C&P#10: PEA for COVID + cannabis for neuropathic pain + how THC affects your sociality
Rhode Island goes legal, delta-8 THC has its day in court & the VA continues to be regressive
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This week, we see the strongest evidence yet for PEA helping prevent infection by the COVID-19 virus, a good clinical look at using cannabis for neuropathic pain of diabetes & a fun study on how THC alters your sociality (including one result I did not expect).
Sorry for the delay in this week’s newsletter but our family has been sick for two weeks now. #kidlife
On the logistical end, because of your strong interest in psychedelics & plant medicines, I’m moving that section up to above the cannabinoid science section. My coverage of these issues is more slanted towards what interests me & not as completionist as the cannabinoid science – but hopefully it gives you a sense of what’s going on. Feel free to ask me for more coverage of any areas that interest you. Also, don’t forget about the Living Glossary at the bottom for any terms that you need defined or any cannabinoid/whale classifications elucidated. No nonsense.
My ad: Cannabis counseling sessions for your health
The cannabinoids are powerful medicines. You can see here my advice for using them for pain, neurodegeneration, autism, insomnia & anxiety/depression. However, with the many tools out there such as CBD, THC, PEA, OEA & CBDA, it takes time & self-experimentation to find out what works for you. 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.
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.
Best of cannabinoid science...
The great Dr. Donald Abrams with a new clinical study on cannabis helping diabetics with their neuropathic pain
Cannabis Ameliorates Diabetic Neuropathy Pain
If you don’t know Dr. Abrams, during the early days of the AIDS crisis, he helped to define many of the conditions related to the virus & then began some of the first-ever US clinical trials to use cannabis.
In a study of healthy young adults, THC effects on sociality were found to be: in both genders, higher scores for prosociality, empathy & fairness but with lower levels for ingroup loyalty while for females specifically, users scored higher on aggression(?) while male users scored higher on agreeableness
Cannabis consumption and prosociality
A study of cancer patients found medical cannabis helpful for a range of their symptoms (hattip to Stuart Tomc)
The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients
How PEA helps to inhibit SARS-CoV-2: causes a 70% drop in viral infection by binding to a key protein + dismantles the lipid droplets that the virus uses as an energy source
Palmitoylethanolamide (PEA) Inhibits SARS-CoV-2 Entry by Interacting with S Protein and ACE-2 Receptor
In a rat model of temporal lobe epilepsy, PEA reduced the amount of neurodestruction & helped to retain healthy behaviors
Neuroprotective Effect of Palmitoylethanolamide in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy
In a cellular model of a wound in your gum, hemp extracts & CBD decreased inflammatory factors & significantly improved wound closure
Anti-inflammation and gingival wound healing activities of Cannabis sativa L. subsp. sativa (hemp) extract and cannabidiol: An in vitro study
A review of treating complex pain with ketamine, psilocybin & the cannabinoids
Alternative Options for Complex, Recurrent Pain States Using Cannabinoids, Psilocybin, and Ketamine: A Narrative Review of Clinical Evidence
Now that sounds like my kind of party. No joke, K, shrooms & weed is a wonderful combination if you get the timing & dosage right.
But more importantly, it seems clear that they would be helpful for the pain of some people – but as always, it doesn’t work for everyone.
Here's my primer on using cannabinoids for pain – and if you’re interested in the other two compounds, book a session with me & I can advise about how to explore those.
A review of the effects of cannabinoids on sleep & sleep architecture concludes there’s not yet enough evidence “to support the routine use of medicinal cannabis as an effective and safe treatment option for any sleep disorder
Is There a Place for Medicinal Cannabis in Treating Patients with Sleep Disorders? What We Know so Far
But just because the clinical evidence isn’t there, doesn’t mean that it’s not always in the top 3 reasons that people surveyed give for why they use cannabis or CBD.
It doesn’t work for everyone – and indeed, for some, THC or CBD in the evening makes their sleep worse – but for many, cannabis & CBD for sleep changed everything.
See my advice here for any insomniacs looking to utilize the old cannabis plant for their slumbers.
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.
Popular science news, articles & videos
One of the UK’s leading pain specialists, Dr Anthony Ordman, is now prescribing cannabis (by Lotte Evans for Leafie)
Leafie is a good outfit to follow if you want cannabis updates with a UK slant.
