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Hello everyone,

This newsletter collects all the new cannabinoid science each week & is a free offering from my company White Whale Creations. We produce educational content for cannabis & psychedelic companies. You can see my portfolio here.
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Each newsletter takes about 1.5 days out of my working week so any help is appreciated.

Editor’s note:
This week, I got through a little less science than usual. My wife has COVID & the kids have been at home because of it. So papa is slow…
While she’s doing better & better, prayers for health are greatly appreciated.

This week…

  • Cannabis for your MS, stuttering & spirituality,
  • for your autoimmune disorders, neurodegeneration & obesity
  • CBD for new brain cells!
  • Strong results for cannabis & autism
  • Thesaurus: when you use the combo of alcohol & cannabis, the kids are calling it cross-faded
  • Pregnant women using cannabis less likely to get COVID-19 + a study of CBD-rich hemp extracts helping long COVID
  • How your ECS genetic variants alter what drugs work for your depression as well as how much of a kick you get from amphetamines
  • Does cannabis make you more or less likely to use a condom? Depends on your personality & why you use cannabis…

I’m proud to promote the CBD-rich hemp extracts of PlusCBD because I know from the inside about their commitment to quality.

They start with agricultural non-GMO hemp grown with no pesticides: only water, soil & sunlight.

Then they use the clean, safe method CO2 extraction to get out all of the terpenes, minor cannabinoids & fatty acids that go into a quality hemp extract.

And finally, they test their products at least 3 times internally & once externally by third-party labs before it ever goes out the doors.

The result is an excellent CBD-rich hemp extract product that changes people’s lives.

Buy your CBD from PlusCBD today.

My EU report for Weed Talk News

Here’s my report this week on what’s happening in the EU…
https://www.youtube.com/watch?v=Ljd4dJovd4Y
(yes yes. papa is hoping to get a better quality camera for Christmas)

‘Cannabis, Menopause & the Endocannabinoid System’ by Mary Biles
https://www.projectcbd.org/cannabis-menopause-and-endocannabinoid-system

Best of cannabinoid science...

A survey of the spiritual benefits of cannabis
Spiritual Benefit from Cannabis
https://pubmed.ncbi.nlm.nih.gov/34225558
“Spiritual benefit from cannabis was reported by 66.1% of the sample, and 5.5% reported it had sometimes been a spiritual hindrance.”

In an industry study of long COVID, one month of a CBD-rich cannabis extract formulation improved their scores
A Single-Blind, Randomized, Placebo Controlled Study to Evaluate the Benefits and Safety of Endourage Targeted Wellness Formula C Sublingual +Drops in People with Post-Acute Coronavirus Disease 2019 Syndrome
https://pubmed.ncbi.nlm.nih.gov/36252151

2021: In patients with multiple sclerosis & spasticity resistant to treatment, a 1:1 THC:CBD spray caused 60% to have clinically relevant symptomatic effects
Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience
https://pubmed.ncbi.nlm.nih.gov/34157999

In kids with autism, CBD-rich cannabis extracts for 6 months most showed improvement in repetitive behaviors & social communication abilities, especially those with more severe starting symptoms
Children and adolescents with ASD treated with CBD-rich cannabis exhibit significant improvements particularly in social symptoms: an open label study
https://pubmed.ncbi.nlm.nih.gov/36085294

In autism, a review of why the endocannabinoid control of lipid signaling helps to balance inflammation & oxidation & why this makes it a treatment target
Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder
https://pubmed.ncbi.nlm.nih.gov/36077195

2021: A case report of cannabis improving stuttering
Cannabis Improves Stuttering: Case Report and Interview with the Patient
https://pubmed.ncbi.nlm.nih.gov/34314602

A look at how CBD promotes new brain cell growth via the Akt & Erk pathways & the CB1 receptor
Cannabidiol Promotes Neuronal Differentiation Using Akt and Erk Pathways Triggered by Cb1 Signaling
https://pubmed.ncbi.nlm.nih.gov/36080415

In a neuronal model of blood loss to the brain, CBD caused its benefits via lowering the amount of CB2/serotonin heteromer complexes (two receptors joined together)
Regulation of Expression of Cannabinoid CB2 and Serotonin 5HT1A Receptor Complexes by Cannabinoids in Animal Models of Hypoxia and in Oxygen/Glucose-Deprived Neurons
https://pubmed.ncbi.nlm.nih.gov/36077095

In a mouse model of stroke, CBD prevented neurological impairment, reduced neural deficits & protected against neurodegeneration
Cannabidiol Exerts a Neuroprotective and Glia-Balancing Effect in the Subacute Phase of Stroke
https://www.mdpi.com/1422-0067/23/21/12886

A review of the evidence for low doses of isolated CBD (below 400 mg per day) finds help for anxiety & anti-addiction as well as less strong evidence for insomnia, neurological disorders & chronic pain
The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence
https://pubmed.ncbi.nlm.nih.gov/36259271
There are 2 lessons here:
1. Isolated CBD usually does not work as well as full-spectrum CBD hemp extracts
2. While it’s always best to start low & go slow, do not be afraid to go high & fly. The sweet spot for your health might be in the range of hundreds of milligrams of CBD per day. And luckily, at those levels, as this review confirms, there are so few side effects.

