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As always, at the bottom there’s a Living Glossary of cannabinoid terms along with the weekly music recommendation.

This newsletter is a free offering from my company White Whale Creations.
I produce educational content such as writing, newsletters & podcasts for cannabis & psychedelic companies.

It’s hard to care about cannabinoid science at this moment. After the terrible news in the US about the end of abortion rights with Roe v Wade, sitting here & typing away seems so useless. I believe this is one of the worst things I’ve witnessed in my lifetime & my heart goes out to all the women & people with uteruses who will die quickly, or slowly, because of this ruling. One organization that you can support is the National Advocates for Pregnant Women who have been long fighting against the criminalization of birth. And unfortunately, this is just the beginning as contraception & same-sex marriage have already been mentioned for being on the chopping block. So we will do what we can.
Resist, Educate & Organize.

Cannabinoids & Women:
In odd timing, I just completed a new page on the CVResearch page about hormones & female-specific conditions here:
CBD is especially helpful for balancing our hormonal changes & THC often helps with the diseases mentioned here.
[It’s hard to be gender inclusive around these subjects. Gender effects run strong in the cannabinoid field – but gender is a spectrum & the body parts involved can differ. I think the varied effects of cannabinoids match up to our varied experiences of gender in something quite beautiful. But it’s hard to write about this in science shorthand. So if anybody has any advice on gender-inclusive scientific language, I’m happy to hear it]

My lecture ‘Glutamate, GABA & the Ouroboros of the Cannabinoids’
- this Thursday, June 30th @ 11AM PST / 2PM EST:
Hosted by the Cannabis Chemistry Subdivision of the American Chemical Society (CANN), I’ll be lecturing on the uber-important neurotransmitters glutamate & GABA. The endocannabinoid system uses these two as the runners who carry out so many of its functions & help to treat so many diseases. It’ll be a mix of neuroscience & practical healthcare for conditions.
Come check it out for free & ask a nice question at the end:

Errata: drug buying
Last week, the link in my ad about how easy it is to buy drugs on the Dark Web accidentally pointed to a Smirnoff cocktail recipe when it should have pointed to an FAQ. I realized this because more of you clicked on that link than anything else in the email (yes, I can see what you click on it). So good on ya!
Buy your drugs online. Get them delivered safely & anonymously. Use a DanceSafe test kit to test for purity.
You’re in luck! It’s never been easier, simpler or safer to acquire psychoactives.
If you’ve ever been curious, there’s no excuse now. The only thing between you & the major headtwisters is a few hours of work & a little cryptocurrency.
So go forth. Enjoy the ride.

Living Glossary:
Remember, if I don’t define a term, it’s probably in the Living Glossary at the end of every email where I define all the cannabinoids & their machinery.
[plus, what kind of whale each of them would be. No nonsense]

My ad: Cannabis counseling sessions for your health

Cannabis is the medicine for aging. Its use goes far back through human history & now we understand more of how it works because of the endocannabinoid system. But for all the research & knowledge, the practical application is still trial & error. Everyone is different & everyone finds a different set of cannabinoids that work for them. If you – or someone in your life – needs help in figuring out what works best for you, I’m here to help.

I counsel people about using medical cannabis, CBD, CBD Acid (guts) & the lesser known but powerful medicines like PEA (immunity) & OEA (sleep). We’ll meet to discuss what you want to fix, we’ll come up with a game plan of what to try & I’ll help you to buy it (almost always, the cost of products comes out to less than $100). After that, I’ll be there to talk you through trying them out & finding the best routine for you. You can see my advice for using cannabinoids for pain, neurodegeneration, autism, insomnia & anxiety/depression here.

If you want someone experienced in listening to patients & coming up with a plan to help you find relief, book a 1-on-1 session with me here:
Cannabinoid Education Sessions

Best of cannabinoid science...