Coverage of the recent CBD safety study in High Times by AJ Harrington (hattip to Michelle Morganti)
Good news for researchers: NIDA is seeking new cannabis suppliers for their research materials
The weed grown at the federally contracted University of Mississippi grow is notoriously bad: 80’s-style seeds & stems bad. It’s quite out of touch with modern cannabis being consumed by patients & people. This will be good for the scientists using federal money to fund cannabis studies because they’ll have a more realistic supply to examine.
This study finds that while some strain names of cannabis sold recreationally showed a surprising consistency, the concept of indica vs sativa is mostly bunk & should be thrown out
What really matters – besides the THC & CBD levels – are the amount of terpenes. Unfortunately for dispensaries, that’s not an inexpensive thing to test for in every new cannabis cultivar that you’re offering for sale.
the Headlines & Fav Articles
UK man caught with a kilo of cannabis spared jail because he’s a hero giving life-saving oils (via Ruby Devoy)
Ruby is a great person to follow for medical cannabis updates in the UK.
Rhode Island legalizes cannabis correctly: they included allowance for homegrows & for automatic expungement of cannabis possession charges
If there’s any provisions that should be in a state or federal cannabis law, it’s those two.
A CEO on how social equity dispensary licenses are set up to fail
A federal court in California rules delta-8 THC legal
But as the wise old activist Dale Gieringer, director of California NORML, points out that the decision “is federally legalizing a psychoactive cannabinoid about which relatively little is known while keeping the amply studied Delta-9 illegal.”
Meanwhile, The FDA sends cease & desist letters to 5 companies selling delta-8 THC products
These warnings also included some CBD products – but the focus on delta-8 THC is new.
France is finally legalizing medical cannabis (by Dario Sabaghi)
Dario writes an excellent & digestible newsletter ‘Inshallah’ on what’s happening in the Middle East each week. Check it out.
Two great journalists on a podcast talking about cannabis, psychoactives & spirituality
Set and Setting – Madison Margolin – Ep. 13 – Cannabis, Psychedelics, & Spirituality with Donnell Alexander
The Veterans Affairs office denied the eligibility of a veteran’s hemp business for a ‘Service-Disabled Veteran-Owned Small Business’ certification & the US Hemp Roundtable is protesting
There are elements of the VA that are quite progressive on cannabis & even psychedelics – but by & large, they’re a criminally regressive organization that’s denying veterans the healing power of cannabis at every turn – and in this case, not even giving a standard certification to a *federally legal* hemp business.
In today’s meme-iest headline: ‘Generation Hemp helping to power cryptocurrency mining operations using hemp biofuel feedstock’
Law & Business
Biden’s Justice Department asks the Supreme Court to not take up a case about employers paying for medical cannabis after on-the-job injuries
Canopy Growth of Canada shut down their Social Impact & Advocacy team
TikTok keeps blocking public education ads about cannabis from New York's Office of Cannabis Management
TikTok is so censorious of drugs. Their only rival for prudery is Instagram.
For cannabis DUIs, a Salt Lake City company offers prepaid defense plans
In Canada, the makers of Sam Adams beer plan to release TeaPot – a line of cannabis-infused ice teas
The War on Drugs & Harm Reduction
The Drug Policy Alliance called out Biden’s new executive order on police reform for not banning militarized drug raids
Speaking of, here’s an excellent legal review of the history of federal cannabis prohibition & the power of Biden to change it (he can’t do it himself, but he doesn’t support cannabis legalization anyway)
Playing Hot Pot-ato: Does Biden’s Presidency Signal the End of Federal Marijuana Prohibition?
A recent Department of Justice report shows a continuous downward trend for federal cannabis arrests since 2010
That being said, the federal government was never the major source of cannabis arrests. It was always the states & the local jurisdictions that popped people on pot charges.
The firebrand Dana Larsen on how the global drug war is the #1 cause of corruption & abuse among the world’s police
In a California study, underage youths sent it to buy cannabis at a dispensary were stopped 100% of the time
What is the likelihood that underage youth can obtain marijuana from licensed recreational marijuana outlets in California, a state where recreational marijuana is legal?