A review of cannabis as a treatment for obesity both for its anti-inflammatory effects & its ability to help restore metabolic homeostasis
Cannabis sativa as a Treatment for Obesity: From Anti-Inflammatory Indirect Support to a Promising Metabolic Re-Establishment Target
https://pubmed.ncbi.nlm.nih.gov/34242511
It might give you the munchies, but in general, cannabis smokers have a more balanced metabolism.

2021: A review of how cannabis helps so well with autoimmune disorders
Cannabis and Autoimmunity: Possible Mechanisms of Action
https://pubmed.ncbi.nlm.nih.gov/34322454

Strong review of all the mechanisms the cannabinoids use to help with neurodegeneration
Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions
https://pubmed.ncbi.nlm.nih.gov/36290771

A review of cannabis use & violent behavior
Cannabis use and violent behavior
https://europepmc.org/article/pmc/pmc9567890
I know I sound like a broken record – but this is a true moderate association. From the Sikh warriors who used bhang to kill a battle elephant single-handedly to the toughs of the ‘50s who used reefer to rev themselves up for fights, cannabis can induce violence in those who wish violence to be induced. Despite our current stereotypes of lazy loving stoners, the stereotype of cannabis-produced violence was current in other ages – and both of them have a grain of truth.

A great review of the vanilloid TRPV1 & how the cannabinoids interact with this ion channel for lowering pain & nausea
TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids
https://pubmed.ncbi.nlm.nih.gov/36077412

How CB1 is bound by the other cannabis molecules
Modulation of type 1 cannabinoid receptor activity by cannabinoid by-products from Cannabis sativa and non-cannabis phytomolecules
https://pubmed.ncbi.nlm.nih.gov/36091813
You can see the table here.

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.
3 other helpful browser extensions are: Unpaywall, Open Access Button & PaperPanda
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.

My cannabis & psychedelic consulting sessions

For patients:

I make it simple for people with health conditions to use CBD, THC & other tools to improve their pain, their anxiety, their sleep & their health. Book a 30-minute session with me & we’ll talk over what you want to fix, I’ll create a gameplan & then send it over to you. It will include what to take & when, where to buy it & how to experiment with taking higher levels. Plus, unlimited email follow-ups for all of your questions.

See my advice for using cannabinoids for pain, neurodegeneration, autism, insomnia & anxiety/depression.

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:
Your Cannabis Counseling Sessions.

For healthcare practitioners:

I also meet with medical professionals to advise them on using cannabis, cannabinoids & psychedelics in their practice. Plus, you get a follow-up email with all of the relevant scientific research to your fields of interest & all of the notes on what we talked about.

I can help you better use these powerful tools of health.
Book a session here:
Cannabinoid & Psychedelic Education Sessions

the Headlines & Fav Articles

A cannabis research bill approved by the US Congress becomes the first standalone cannabis reform law ever sent to the President’s desk
https://www.marijuanamoment.net/senate-lifts-hold-on-house-passed-marijuana-research-bill-with-expedited-vote-expected-soon

A report from the Congressional Research Service lays out 6 limitations of Biden’s cannabis pardons
https://www.marijuanamoment.net/congressional-researchers-lay-out-six-key-limitations-of-bidens-marijuana-pardons

Almost 70% of Americans support cannabis legalization
https://www.marijuanamoment.net/nearly-seven-in-ten-americans-back-marijuana-legalization-including-majority-of-republicans-latest-gallup-poll-finds

A study by NIST & the DOJ found that the majority of hemp flower sold online exceeds the legal limit of 0.3% THC
https://www.ganjapreneur.com/study-majority-of-hemp-flower-purchased-online-exceeds-federal-thc-limits

On the cannabis apartheid between Israel & Palestine by Jesse Rosenfeld
https://theintercept.com/2022/10/30/israel-palestine-weed-cannabis

In the EU, lots of finger-pointing over the European Industrial Hemp Association’s toxicology study that set the proposed level of Acceptable Daily Intake

of CBD at 17.5 mg (hattip to Stuart Tomc)
https://businesscann.com/eiha-responds-to-criticisms-over-its-novel-food-applications-tox-studies

Cows fed on hemp can produce milk with enough THC to make you fail a drug test
https://www.washingtonpost.com/science/2022/11/14/cows-hemp-milk-thc
Transfer of cannabinoids into the milk of dairy cows fed with industrial hemp could lead to Δ9-THC exposure that exceeds acute reference dose
https://www.nature.com/articles/s43016-022-00623-7
“Officer, it’s most certainly the cow’s fault.”