In humans with COVID-19, PEA reduced inflammatory markers & may reduce the severity of the disease
Effects of Palmitoylethanolamide on Proinflammatory Markers in Adults Recently Diagnosed With COVID-19

In humans with pelvic pain, a combination of PEA & magnesium reduced pain & increased quality of life
A Palmitoylethanolamide (PEA) and Magnesium Based Product (PEAMag) Reduces the Pain and Improves Quality of Life in Patients Affected by Acute and Chronic Pelvic Pain

A case report of using CBD for a severe epilepsy that caused this 3-year-old to be seizure free for 16 months
Cannabidiol Successful Therapy for Developmental and Epileptic Encephalopathy Related to CYFIP2

A review of the evidence suggests the promising benefits of cannabis for migraine
Medical Cannabis for the Treatment of Migraine in Adults: A Review of the Evidence
It’s a bit funny. Doctor scientists have been writing about this since 1843. And Queen Victoria’s famous physician John Russel Reynolds said it was the best thing to take at the onset of an attack. But here we are rehashing the evidence when we should just be using it.

A review of the use of CBD for sick skin
Topical cannabidiol (CBD) in skin pathology - A comprehensive review and prospects for new therapeutic opportunities
“Topical cannabis has anti-inflammatory, anti-itching, analgesics, wound healing and anti-proliferative effects on the skin.”

An editorial on using cannabis & cannabinoids for treating the pain of endometriosis
Is it the Ideal Time to Start Prescribing Cannabis Derivatives to Treat Endometriosis-associated Pain?

A systematic review on translating the chronic pain research into clinical cannabinoid action
Cannabinoids for Chronic Pain: Translating Systematic Review Findings Into Clinical Action

In a model of infection by the virus of COVID-19, CBD enhanced the cellular anti-viral response & increased the infected cell’s rate of apoptosis (cellular suicide)
Effect of cannabidiol on apoptosis and cellular interferon and interferon-stimulated gene responses to the SARS-CoV-2 genes ORF8, ORF10 and M protein

In skin stem cells, UVB radiation causes cell death while the presence of anandamide & CBD protected them from cell death, partially via the COX2 pathway
Influence of Inhibition of COX-2-Dependent Lipid Metabolism on Regulation of UVB-Induced Keratinocytes Apoptosis by 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.
For Twitter users, send a Tweet of the paper’s title with the hashtag #icanhazpdf. It works because people are beautiful(ish).
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.

“The Doctor Who Changed Her Patient–Doctor Paradigm Through Cannabis” by David Hodes on Dr. Michelle Weiner

A comprehensive report on delta-8THC by one of our favorite ECS scientists, Dr. Linda Klumpers

the Headlines & Fav Articles

The US Supreme Court, at the urging of the Biden administration, refused to hear two cases about worker’s compensation for medical marijuana, arguing that it’s better to let Congress & the executive branch decide
That Court is having quite a week. Besides their gun ruling, they also weakened Miranda rights. And I saw a post that seemed to sum it up, it’s not that the Democrats are weak. It’s not that they’re indecisive. It’s that they’re complicit. Despite all the warnings about this abortion ruling, the only thing they had ready were the fundraising emails.
And Biden? Let Congress & the executive branch decide on cannabis? Ha!
When, despite campaign promises, he has done nothing on cannabis – nothing besides freeing a few dozen prisoners. No new laws. No executive actions. No reining in overzealous enforcement. Meanwhile, his DEA arrested over 6k this year alone

The DEA says cannabis arrests are up to a 9-year high: 5.5M plants chopped & 32% more arrests

Study of auto insurance data finds medical cannabis linked to reduced auto insurance premiums, probably because of less drunk driving
& in a comparison of alcohol & cannabis for driving, only alcohol caused worse driving
Comparison of the effects of alcohol and cannabis on visual function and driving performance. Does the visual impairment affect driving?
& in a related review about policy guidelines, they recommend a "per se limit" with a quantitative THC cut-off between 3.5 and 5 ng/ml in the bloodstream to “currently be considered the most balanced [policy] choice”
Cannabis and Driving: Developing Guidelines for Safety Policies
We often talk around here about driving as one of the thorniest problems. It’s clear that very stoned drivers shouldn’t be on the roads, especially young newbies. But ‘per se limits’ aren’t the answer. With the different tolerance levels of cannabis users – especially those regularly using high doses for cancer treatments or PTSD – an arbitrary blood level THC limit does not correlate to impaired driving. People can have that much THC in their blood days after using. Arbitrary limits will become one more tool of the Drug War & will be applied in a racially malignant way.

Major League Baseball to allow CBD sponsorships
This one surprised me. Didn’t have them on my Bingo card for another year or two at least. MLB tends to be one of the more conservative of the sports cartels. But my money says that the NFL will be the last to fall. Meanwhile, the NBA will be the first one with weed edibles being sold next to the booze.