Colorado Gov. Jared Polis signed a bill making it a felony to be in possession of any one-gram substance containing fentanyl
I’ve liked Polis for cannabis – but on fentanyl, this is a terrible move in the wrong direction. Most people – dealers & users alike - do not know that they have fentanyl in their drugs. And furthermore, doubling down on the War on Drugs just keeps people from seeking help. Only legalization, free testing & real funds for harm reduction will start to alleviate this opioid crisis. More War on Drugs will simply worsen it.
The Plant & the History
A report by activist Michael Krawitz et al. on the international 1935 study on cannabis & the politics involved
Cannabis amnesia – Indian hemp parley at the Office International d’Hygi`ene Publique in 1935
In construction, combining phase change materials with hempcrete
Dynamic hygrothermal behavior and energy performance analysis of a novel multilayer building envelope based on PCM and hemp concrete
Phase change materials (PCM) are good at retaining heat. Hygroscopic materials (such as hemp concrete) are good at retaining water. This study found that putting a PCM in the middle of hempcrete did the best for energy efficiency as well as humidity.
Our Construction Knowledge Maven Ned Pelger comments, “Yeah, I was fascinated by the PCMs when I was in college and tried to make them work in passive solar design. They seem to work in the lab but are a bit tricky in day-to-day operations. I've not seen them work in any large-scale projects. Though perhaps they have and I just don't follow that anymore.”
A review of hempcrete
A comprehensive review on the use of hemp in concrete
Our Construction Material Dialectic Skeptic Ned Pelger’s verdict: “Looney tunes”
Plant Medicines & Psychoactives
A review of the psychedelic therapy training programs out there by Katie Stone
On psychedelics & the menstrual cycle by Erica Avey for Doubleblind
A cool thread from Manvir Singh on what he learned about indigenous psychedelic use in the Northwest Amazon
A “satanic” ritual involving “copious” ayahuasca caused a man to have inappropriate hormone secretions & caused psychiatric effects requiring hospitalization
Syndrome of Inappropriate Antidiuretic Hormone Secretion Following Ayahuasca Use in a Satanic Ritual: A Case Report
Plant medicines are not good or bad. They are tools.
And if you think the headline above sounded bizarre, check this one out: ‘Forget Burning Man — Psychedelic Shamans Now Heading to Davos’ by Tiffany Kary
I just signed up for her newsletter on drugs & business.
A gripping piece on the patent mess around psychedelics
A systematic review of microdosing “found good evidence that psychedelic microdoses can influence pain perception, time perception, and subjective awareness, and emerging evidence for possible improvements in mental health, substance use disorders, and psychological functioning”
The emerging science of microdosing: A systematic review of research on low dose psychedelics (1955 - 2021) and recommendations for the field
Wow. And this just in: a Canadian Senator revealed that his wife secretly microdosed his morning coffee with psilocybin to help with his depression. And it worked!
That’s great. I mean – don’t do that. It’s terrible. And terribly unethical. Don’t give drugs to people without their knowledge.
But if you have a grumpy husband in government service, I can see how it would be tempting.
The ability of IV ketamine to lower suicidal ideation seems to be mediated by improved cognition
Cognitive Function Mediates the Anti-suicide Effect of Repeated Intravenous Ketamine in Adult Patients With Suicidal Ideation
If it turns out that ketamine turns out to be helping via neurogenesis, the growth of new brain cells, I wouldn’t be surprised.
This review suggests CBT (cognitive behavioral therapy) as the best psychotherapy method for psychedelics
Psychedelics and Psychotherapy: Cognitive-Behavioral Approaches as Default
“Our primary reasons for advocating for cognitive-behavioral approaches include, (1) they avoid issues of cultural insensitivity, (2) they make minimal speculative assumptions about the nature of the mind and reality, (3) they have the largest base of empirical support for their safety and effectiveness outside of psychedelic therapy.”
A scientific review looking at using psychedelics as catalysts of creativity & insight
Psychedelics as potential catalysts of scientific creativity and insight
As always, glad they wrote it – but who, by 1967, hadn’t grasped this fakt?