On the rise of reliable e-rigs for dabbing on the go by Jackie Bryant
https://www.gearpatrol.com/food/a40098298/weed-gear-paradox
I’m glad about this for stoners – but I’m even more happy for the medical patients who need high levels of THC throughout the day. This is an important & safe ingestion method.
Also, check out Jackie’s excellent Cannabitch newsletter. She’s one of the most hardworking cannabis journalists on the beat.

A terrible story from the UK about a young patient with a rare epilepsy abandoned by his neurologist by Sarah Sinclair
https://cannabishealthnews.co.uk/2022/11/16/family-left-reeling-nhs-neurologist-turns-their-back-cannabis-patient

The War on Drugs & Prohibition

A former DEA agent on the rampant corruption & his conviction of money laundering with a Colombian cartel…

Exclusive: A disgraced DEA agent accuses colleagues of joining him in skimming millions from drug money laundering stings to fund a worldwide joyride of luxury travel, strip clubs and prostitutes. apne.ws/7sktjjf

https://apnews.com/article/soccer-sports-la-liga-money-laundering-puerto-rico-38aed2da8cd0ac237aca28aa39321105
As someone who has been studying this most of my adult life, a scandal like this breaks every year or two – and then the War on Drugs roars on as before.
Two books to read are Douglas Valentine’s ‘The Strength of the Wolf’ & ‘The Strength of the Pack’ on the Federal Bureau of Narcotics & its later iteration as the Drug Enforcement Agency. The history is more racist & more corrupt than you would even guess.

Psychedelics, Plant Medicines & Other Psychoactives

[This isn’t a deep dive into all of the science of psychedelics like I do for the cannabinoids. If a weekly newsletter with all the new psychedelic science would be of interest to your company, reach out to me]

A good thread on the toxic spirituality running through the psychedelic scene

Over the past year, I’ve spent a lot of time in psychedelic circles. For the most part, it has been an enriching experience, yet in recent months I’ve felt disquiet about the prominence of a new form of ‘toxic spirituality’. (1/8)

As my wife wisely remarked, if these drugs worked so well, then the psychedelic scene would be different than all the others…

The famed drug enema study of the ancient Mayans won this year’s IgNobel Prize
https://www.ancient-origins.net/news-history-archaeology/drug-enema-0017286

On the status of psychedelics in India by James Halifax
https://psychedelicspotlight.com/what-is-the-status-of-psychedelics-in-india

In brain scans of people who use ayahuasca, they had a thicker corpus callosum (the big cable connecting the two halves of your brain)
Preliminary evidence of links between ayahuasca use and the corpus callosum
https://pubmed.ncbi.nlm.nih.gov/36386967
As much as I like this finding, the new wisdom is that for brain scan studies to be of value, you need to scan thousands of people to start getting to any kind of statistical significance. Our brains are just too damn different.

Nature Outlook: Psychedelics for chronic pain
The psychedelic remedy for chronic pain
https://www.nature.com/articles/d41586-022-02878-3
Nature is the only science magazine I read every week. And in a heartening sign of the times, I’ve seen them go more & more pro-cannabis & pro-psychedelics these last years.

For psilocybin, body mass index did not alter their experience
Body mass index (BMI) does not predict responses to psilocybin
https://pubmed.ncbi.nlm.nih.gov/36373934

A review of how the visuals & other sensory dimensions shape the therapeutics of psychedelics by Leor Roseman & Marco Aqil
More than meets the eye: The role of sensory dimensions in psychedelic brain dynamics, experience, and therapeutics
https://pubmed.ncbi.nlm.nih.gov/36334767

In a mouse model of stroke, DMT helps reduce the damage & improve the recovery
N,N-dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats
https://pubmed.ncbi.nlm.nih.gov/32067950
There’s countless stories of miracle healings of brain conditions from psychedelics, especially ayahuasca (whose main active ingredient is DMT). Research like this confirms that in the future, psychedelics will also be tools for our neural recovery.

A new mescaline analogue found in Australia
N,N-Diformylmescaline: a novel analogue of mescaline detected in Queensland
https://pubmed.ncbi.nlm.nih.gov/36245421

Business & Law

Shaleen Title of the Parabola Center writes an op-ed on the backdoor efforts of Big Tobacco & Big Alcohol to control cannabis federal policy must be stopped
https://www.marijuanamoment.net/how-to-ruin-marijuana-legalization-put-big-alcohol-and-tobacco-corporations-in-charge-op-ed

The American Bar Association says that just because cannabis is illegal federally, those businesses still have to comply with federal anti-discrimination laws

Recent federal cases and administrative actions make it clear that, although marijuana remains illegal under federal law, cannabis industry participants must still comply with federal anti-discrimination laws. ambar.org/ftz85z

Nancy Whiteman of Wana Brands makes a $3M donation to psychedelic & cannabis research
https://www.cannabisbusinesstimes.com/article/wana-brands-edibles-company-to-donate-money-cannabis-research

A breakdown on the messy lawsuits around High Times
https://www.greenmarketreport.com/hightimes-sues-original-magazine-owners