The Swiss Federal Council voted to allow any doctors to prescribe medical cannabis & to remove the need for a special permit

A nice article about how Thailand went from the War on Drugs to giving away 1M cannabis plants
But apparently cannabis is still illegal recreationally
Like most nations struggling with cannabis laws, different elements of the government have different ideas of what’s going on.

The elderly of Japan are getting into cannabis products – but the government is hesitating to consider legality (via Ned Pelger)

A poll finds that in the US, a third now support decriminalizing “hard drugs”
This is moving in the right direction & one hopes that it means a more sane & compassionate way to handle addiction may be dawning.

The War on Drugs & Harm Reduction

In Mississippi (which recently legalized medical cannabis), their Supreme Court upholds a man’s life sentence for possessing less than 2 ounces of weed
It’s so shameful. Everything about the War on Drugs is so shameful. I can only hope that in generations to come, we look back on these times with the same repugnance that we hold for Jim Crow & slavery.

Owner of a CBD store in Pennsylvania arrested for the second time for his legal hemp because it smelled like illegal weed

A terrible story about a mother’s experience with cannabis stigma & the New York school system
‘Good moms and dads sometimes smell like weed’: How the marijuana stigma nearly destroyed one New York mother

Colorado study finds that teen cannabis use is dropping & that they’re finding it harder to access cannabis now than before legalization

An important Wired article on drugs, mental illness & the evidence against the carceral approach by the great drug journalist Maia Szalavitz
The Story You’ve Heard About Cities, Drugs, and Mental Illness Is Wrong

I love the chutzpah on this one…
The United Kingdom's first unsanctioned overdose prevention site; A proof-of-concept evaluation
Basically, ‘we opened an illegal overdose prevention site & it went great & you should do it too!’

It’s about to get harder to fulfill your ADHD prescription for Adderall because of a government crackdown that involves the lowering of production caps
The fact that the government can just step in & lower the amount of a vital medication is astounding.

Law & Business

The Treasury Department again states that State Small Business Credit Initiative assistance is not open to cannabis businesses

A review of medical cannabis models around the world (with a focus on Brazil) finds that the key difference is the type of products available & their applied technical requirements
Medical cannabis regulation: an overview of models around the world with emphasis on the Brazilian scenario
I’ve heard good things about the Brazilian model & if you want to sponsor a research trip, I’m ready to fly.

A Massachusetts mayor sentenced to probation for extorting cannabis businesses
Around here, we always go for a good corruption case because they’re always just the tip of the iceberg. New industries are notorious for higher levels of corruption – and when you have formerly illegal products coming onto the market under a host of confusing recently enacted laws with a lot of money at stake, palms get greased. And in most cases, they get away with it. When you have crimes where all of the involved parties want to keep it a secret, only the overly greedy, the unlucky or the patently stupid get caught.

How Millennials are buying their cannabis (from the CannaBit newsletter by New Frontier Data)

The Plant & the History

Using cannabis leaves to produce gold nanoparticles (?)
Formation of Stable Cruciform Assembly of Gold Nanoparticles from Cannabis Indica Leaves
It’s great. So often I still get to mutter to myself, what a crazy plant?

An analysis of hemp seeds nutrition values & antioxidative strength
Nutritional value and antioxidant properties of Cannabis seeds from Makwanpur district of central Nepal

In mice, a look at the effects of hemp seed oils on lipid levels found that it “decreases plasma total cholesterol, triglycerides, and LDL-cholesterol while increases HDL-cholesterol” suggesting it “for the treatment of hyperlipidemia and prevention of atherosclerosis”
Hypolipidemic Effect of Hemp Seed Oil from the Northern Morocco Endemic Beldiya Ecotype in a Mice Model: Comparison with Fenofibrate Hypolipidemic Drugs

Using nanoparticles of silver & titanium dioxide on hemp seedlings for longer shoots, roots, weight & chlorophyll levels
Deciphering the iPBS retrotransposons based genetic diversity of nanoparticles induced in Vitro seedlings of industrial hemp (Cannabis sativa L.)

An analysis of how the harvest time of cannabis affects its levels of cannabinoids, essential oils & waxes
Effect of harvest time on the compositional changes in essential oils, cannabinoids, and waxes of hemp ( Cannabis sativa L.)
Early harvesting helps to keep your CBD levels high & your THC levels low.