Clinical Studies & Surveys
A study in exercising women found that the effects on their endocannabinoid tone could be modulated by their diet of the previous week: Mediterranean diet vs control diet
Influence of diet on acute endocannabinoidome mediator levels post exercise in active women, a crossover randomized study
A survey of why people use cannabis for exercise
How and why adults use cannabis during physical activity
“The most frequently reported modes of exercise included hiking (60%), yoga (58%), and aerobic machines (50%). The primary reasons for using cannabis before exercise were "helping to focus/concentrate" (66%), "helping enjoy the exercise experience" (65%), and "enhancing mind-body-spirit connection" (65%).”
My answer: to keep running from being so damn boring.
The medical THC inhaler Syqe helped patients with their chronic neuropathic pain
Long-term effectiveness and safety of medical cannabis administered through the metered-dose Syqe Inhaler
In Parkinson’s patients, an eye-tracking study found that nabilone (synthetic THC derivative) did not cause any negative effects on cognition
Eye Tracking in Patients with Parkinson's Disease Treated with Nabilone-Results of a Phase II, Placebo-Controlled, Double-Blind, Parallel-Group Pilot Study
In a study of cannabis impairment via cannabinoid levels in blood & breath, they found that the levels of ∆9-THC did not relate to impairment but that the levels of minor cannabinoids in the breath might be a reasonable indicator of recent ingestion
Indeterminacy of cannabis impairment and ∆ 9-tetrahydrocannabinol (∆ 9-THC) levels in blood and breath
Quite an interesting finding. But then again, this study was only done on smokers. Cannabis edibles will probably be the primary ingestion method in the coming years & their effects on motor control can be even more potent due to the liver converting ∆ 9-THC to the even stronger ∆ 11-THC (that’s why eating an equivalent amount of THC will affect you more than smoking it). So I’d be curious if this breath measurement still works for orally ingested cannabis.
Also, if you happen to be smoking pure THC with no minor cannabinoids in it, then you could still test clean on the minor cannabinoid breath test while being zonked to the gills.
In humans, a dual-study method using an fMRI of the striatum (key brain area for both movement & rewards) found that THC disrupted connectivity with the rest of the brain while CBD (mostly) increased connectivity
Individual and combined effects of cannabidiol and Δ 9-tetrahydrocannabinol on striato-cortical connectivity in the human brain
Though really, it was more nuanced than that. Specifically, the first study found a “strong disruptive effects of both THC and THC + CBD on connectivity in the associative [memory of relationships] and sensorimotor [movement] networks, but a specific effect of THC in the limbic [emotional] striatum network which was not present in the THC + CBD condition” while in the second study “CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks.”
Basically, THC is strongly disruptive (probably in a fun, creative way) while co-administration with CBD tamps down that disruption. CBD alone has a more complex effect of relative increases & decreases in connectivity, speaking to its nature as a natural balancer.
An fMRI study of heavy cannabis users found that chronic use did not impact their motor function
Heavy and Chronic Cannabis Addiction does not Impact Motor Function: BOLD-fMRI Study
In a study of driving, vaporizing low THC/high CBD products caused no effects on driving-related ability
Effect of vaporizing cannabis rich in cannabidiol on cannabinoid levels in blood and on driving ability a randomized clinical trial
A study of women in different phases of their menstrual cycle find no strong differences in their response to THC
Effects of Oral Delta-9-Tetrahydrocannabinol in Women During the Follicular Phase of the Menstrual Cycle
A case report of cannabis helping with generalized anxiety disorder
A Case Report on Generalized Anxiety Disorder through Medical Cannabis
In patients with lung scarring of unknown origin, the ability of the drug icariin to protect the lung tissue may be by the decreasing of CB1 & CB2 levels
Endocannabinoid signalling/cannabinoid receptor 2 is involved in icariin-mediated protective effects against bleomycin-induced pulmonary fibrosis
A survey of couple functioning & relationship conflict skills among cannabis users finds that they tend to be more avoidant during conflict, have less effective behavioral recovery after conflict & to have a more positive view of their relationship functioning compared to independent raters’ reports
Relationship Perceptions and Conflict Behavior among Cannabis Users
Oh man. Sometimes these things hit too close to home. As Mr. Waits said, “You must be reading my mail.”
Fun fakt: My wife is a couples therapist.