The Plant & the History

For the highest yield from cannabis, a photoperiod of 16/8 was most ideal
Effect of Prolonged Photoperiod on Light-Dependent Photosynthetic Reactions in Cannabis
https://pubmed.ncbi.nlm.nih.gov/36077099

How harvest date affects cannabinoid levels & biomass
The Effect of Harvest Date on Temporal Cannabinoid and Biomass Production in the Floral Hemp (Cannabis sativa L.) Cultivars BaOx and Cherry Wine
https://www.mdpi.com/2311-7524/8/10/959

A simulation of 100 years of growing hemp in France & the value for carbon dioxide storage,
From hemp grown on carbon-vulnerable lands to long-lasting bio-based products: Uncovering trade-offs between overall environmental impacts, sequestration in soil, and dynamic influences on global temperature
https://pubmed.ncbi.nlm.nih.gov/35843325

A study & historical review of how the plant makes the cannabinoids
Cannabinoid Photochemistry: An Underexplored Opportunity
https://pubmed.ncbi.nlm.nih.gov/36251456

Flavonoid genes & enzymes
Genome-wide identification of key enzyme-encoding genes and the catalytic roles of two 2-oxoglutarate-dependent dioxygenase involved in flavonoid biosynthesis in Cannabis sativa L
https://pubmed.ncbi.nlm.nih.gov/36243861

Cannabinoid Science

A new eBook for practitioners on the use of cannabis in medicine
Cannabis Use in Medicine: A Concise Handbook
https://link.springer.com/book/10.1007/978-3-031-12722-9

A history of cannabis in Chinese Medicine
Cannabis in Chinese Medicine: Modern Interpretations and Integrations
https://www.journalofchinesemedicine.com/the-journal/cannabis-in-chinese-medicine-modern-interpretations-and-integrations.html

Clinical Studies & Surveys

A systematic study of CBD safety
Cannabidiol Safety Data: A Systematic Mapping Study
https://pubmed.ncbi.nlm.nih.gov/36251454

A survey of singers finds that they use CBD for stress, anxiety or chronic pain
Alternative and Complimentary Medication Use in Singers: A Pilot Survey
https://pubmed.ncbi.nlm.nih.gov/36270919

In humans, cannabis increased endocannabinoid levels in the blood while CBD did not
Effects of cannabidiol and delta-9-tetrahydrocannabinol on plasma endocannabinoid levels in healthy volunteers: a randomised double-blind four-arm cross-over study
https://kclpure.kcl.ac.uk/portal/en/publications/effects-of-cannabidiol-and-delta9tetrahydrocannabinol-on-plasma-endocannabinoid-levels-in-healthy-volunteers-a-randomised-doubleblind-fourarm-crossover-study(edd058cd-7b2f-4c26-b08f-3cfd9ec233db).html

2021: For driving, people with greater impulsivity had a greater reduction in driving speed when using cannabis
Influence of personality on acute smoked cannabis effects on simulated driving
https://pubmed.ncbi.nlm.nih.gov/34291988

A study of how young people describe the combination of cannabis & alcohol: “cross-faded”
Using Young Adult Language to Describe the Effects of Simultaneous Alcohol and Marijuana Use: Implications for Assessment
https://pubmed.ncbi.nlm.nih.gov/36083235

2021: An analysis of cannabis social clubs in Catalonia, Spain as models of harm reduction
Harm reduction and cannabis social clubs: Exploring their true potential
https://pubmed.ncbi.nlm.nih.gov/34252786

2021: In young adults having sex, if they used cannabis to conform socially, they were more likely to have condomless sex – but if they used cannabis to be social, they were less likely to engage in condomless sex
Examining Same-Day Associations Between Cannabis Use Motives and Condom Use in Urban Emerging Adults: A Brief Report
https://pubmed.ncbi.nlm.nih.gov/34343084

Mental Health, Addiction & Mental Effects

A review of cannabis use among those with ADHD
Attention-Deficit Hyperactivity Disorder and Therapeutic Cannabis Use Motives
https://pubmed.ncbi.nlm.nih.gov/36055735

In humans, spatial-motor processing is an important component of economic decision-making & its governance by the executive function is altered by cannabis differently between men & women
Cannabis use is associated with sexually dimorphic changes in executive control of visuospatial decision-making
https://pubmed.ncbi.nlm.nih.gov/36081608

Recommended for You

2021: In tests of memory, they looked at the effects of flower with CBD, flower without CBD & concentrates with CBD
Acute effects of high-potency cannabis flower and cannabis concentrates on everyday life memory and decision making
https://pubmed.ncbi.nlm.nih.gov/34215784
“High-potency cannabis flower with CBD impaired free recall, high-potency flower without CBD and concentrates had detrimental effects on source memory, and all three products increased susceptibility to false memories. CBD did not offset impairments and concentrates were self-titrated producing comparable intoxication and impairment as flower.”