In a study of hemp, acute exposure to the cold had few negative effects but long-term cold decreased total THC & CBD levels
Effects of Cold Temperature and Acclimation on Cold Tolerance and Cannabinoid Profiles of Cannabis sativa L. (Hemp)

Plant Medicines & Other Psychoactives

A summary of the common notion that modern psychiatric drugs only treat symptoms in the short term & in the long-term, do nothing to improve the underlying mental disease or to extend life (via Dr. Efrem Nulman)

Truth: ‘Psychedelic Therapy Will Not Save Us’ by Erica Rex

The always excellent Erik Davis on why we shouldn’t forget about LSD

Burning ShoreThe Elephant LSDI am currently recovering from three very full days of the Chacruna Institute’s Religion and Psychedelics Forum. The event went amazingly well, with a high level of discourse from both panelists and chatting attendees, a diverse and ecumenical array of views unmarred by haters and trolls, and a lovely fusion of head and heart rare to find in such an a…Read more4 months ago · 31 likes · 31 comments · Erik Davis

His Burning Shore is one of my favorite newsletters. Definitely recommend a subscribe

And in this vein, a review of the pathways LSD uses to enhance neural plasticity for cognitive gains
Nootropic effects of LSD: Behavioral, molecular and computational evidence

In mouse cells, the ability of ketamine to cause neurotoxicity (neuronal cell death) is mediated by stress to the endoplasmic reticulum (the protein factories of a cell)
Ketamine-induced neurotoxicity is mediated through endoplasmic reticulum stress in vitro in STHdhQ7/Q7 cells
Yes, even good old ketamine, a drug so safe that it’s the standard for knocking out infants for surgery, also has its downsides. At the high levels of recreational uses, it’s certainly possible that months or years of this isn’t good for your brain health.

A thread on the race to develop short-acting psychedelics might be shortening the post-peak window where so much of the Good Work happens

Balazs Szigeti @psybalazsThere is a race to develop short acting #psychedelics for #therapy as it could reduce costs. However, by shortening the #trip, the post-peak window is also shortened, which is anecdotally the most therapeutic part of a trip [short 🧵👇].

June 25th 2022

12 Retweets64 Likes

A scientific review of the big debate: is DMT located in the mammalian nervous system & if so, what’s its function there?
Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-year-old debate

A review by the psychedelic researcher Matt Johnson on using the classic psychedelics to treat tobacco addiction
Classic Psychedelics in Addiction Treatment: The Case for Psilocybin in Tobacco Smoking Cessation

The entire PsychedelicX student-led conference is available free online (via the Intercollegiate Psychedelics Network)
The kids are alright.

An interview of the AI chatbot GPT-3 on psychedelics
When asked what it would play for someone tripping, it had pretty good suggestions: “Weightless” by Marconi Union, “Dreamstate” by Entheogenic, and “Slow Wave Sleep” by Emancipator

What we should learn from the legalized cannabis world to apply to the psychedelic world
Applying Lessons From Cannabis to the Psychedelic Highway - Buckle Up and Build Infrastructure
If there’s one thing that’s clear to me, no lessons will be learned.

Cannabinoid Science

Clinical Studies & Surveys

An analysis of a THC:CBD spraying device for use by multiple sclerosis patients with impaired use of their hands found the device to be helpful
Usability of an application device for nabiximols oromucosal spray in patients with upper limb impaired multiple sclerosis

In obese patients with nonalcoholic fatty liver disease, 250 mg of oleoylethanolamide per day had a significant effect on weight, body mass index, waist-to-hip ratio & weight to height ratio
The effect of oleoylethanolamide supplementation on pyroptotic cell death in obese patients with nonalcoholic fatty liver disease: A double-blinded randomized controlled clinical trial

In children with inflammatory bowel disease, their intestines had increased levels of CB2, making it a potential target for treatment
Increased expression of CB2 receptor in the intestinal biopsies of children with inflammatory bowel disease

After strenuous exercise in female athletes, isolated CBD did not alter their inflammation, muscle damage or fatigue
Acute Supplementation with Cannabidiol Does Not Attenuate Inflammation or Improve Measures of Performance following Strenuous Exercise