Other fun fakt: When I had ideas for more jokes here, she reminded me that you co-create your reality. So I’d just like to say that I’m better at relationships than my stoner profile would suggest.
Harms & No Help
In postpartum women with a history of depression, the use of cannabis during their pregnancy was linked to higher rates of postpartum depression
Evaluating the Frequency of Postpartum Depression in Marijuana Users With and Without a History of Depression
A case report of a 62-year old woman with severe, sudden-onset dizziness from an unintentional cannabis edible ingestion
Severe Dizziness from Unintentional Marijuana Edible Ingestion
This is quite a scary thing for someone to experience. In California, one of the underground treatments for too much THC is dabbing pure CBD extract. It’s often called “pulling the ripcord” because CBD is like a parachute that arrests the THC fall. CBD’s ability to calm THC’s effects can help pull someone back from a bad trip.
(Dabbing is the heating & inhaling of a very potent cannabis extract. It’s a very fast way to get a lot of cannabinoids in your system. For those with PTSD, dabbing is often the method of choice for quickly ingesting a lot of THC)
A case report of heart artery restrictions due to synthetic cannabinoid use
Coronary Vasospasm Associated With Synthetic Marijuana Resulting in Transient Electrocardiogram Changes and Troponin Elevation
In oral & pancreatic cancer cells, the synthetic cannabis WIN 55,212–2 inhibited tumor proliferation & induced cell death, with a stronger effect on the cancer stem cells, via a pathway other than CB1 or CB2
Synthetic cannabinoid WIN 55,212–2 inhibits growth and induces cell death of oral and pancreatic stem-like/poorly differentiated tumor cells
In human colorectal cancer cells, CBD caused cell cycle arrest, repressed cell viability & induced apoptosis (cellular suicide) via the CB2 receptor
Cannabidiol exerts anti-proliferative activity via a cannabinoid receptor 2-dependent mechanism in human colorectal cancer cells
“Anti-proliferative activity was also observed for other non-psychoactive cannabinoid derivatives including cannabidivarin (CBDV), cannabigerol (CBG), cannabicyclol (CBL), and cannabigerovarin (CBGV).”
An in-depth review of treating depression by focusing on the brain’s lateral habenula (the “anti-reward system”) & the CB1 receptors on its astrocytes (brain regulatory/immune cells)
The intersection of astrocytes and the endocannabinoid system in the lateral habenula: on the fast-track to novel rapid-acting antidepressants
In mice addicted to cocaine, this review looks at how the ability of CB1 receptors to regulate glutamate (the brain’s basic excitatory neurotransmitter) in the astrocytes (brain immune cells) in the brain’s nucleus accumbens (place of neural interface between motivation and action) may represent a potential treatment pathway
Regulation of glutamate homeostasis in the nucleus accumbens by astrocytic CB1 receptors and its role in cocaine-motivated behaviors
A review of fibromyalgia & the potential for cannabinoids to help via the endocannabinoid system
Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research
This review suggests the possibility of using cannabinoids for wound care
Evidence-based Potential Therapeutic Applications of Cannabinoids in Wound Management
There’s so much pre-clinical, historical & anecdotal data to back this up – and I dream of the day when the hospital slaps a cannabinoid-infused Band-Aid on your flesh wound.
The famed Dr. Donald Tashkin with an evenhanded article on the effects of smoked marijuana on the lungs
Inhaled Marijuana and the Lung
A look at how alcohol addiction affects the endocannabinoid system with a focus on how boosting the brain's endocannabinoid levels may help at different stages of the disorder
Alcohol-Endocannabinoid Interactions: Implications for Addiction-Related Behavioral Processes
A review of the genetic polymorphisms that may predispose someone to cannabis-induced psychosis
Cannabis induced psychosis: A systematic review on the role of genetic polymorphisms
A review of bipolar disorders & the potential endocannabinoid alterations underlying it
The endocannabinoid system in borderline personality disorder and antisocial personality disorder: A scoping review
In roundworms, anandamide alters the sensitivity of their smell to increase their pleasure in feeding
The conserved endocannabinoid anandamide modulates olfactory sensitivity to induce hedonic feeding in C. elegans
It’s a fascinating part of cannabis causing the munchies. It’s not just that they induce a reptile-brain reaction of “eat food now”, they also alter your higher-level enjoyment of the food – technically known as hedonic feeding – to enhance your pleasure while eating it. So not only does cannabis make you hungry, it makes you happier when you satisfy that hunger.