2021: In men with major depressive disorder, their genetic variant for the CB1 receptor was not associated with depression but their ability to be helped by the drug Escitalopram was
Associations of the Cannabinoid Receptor -1 Polymorphisms with the Susceptibility to Major Depressive Disorder and the Response to the Antidepressant Escitalopram in a Sample of Egyptian Patients
https://www.researchgate.net/publication/353372451_Associations_of_the_Cannabinoid_Receptor_-1_Polymorphisms_with_the_Susceptibility_to_Major_Depressive_Disorder_and_the_Response_to_the_Antidepressant_Escitalopram_in_a_Sample_of_Egyptian_Patients

In mouse models of schizophrenia, the effects of CBD & THC
Cannabidiol, but Not Δ9-Tetrahydrocannabinol, Has Strain- and Genotype-Specific Effects in Models of Psychosis
https://pubmed.ncbi.nlm.nih.gov/36251462

In tests of tolerance in mice to activators of the CB1 receptor, they found a gendered difference in the response via the GRK/βarrestin2 pathway
Sex-specific mechanisms of tolerance for the cannabinoid agonists CP55,940 and delta-9-tetrahydrocannabinol (Δ9-THC)
https://pubmed.ncbi.nlm.nih.gov/34165606

2021: In adolescent mice frequently exposed to THC, exposure to painful stimuli led to impaired sociability
Frequent Δ9- tetrahydrocannabinol exposure during adolescence impairs sociability in adult mice exposed to an aversive painful stimulus
https://pubmed.ncbi.nlm.nih.gov/34358818
“The findings suggest that frequent exposure to Δ9-THC during adolescence causes in male mice a dormant dysfunction in social behavior which can be unmasked in adulthood when the animals experience an aversive state.”

In a mouse model of alcohol withdrawal, 2-AG modulated the sensitivity to mechanical pain, suggesting the boosting of 2-AG for treating alcohol withdrawal
2-Arachidonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice
https://pubmed.ncbi.nlm.nih.gov/36125319

The Brain & its Diseases

In humans with stroke, adding oleoylethanolamide (an anandamide analogue) to the standard treatment “improves short-term inflammatory, [oxidative stress], lipid, and biochemical parameters”
The Effect of Oleoylethanolamide (OEA) Add-On Treatment on Inflammatory, Oxidative Stress, Lipid, and Biochemical Parameters in the Acute Ischemic Stroke Patients: Randomized Double-Blind Placebo-Controlled Study
https://pubmed.ncbi.nlm.nih.gov/36120593

Using twin studies, no difference between cannabis users on the resting state cerebellar-cortical connectivity (a brain network of cognition & emotion)
Evidence of familial confounding of the association between cannabis use and cerebellar-cortical functional connectivity using a twin study
https://www.sciencedirect.com/science/article/pii/S2213158222003023

In monkeys with SIV (their form of HIV), treatment with THC decreased the levels of 11 miRNAs & increased 37 miRNAs (regulators of genetic transcription) related to inflammation & immune regulation
Chronic delta-9-tetrahydrocannabinol (THC) treatment counteracts SIV-induced modulation of proinflammatory microRNA cargo in basal ganglia-derived extracellular vesicles
https://pubmed.ncbi.nlm.nih.gov/36096938

In the prefrontal cortex of mice, CB1 receptors help to shape the columnar structure (an important feature of the brain’s shape thought to be the basis of information processing)
Endocannabinoid-dependent formation of columnar axonal projection in the mouse cerebral cortex
https://pubmed.ncbi.nlm.nih.gov/36067295

In a mouse model of neuropsychiatric diseases, they had higher levels of CB2 receptors in their amygdala (fear center), prefrontal cortex (executive function) & hippocampus (memory center) & blocking the CB2 receptor helped with anxiety while activating it worsened their fear extinction & startle reflex
CB2 cannabinoid receptor expression is increased in 129S1/SvImJ mice: behavioral consequences
https://pubmed.ncbi.nlm.nih.gov/36081934

In rats, cannabis ethanol extract caused higher glutamate & dopamine levels in the brain’s prefrontal cortex (executive function), less locomotor activity & spatial memory as well as neurodegeneration
Peroral Exposure to Cannabis Sativa Ethanol Extract Caused Neuronal Degeneration and Astrogliosis in Wistar Rats’ Prefrontal Cortex
https://journals.sagepub.com/doi/pdf/10.1177/09727531221120988

In neurons, the terpene nerolidol altered 2-AG signaling – while myrcene, linalool, limonene & α-pinene did not change cannabinoid signaling
A Critical Evaluation of Terpenoid Signaling at Cannabinoid CB1 Receptors in a Neuronal Model
https://pubmed.ncbi.nlm.nih.gov/36080421

2021: A review of the brain disease treating potential of JWH133 – a synthetic cannabinoid that activates the CB2 receptor
Pharmacological potential of JWH133, a cannabinoid type 2 receptor agonist in neurodegenerative, neurodevelopmental and neuropsychiatric diseases
https://pubmed.ncbi.nlm.nih.gov/34332924
For so many conditions, targeting the CB2 receptor is where it’s at.
“JWH133 has been reported to exhibit numerous pharmacological activities including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, and immunomodulatory. Recent studies have shown that JWH133 possesses potent neuroprotective properties in several neurological disorders, including neuropathic pain, anxiety, epilepsy, depression, alcoholism, psychosis, stroke, and neurodegeneration. Additionally, JWH133 showed to protect neurons from oxidative damage and inflammation, promote neuronal survival and neurogenesis, and serve as an immunomodulatory agent.”