Recommended for You

The Germans – in a very German way – came up with a questionnaire using 17 items to rank your acute cannabis intoxication
Development and initial validation of a reliable German self-report measure to assess acute cannabis intoxication-effects (CanTox-17)

In Iowa – in a very Iowan way – figured out that people who smoke a lot of pot need more THC to get high
Effect Compartment Model for Evaluation of Tolerance to Psychological Highness following Marijuana Smoking

In a clinical study of THC versus a common synthetic cannabinoid (JWH-018), they caused similar levels of the usual effects – but the synthetic caused more dissociation
A Comparison of Acute Neurocognitive and Psychotomimetic Effects of a Synthetic Cannabinoid and Natural Cannabis at Psychotropic Dose Equivalence
“At equal subjective intoxication levels, both drugs impaired psychomotor, divided attention, and impulse control, with no significant difference between the two drugs. Both drugs also caused significant psychotomimetic effects, but dissociative effects were considerably more pronounced for JWH-018 than THC.”

CBD helps with fish welfare
Cannabidiol improves fish welfare Bruno Camargo-dos-Santos (  )
I didn’t even know fish had welfare.

Monitoring Reddit to learn about how people are using and finding delta-8 THC

In sea lions with temporal lobe epilepsy, even though they had fewer CB1 receptors in their hippocampus, the surviving cells had enhanced effects
Cannabinoid receptor 1-labeled boutons in the sclerotic dentate gyrus of epileptic sea lions
I was today years old when I learned that sea lions are a good match for humans when studying epilepsy, specifically the type of epilepsy that makes you hear the Voice of God.

Harms, Synthetic Cannabinoids & Cannabis Use Disorder

A small study of using a CBD vape for treating cannabis use disorder helped 30% of the patients reduce their use by half
Efficiency of Inhaled Cannabidiol in Cannabis Use Disorder: The Pilot Study Cannavap

In a Canadian review of clinical studies with bipolar disorder & major depressive disorder, cannabis use was associated with worsening symptoms & course of the disease as well as increased suicidality & decreased functioning
Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: A Systematic Review and Recommendations of Cannabis use in Bipolar Disorder and Major Depressive Disorder

In patients with major depressive disorder, abstinence from cannabis for one month improved their performance in some cognitive domains
Effects of 28 days of cannabis abstinence on cognition in major depressive disorder: A pilot study

A study of cannabis users shows an association with greater levels of cardiac arrhythmias
Self-reported marijuana use and cardiac arrhythmias (from the Multiethnic Study of Atherosclerosis)

In humans with cannabis use disorder, an EEG can detect “the excessive spectral power of the[ir] alpha rhythm (8-12 Hz)” – though no one exactly knows what this means
Electrophysiological and behavioral correlates of cannabis use disorder
As one friend described it, cannabis makes the outlines fuzzy. That can make it good for out there ideas – but bad for making small decisions such as the best way to wash the dishes.

Thirdhand smoke is the new bugaboo of things to be scared of & in this case, it’s the deposition of cannabis smoke onto objects that you touch & the potential hazards from those chemicals
Ozonolysis Lifetime of Tetrahydrocannabinol in Thirdhand Cannabis Smoke

A review looking for epigenetic changes caused by synthetic cannabinoids (as well as cathinones)
Epigenetic Studies for Evaluation of NPS Toxicity: Focus on Synthetic Cannabinoids and Cathinones
Isn’t it crazy that taking a drug can turn on or off the expression of your genes – and that it can be passed down to your offspring?
Epigenetics is like the revenge of Lamarck. Now mostly remembered as the failed alternative idea to Darwin’s evolution, Lamarck said creatures changed & passed those traits onto their children. Giraffes stretched their necks & passed on longer necks to their children - instead of in evolution where the giraffes who happened to have the tallest necks had more babies. Lamarckism mostly got mocked the last century.
But with epigenetics, it’s quite clear that the trauma & stress & bad habits of this life can deliver turned off genes to your kids – and probably vice versa, but there’s a lot less studies on the happy side of epigenetics. However, we must believe in a world where your acts of kindness & secret gifts of generosity do turn on good genes for your kids.