Speaking of, in Siberian sturgeon, the ability of ghrelin (known as your hunger hormone) to promote food intake is mediated by their CB1 receptors
Ghrelin-Ghrelin receptor (GSHR) pathway via endocannabinoid signal affects the expression of NPY to promote the food intake of Siberian sturgeon (Acipenser baerii)
How does your hunger hormone work? Via your ECS!
That’s why the intimate relationship between your guts & your endocannabinoid system makes so much sense.
In a mouse model of Alzheimer’s disease, activating the CB2 receptor lowered overexcitation & protected the neurons of the hippocampus (memory area of the brain)
Activation of Cannabinoid Receptor 2 Protects Rat Hippocampal Neurons against Chronic, Oligomeric Aβ-induced Neuronal Hyperexcitation
A rather torturous set of mouse experiments to determine that both cannabinoid & serotonin receptors play a role in memory formation in the hippocampus
Cross state-dependent memory retrieval between cannabinoid CB1 and serotonergic 5-HT1A receptor agonists in the mouse dorsal hippocampus
In an examination of sex differences, both genders appeared to have similar levels of CB1 receptors in their lumbar spinal cord (lower back – key for pain pathways)
Sex-specific characteristics of cells expressing the cannabinoid 1 receptor in the dorsal horn of the lumbar spinal cord
“Over 50% of CB1 RGFP cells were GABAergic neurons, and approximately 25% were glycinergic and 20-30% were glutamatergic neurons.”
In female rat’s reproductive cells, THC caused increased growth factors as well as survival rates when challenged with an apoptosis(suicide)-inducing factor
Delta-9-tetrahydrocannabinol increases vascular endothelial growth factor (VEGF) secretion through a cyclooxygenase-dependent mechanism in rat granulosa cells
In mice exposed to the smell of a predator, their 2-AG levels increased & in the short term, that increased excitability in their amygdala (fear center of the brain) – but in the long term, it helped to reduce continued fearful behavior
The Endocannabinoid 2-Arachidonoylglycerol bidirectionally modulates acute and protracted effects of predator odor exposure
In a neuronal culture model of neuropathic pain from chemotherapy, the novel cannabinoid-like compound KLS-13019 (an activator of GPR55, which may one day be known as the CB3 receptor) lowered inflammatory markers & protected the neurons
Anti-inflammatory properties of KLS-13019: a novel GPR55 antagonist for dorsal root ganglion and hippocampal cultures
Cannabinoid Chemistry & Technology
A computer analysis of the efficacy of molecules extracted from cannabis leaves as a therapy for Alzheimer’s
Computational prediction of potential drug-like compounds from Cannabis sativa leaf extracts targeted towards Alzheimer therapy
A look at a new synthetic cannabinoid designed to evade China’s ban on synthetic cannabinoid receptor agonists: ADB-FUBIATA
A new cannabinoid receptor 1 selective agonist evading the 2021 "China ban": ADB-FUBIATA
A novel cannabinoid detection method for plants that uses near-infrared spectroscopy
A novel handheld FT-NIR spectroscopic approach for real-time screening of major cannabinoids content in hemp
How to screw with MAGL: a 2-AG story
Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency
This “down to the amino acid” level of chemistry interactions really gets to the heart of the place where an enzyme starts to look like a living organism.
Chemists are biologists at a smaller scale.
PS: Today’s album is ‘Swinging the Classics’ by Eugen Cicero, the Romanian jazz pianist known as Mister Golden Hands. The son of an Orthodox priest & a professional singer, by the age of 6, he was performing Mozart piano concertos with a symphony orchestra. By the age of 16, he could play the most difficult pieces by Liszt & simply stopped practicing. Instead, he played all over Europe & produced over 70 recordings of his mixed classical-swing style. Here’s a trailer from the documentary that his son made about him. Unfortunately, he died unexpectedly at just 57 from a cerebral apoplexy. So it goes.
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)
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]
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…]
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.
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]
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]
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 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]
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]
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.
A synthetic derivative of THC approved for treating the nausea of chemotherapy patients.