Harms, Cannabis Use Disorder & Street Synthetics

A higher risk of heart problems in young adults with cannabis use disorder
Hypertensive Crisis-Related Hospitalizations and Subsequent Major Adverse Cardiac Events in Young Adults with Cannabis Use Disorder: A Nationwide Analysis
https://pubmed.ncbi.nlm.nih.gov/36295625
And increased heart arrhythmias in those using cannabis for chronic pain
Cardiovascular risk following cannabinoid treatment for patients with chronic pain
https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2731/6745723

A behavioral economic look at cannabis use disorder
Cannabis Use Disorder: A Behavioral Economic Perspective
https://pubmed.ncbi.nlm.nih.gov/36091647

A review of interventions to help with depression & cannabis use found that while motivational interviewing & cognitive behavior therapy did help, the drugs quetiapine, venlafaxine & fluoxetine did not
Interventions for Co-occurring Cannabis Use and Depression
https://pubmed.ncbi.nlm.nih.gov/36072196

4 case studies of adult cannabis users with intussusception (a section of the intestines sliding into another section)
Adult Intussusception in Chronic Marijuana Users
https://www.gastrores.org/index.php/Gastrores/article/view/1554/1537

In those with cannabis use disorder, they were more likely to have a certain genetic variant for dopamine as well as differences on scores for openness & extraversion
Association between Polymorphism rs1799732 of DRD2 Dopamine Receptor Gene and Personality Traits among Cannabis Dependency
https://pubmed.ncbi.nlm.nih.gov/36078646
Relatedly, in rats, both their dominance status & the reward they get from amphetamines is linked to a certain genetic variant of the CB1 receptor
Dominance status is associated with a variation in cannabinoid receptor 1 expression and amphetamine reward
https://pubmed.ncbi.nlm.nih.gov/36270348

In adolescent rats, the ability of THC to cause negative cognitive changes can be blocked by an antagonist of the 5‐HT6 serotonin receptor or rapamycin (an immunosuppressive) via the mTOR pathway
Early 5-HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse
https://pubmed.ncbi.nlm.nih.gov/32329240

A review of the acute lung injuries from e-cigarette vaping & how we still don’t know what’s causing it
E-cigarette vaping associated acute lung injury (EVALI): state of science and future research needs
https://pubmed.ncbi.nlm.nih.gov/35822508
“The literature review of 161 medical case reports revealed that the predominant demographic pattern was healthy white male, adolescent, or young adult, vaping illicit/informal THC-containing e-cigs.”

How the synthetic cannabinoids 2F-QMPSB & SGT-233 get broken down in the body
In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists 2F-QMPSB and SGT-233 Including Isozyme Mapping and Carboxylesterases Activity Testing
https://pubmed.ncbi.nlm.nih.gov/36083120

2021: Animals tests on the toxicity of AB-CHMINACA
Acute Toxic Effects of AB-CHMINACA on Lung, Heart and Liver: An Experimental Pilot Study
https://ajfm.journals.ekb.eg/article_182715_7405fbf53564b7676fd5196acc48ecb0.pdf

Pain & Inflammation

Using cannabis before a hip replacement surgery did not increase opioid use afterward
Preoperative cannabis use does not increase opioid utilization following primary total hip arthroplasty in a propensity matched analysis
https://pubmed.ncbi.nlm.nih.gov/36129515

In trauma surgery, those who use cannabis had less need for blood pressure support during their general anesthesia
Cannabis Exposure Decreases Need for Blood Pressure Support During General Anesthesia in Orthopedic Trauma Surgery
https://pubmed.ncbi.nlm.nih.gov/34227872

In a human model of acute pain induced by opioids, one dose of 1600 mg of CBD did not help
Pain response to cannabidiol in opioid-induced hyperalgesia, acute nociceptive pain, and allodynia using a model mimicking acute pain in healthy adults in a randomized trial (CANAB II)
https://pubmed.ncbi.nlm.nih.gov/35239547

2021: A book on cannabinoids & pain
Cannabinoids and Pain
https://link.springer.com/book/10.1007/978-3-030-69186-8?page=1#toc

In a rat model of sciatic nerve damage, PEA decreased the intensity & duration of the pain, stabilized the microglia & astroglia (brain immune cells) & lowered neuroinflammation by several mechanisms
Analgesic Activity of Palmitoylethanolamide on Neuropathic Pain in Rats
https://link.springer.com/article/10.1134/S1819712422030047