In a Norwegian study of cannabis use disorder, their Cannabis Cessation Program helped youth to lower or stop using cannabis, but the participants socialized with fewer friends & didn’t make any drug-free friends
Successful outcomes with low-threshold intervention for cannabis use disorders in Norway - an observational study
Yep. Sounds like how it goes when you give up drugs…
That’s why when you quit, you usually have to give up being around the people still using.

In a study of brief interventions for cannabis use during a primary care visit such as motivational interviewing techniques or personalized feedback, the handful of studies showed no significant reduction in cannabis use
Effectiveness of brief interventions in primary care for cannabis users aged from 12 to 25 years old: a systematic review

Death of a man after smoking two new synthetic cannabinoids
Fatal intoxication with new synthetic cannabinoids 5F-MDMB-PICA and 4F-MDMB-BINACA-parent compounds and metabolite identification in blood, urine and cerebrospinal fluid


A review of cannabis & pregnancy uses imaging evidence to suggest that cannabis exposure disrupts early brain development, other evidence shows long-term behavioral consequences & the researchers say that maternal postpartum cannabis use “may diminish the maternal-infant bonding process and quality of caregiving”
Cannabis and Pregnancy: Factors Associated with Cannabis Use Among Pregnant Women and the Consequences for Offspring Neurodevelopment and Early Postpartum Parenting Behavior
The first two make sense. I believe there are some slight negative drags from cannabis consumption during pregnancy – though not enough to ban its use. But the idea that mothers who use it will be lesser mothers, that one feels like it’s stretching it. The work of Dr. Melanie Dreher in Jamaica says otherwise. After following cannabis using mothers there for 5 years, NIDA yanked the funding for her 10-year study because all she was finding was positives & they didn’t want that.

An analysis of prenatal cannabis use is in the US over the last 20 years finds that the prevalence did not significantly change & that the percentage who thought of cannabis use as a risk declined sharply
Trends and Characteristics of Prenatal Cannabis Use in the U.S., 2002-2019

In the endometrium of females, this gene analysis study looked at the expression of endocannabinoids & found 4 distinct regulation patterns
Gene expression of the endocannabinoid system in endometrium through menstrual cycle
If you can’t follow it. Don’t worry. I gave up after a while. Hormones might be the most complicated things in the world.

Mixing & other drugs

A review of treating alcohol use disorder by targeting the CB2 receptor
Role of Cannabinoid CB2 Receptor in Alcohol Use Disorders: From Animal to Human Studies
For addiction, it seems to be the CB2 receptor that does it.

A review of the complex relationship between combining alcohol & the cannabinoids
Alcohol and Cannabinoids - From the Editors

In mice, the anti-pain activity of harmaline (an ingredient of ayahuasca) is mediated by the CB1 receptors in the brain’s basolateral amygdala
Basolateral amygdala cannabinoid CB1 receptors mediate the antinociceptive activity of harmaline in adolescent male mice


In prostate cancer cells, when combined with the common treatment cisplatin, CBD worked better than a full cannabis extract
The antitumor activity of cannabis sativa and CBD in prostate cancer PC3 cells

In breast cancer cells, the 5 terpenes of cannabis studied caused cell death - with the strongest being nerolidol and β-caryophyllene
Anti-cancer potential of cannabis terpenes in a taxol-resistant model of breast cancer

In an analysis of human patients with a rare eye cancer called uveal melanoma, higher levels of CB1 were correlated with survival & in cancer cell cultures, activating the CB1 & CB2 receptor increased cancer cell death
Evaluating Cannabinoid Receptors as A Therapeutic Target for Uveal Melanoma

Recent Reviews

A big review of how the endocannabinoid system works with the renin-angiotensin systems (a hormonal system that regulates blood pressure, your balance of fluids & electrolytes, as well as the resistance strength of your circulatory system) & how this might be helpful for treating COVID-19
Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

A chapter suggesting the use of cannabinoids for treating Huntington’s disease
Endocannabinoid System as a New Therapeutic Avenue for the Treatment of Huntington’s Disease

A review of cannabis for PTSD finds that naturalistic studies suggest its use but the only randomized controlled trial showed no help
Effects of Cannabis on PTSD Recovery: Review of the Literature and Clinical Insights
When I read these, all I think about is the limits of science. Especially when the science isn’t completed. With the overwhelming anecdotal evidence of the helpfulness of cannabis for PTSD, that one clinical trial didn’t agree hardly seems conclusive.

