in AIDS patients & the nausea of chemotherapy. These tend to not be popular with patients because it’s a horse dose of THC with no modulation by the other molecules in the cannabis plant like CBD.
Nabilone (Cesamet?)
A synthetic derivative of THC approved for treating the nausea of chemotherapy patients.
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