The Skin

In dogs with eczema, the inflammatory skin cells contained CB2, GPR55, TRPV1 & TRPA receptors
Cannabinoid receptors in the inflammatory cells of canine atopic dermatitis
https://pubmed.ncbi.nlm.nih.gov/36187821

The Guts & Oral Health

In fat stem cells, treating them with CBD protected against oxidative stress by the reduction of inflammation, enhanced their proliferation & lowered apoptosis (cellular suicide)
Cannabidiol (CBD) Protects Adipose-Derived Mesenchymal Stem Cells (ASCs) against Endoplasmic Reticulum Stress Development and Its Complications
https://pubmed.ncbi.nlm.nih.gov/36078578

In mice with colitis, using nanovesicles (drug delivery balls) made of hemp helped to lessen oxidation & to protect against leaky gut & liver injury,
Hemp-Derived Nanovesicles Protect Leaky Gut and Liver Injury in Dextran Sodium Sulfate-Induced Colitis
https://pubmed.ncbi.nlm.nih.gov/36077356

2021: In rainbow trout, injection of high levels of AEA & 2-AG had no impact on food intake but low levels of endocannabinoids worked via orexin (& possibly via GABA) to modulate neural plasticity in brain areas related to appetite control (such as the hypothalamus & telencephalon)
Central administration of endocannabinoids exerts bimodal effects in food intake of rainbow trout
https://pubmed.ncbi.nlm.nih.gov/34242873

The Heart

In patients with cardiac pacemakers, those who used cannabis had less time in the hospital, less respiratory failure & less death
Impact of cannabis use in patients with implantable cardiac defibrillators admitted with acute heart failure: a national perspective
https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2655/6745598

In a mouse model of obesity, oleoylethanolamide (an analog of anandamide) prevented negative changes to the heart, lessened weight gain & improved blood glucose
Oleoylethanolamide mitigates cardiac metabolic alterations secondary to obesity induced by high-fat diet in C57/BL6J mice
https://academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.2898/6745700

The Kidneys

In patients on hemodialysis (a machine to clean the blood because of failed kidneys), they looked at their different levels of endocannabinoids
Blood Levels of Endocannabinoids, Oxylipins, and Metabolites Are Altered in Hemodialysis Patients
https://pubmed.ncbi.nlm.nih.gov/36077177

Reproductive & Maternal Effects

Among pregnant women, the use of cannabis appeared to reduce their chances of getting COVID-19
Association of cannabis use during pregnancy with severe acute respiratory syndrome coronavirus 2 infection: a retrospective cohort study
https://pubmed.ncbi.nlm.nih.gov/36189777

A cohort study finds that prenatal cannabis use is associated with low birth weight, preterm birth & small for gestational age
Prenatal cannabis use associated with adverse birth outcomes
https://pubmed.ncbi.nlm.nih.gov/36058599

A letter on how the problems of prenatal cannabis exposure do not disappear by adolescence
Prenatal cannabis exposure problems do not wear off by adolescence
https://onlinelibrary.wiley.com/doi/abs/10.1002/cpu.30719

2021: A longitudinal study of mothers finds an association between preconception cannabis use & postpartum depression
Association between preconception cannabis use and risk of postpartum depression: Findings from an Australian longitudinal cohort
https://pubmed.ncbi.nlm.nih.gov/34198130

2021: In men going to a fertility clinic, cannabis “may have a detrimental effect on semen quality, particularly morphology and volume, but may be protective against abnormal sperm motility”
Evaluation of the impact of marijuana use on semen quality: a prospective analysis
https://pubmed.ncbi.nlm.nih.gov/34367341

Where is the endocannabinoid machinery in the ovaries of mice?
Expression and Subcellular Localization of Endocannabinoid System in Primary Interstitial Glandular Cells In Situ of Mice Ovary
https://tis.wu.ac.th/index.php/tis/article/view/6231

In mouse babies exposed to THC in the womb, they had abnormalities of the heart
Maternal Delta-9-Tetrahydrocannabinol Exposure Induces Abnormalities of the Developing Heart in Mice
https://pubmed.ncbi.nlm.nih.gov/36255470

In mice exposed in utero to THC & CBD, the males & females had different adult behavioral responses except that both were more resistant to fluoxetine (Prozac) helping depression
Perinatal CBD or THC Exposure Results in Lasting Resistance to Fluoxetine in the Forced Swim Test: Reversal by Fatty Acid Amide Hydrolase Inhibition
https://pubmed.ncbi.nlm.nih.gov/34182795

2021: In mice, prenatal exposure to cannabis caused structural changes in the offspring of the retina, though this returned to normal by adulthood
Lasting effects of prenatal exposure to Cannabis in the retina of the offspring: an experimental study in mice
https://pubmed.ncbi.nlm.nih.gov/34193310

In zebrafish larvae, exposure to THC at high doses caused developmental problems including morphological & behavioral changes
In the Swim of Cannabis: Developmental Toxicity and Metabolomic Pathway Alterations of Zebrafish Larvae Exposed to THC for the Assessment of Its Potential Environmental and Human Health Impact
https://pubmed.ncbi.nlm.nih.gov/36080275