A review of studies on cannabis for palliative end-of-life care found, that despite calling the evidence low-quality, they found positive treatment effects for “pain, nausea and vomiting, appetite, sleep, fatigue, chemosensory perception and paraneoplastic night sweats in patients with cancer, appetite and agitation in patients with dementia and appetite, nausea and vomiting in patients with AIDS”
Cannabis in palliative care: a systematic review of current evidence

In the heart problems arising from diabetes, this review looks at how the ECS is involved in this complex problem & how we might target the endocannabinoids to treat it
Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy

In the treatment of coagulopathies (disorders of blood clotting), this review goes over how different cannabinoids have both anti- & pro-coagulating properties
The Endocannabinoid System: A Potential Therapeutic Target for Coagulopathies

Preclinical Research

In a mouse model of Parkinson’s, not having enough DAGLB (the enzyme that creates the endocannabinoid 2-AG) caused impaired locomotor skill learning & worse disease progression, suggesting increased 2-AG as a treatment
Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction

In mice with kidney injuries, inactivating the FAAH enzyme (something CBD does) protects against scarring via the AEA-COX-2 pathway
Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis

In a mouse model of inner eye inflammation, the levels of CB2 receptors increased with disease progression, suggesting them as a therapeutic target
Cannabinoid 2 (CB2) receptor upregulation in experimental autoimmune uveitis (EAU)

In eye cells, this first test of a mix of PEA & docosahexaenoic acid (DHA – an omega 3 fatty acid) caused no toxicity or surface damage
Safety and Stability of PEA+DHA Ophthalmic Topical Formulation for Potential Treatment of Dry Eye

In a mouse model of itchy skin, a topical synthetic cannabinoid reduced inflammatory cytokines & it combined well with an inhibitor of heat shock proteins
The Effects of Cannabinoid Agonist, Heat Shock Protein 90 and Nitric Oxide Synthase Inhibitors on Increasing IL-13 and IL-31 Levels in Chronic Pruritus

In mice, females experienced more pain relief from CB1 activation than males because in the relevant brain area, they have more neurons with CB1 producing GABA (the brain’s primary inhibitory neurotransmitter (and subject of my next article for Project CBD))
Sex-specific cannabinoid 1 receptors on GABAergic neurons in the ventrolateral periaqueductal gray mediate analgesia in mice

In female teen mice getting their CB1 & CB2 receptor strongly activated by a synthetic cannabinoid, the researchers were surprised to see that this did not lead to depressive or anxious behaviors in adulthood & in short term effects, it caused both anti-depressive & pro-depressive responses as well as increasing the stress response
Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior

In a rat model of epilepsy, activating the CB1 & CB2 receptor caused a lower emotional response than in healthy controls
Cannabinoid 1/2 Receptor Activation Induces Strain-Dependent Behavioral and Neurochemical Changes in Genetic Absence Epilepsy Rats From Strasbourg and Non-epileptic Control Rats

Cannabinoid Chemistry & Technology

This down-in-the-dirt chemistry review looks at the synthetic pathways the cannabis plants use to make their most unusual cannabinoids
Biosynthetic origins of unusual cannabimimetic phytocannabinoids in Cannabis sativa L: A review
I hope to turn this into an action movie someday (perhaps using Lego characters) to show the birth & life cycle of all of these cannabinoid unicorns, dragons & basilisks.
If you want a good breakdown of the basics, here’s a nice chart from Dr. Codi Peterson at Cannaigma:

A new type of peptide drug aims to keep the painkilling effects of THC but not the memory impairment by stopping the formation of CB1 receptor/serotonin receptor dimers (where receptors join together)
A cognitive protection peptide for cannabis-based pain treatment

A review of the cool technologies that allow us to image endocannabinoids & other slippery lipid messengers
Imaging Endocannabinoids and Bioactive Lipid Messengers in Basic Research and Biomedical Application

- lex

PS: From the Queen of the Beatnicks, Judy Henske’s influential 1963 folk-rock album ‘High Flying Bird’. After a varied musical career where she performed blues, jazz, show tunes & her own brand of humorous material – as well as paling around with the greats of a great age of music, Henske passed just a few months ago after a long & fascinating career as a top-shelf singer & songwriter.

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.


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]

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]

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]

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). It’s also worth considering for cancer treatment.
[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.
[whale cars]


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.