2021: In zebrafish larvae, how exposure to THC & CBD cause changes to the turning on & off of genes via CB1 & the PPAR nuclear receptors
Transcriptomic Changes and the Roles of Cannabinoid Receptors and PPARγ in Developmental Toxicities Following Exposure to Δ9-Tetrahydrocannabinol and Cannabidiol
https://pubmed.ncbi.nlm.nih.gov/33892503

Cancer & Chemo

A practical guide for oncologists who want to use cannabis for cancer pain management
Practical Considerations for the Use of Cannabis in Cancer Pain Management-What a Medical Oncologist Should Know
https://pubmed.ncbi.nlm.nih.gov/36078963

A review of cannabinoids against ovarian cancer
Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells
https://pubmed.ncbi.nlm.nih.gov/36077833

Cool Chemistry

The CB1 receptor is found to interact with the growth protein GAP43 which helps to establish network connections in the brain’s hippocampus (memory center)
Control of a Hippocampal Recurrent Excitatory Circuit by Cannabinoid Receptor-interacting Protein Gap43
https://assets.researchsquare.com/files/rs-2128033/v1_covered.pdf

A MGL inhibitor for the blood supply in the brain
A potent and selective inhibitor for the modulation of MAGL activity in the neurovasculature
https://pubmed.ncbi.nlm.nih.gov/36084029
And how to discover new MGL inhibitors
Discovering monoacylglycerol lipase inhibitors by a combination of fluorogenic substrate assay and activity-based protein profiling
https://pubmed.ncbi.nlm.nih.gov/36105202

A look at BAY 59-3074 (Bayer’s cannabinoid that can enter the brain & bind to CB1 & CB2): in rats, it helps with neuropathic & inflammatory pain
Structure-Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074
https://pubmed.ncbi.nlm.nih.gov/36080443

2021: In the TRPV1s (ion channels that act as detectors for toxicity), the endocannabinoids bind to them in a different fashion than capsaicin (the molecule that makes spicy food spicy)
Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin
https://pubmed.ncbi.nlm.nih.gov/34332978
These vanilloid receptors “serves as the detector for noxious temperature above 42 °C, pungent chemicals like capsaicin, and acidic extracellular pH.” And remember, because it interacts with this system so much, anandamide itself can also be defined as an endovanilloid.

Thanks.

- lex

PS: For this week’s early country rock, ‘Through The Morning, Through The Night’ from 1969 by Dillard & Clark. One of the first country-rock groups to ever form, the core was the bluegrass banjo player Doug Dillard & Gene Clark, former member of the Byrds. Besides some originals on this album, they’ve got some great covers, including my old favorite ‘Rocky Top’.

The Living Glossary

This is a running glossary of the basic cannabinoid terms. It 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 the basics are that we treat the human brain like the ocean: deep, mysterious & chockablock with fish, molecules & 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]

2-AG
The second endocannabinoid neurotransmitter discovered. Only 2-AG & AEA have been well studied (thousands of research papers)
[blue whale]

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]

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]

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]

Diacylglycerol lipase (DAGL or DGL)
The enzyme responsible for producing 2-AG.

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]

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…]

NAAA (N-acylethanolamine acid amidase)
The enzyme for breaking down PEA, with a special function as a messenger for pain & inflammation as well as in the control of obesity.
[a giant Giant Pacific octopus that eats Right whales]

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 interacts 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]

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]

CBG (cannabigerol)
Known as the “mother cannabinoid”, CBG is the chemical precursor to THC, CBD, and the other cannabinoids in the plant. CBG occurs only at low levels in cannabis because it tends to be quickly converted to other cannabinoids. Binding slightly to the CB1 and CB2 receptor, it also inhibits the enzymes that break down anandamide and 2-AG, hence raising the levels of those endocannabinoids. CBG interacts with an adrenaline receptor (α-2 adrenoceptor) & a serotonin receptor (5-HT1A Receptor) as well as modulating the expression of glutamate, GABA, and dopamine via the PPAR receptors on the nucleus, controllers of genetic transcription. CBG is also active at the TRP channels involved in the sensations of temperature, pressure, pH, smell, taste, vision, and pain perception whose dysfunction are linked to neuropathic pain, inflammation, and respiratory disorders.
Surveys show patients reporting help for anxiety, chronic pain, depression, and disturbed sleep. In preclinical trials, it's been studied for eye pressure, gut problems, appetite modulation, blood pressure lowering, bladder control, oral care, muscle spasms, airway inflammation, arthritis, painkilling, and most notably for brain health and neuroinflammation. In adult neural stem cells, CBG increased their viability. The breakdown products of CBG have been shown to reduce inflammation via the brain’s immune cells.
[since it’s the first cannabinoid produced, it must be the wooly mammoth

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]
(Easter egg: the first person to email me about this easter egg will get a free copy of my Queer book once I get it printed & up on Amazon soon…)

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.