THE BENEDICTIONS
For cannabis and its components the Defence proposes
besides the well-known social and creative benefits, population-level
anti-obesogenic, antidiabetogenic, antihyperlipidemic, antiatherosclerotic,
antineoplastic, anti-angiogenic, antimigrative, antiadhesive, anti-invasive,
antimetastatic, neutrophilic, anti-allergic, anti-inflammatory, antiviral,
antioxidant, antihypertensive, antisteatotic, anti-ischemic, cardioprotective,
myelinogenic, antiamyloidogenic, antigliomagenic, anti-epileptic,
neuroprotective, antifibrogenic, anti-arthritic, osteogenic, antiosteopenic,
antiosteonecrotic, antipyretic, antinociceptive, antibiotic, probiotic,
anti-emetic, antidiarrheal, anti-choleric, antidysenteric, antidepressive,
anxiolytic, neurogenic, nootropic, anti-aging, anti-addiction (cocaine, alcohol,
tobacco, gambling), anti-aggressive, pro-evolutionary, anti-suicidal,
longevity-promoting and premature death-reducing effects in the healthy and the
sick, with particular relevance to local environmental stressors; a 55% lower
probability of hepatocellular carcinoma; p8/TRIB3-mediated cytotoxic autophagy
in melanoma; RAD51-mediated autophagy in non-small cell lung carcinoma (NSCLC);
reduction of alcohol craving via lower bilateral cue-induced nucleus accumbens
(NAc) activation; reduction of obsessive craving in addiction withdrawal and of
alpha-synucleopathies via inhibition of alpha-synuclein (aSyn, formerly NACP,
non-amyloid component of plaque); enhanced resistance to diets with a higher
than optimum n-6:n-3 polyunsaturated fatty acid ratio; reduced learning
impairment, less soluble amyloid beta-42 (Aβ42) peptide in amyloid plaques,
preferential processing of Notch-1 over amyloid precursor protein (APP), removal
of intraneuronal Aβ, elimination of elevated eicosanoid production in induced
MC65 cells; anti-Aβ aggregation activity via direct THC interaction with Aβ
peptide fibril formation and aggregation; stimulation of the removal of
intracellular Aβ and blockade of the inflammatory response; inhibition of
amyloidogenesis via binding with the peripheral anionic site (PAS) of the enzyme
acetylcholinesterase (AChE) activity more effectively than approved drugs for
AD, and of the excitatory neurotransmitter glutamate; upregulation of
mitogen-activated protein kinase 1 (MKP-1), prevention of increased BBB
permeability, reduced macrophage/microglia cell counts, enhanced neurogenesis in
the brain, especially in the hippocampus, and an age-reversing improvement of
cognitive functions, with glutamatergic CB1R and histone acetylation dependent
enhanced expression of synaptic marker proteins and increased hippocampal spine
density, pro-cognitive increases in mTOR activity, energy production, amino
acids, and PUFAs specifically arachidonate, dihomo-linoleate dihomo-linolenate,
docosadienoate, docosahexaenoate, docosapentaenoate, eicosapentaenoate,
hexadecadienoate, linoleate, linolenate, mead acid, nisinate, stearidonate, and
tetradecadienoate in cortex and hippocampus, significant increases of serum
arachidonoylcarnitine, linoleoylcarnitine, oleoylcarnitine,
palmitoleoylcarnitine palmitoylcarnitine, cortical synaptophysin and PSD95, and
anti-aging reduction of mTOR, carbohydrates, amino acids and lipid metabolism in
serum and visceral fat; a 19% reduction in long term cognitive decline measured
by IQ; a 96% reduction in subjective cognitive decline (SCD); protection in the
brain from lipopolysaccharide (LPS) neuroinflammation-induced cognitive damage;
in inflammation, pro-resolving modulation of specialized pro-resolving mediator
(SPM) profiles including levels of resolvin (Rv)D1, RvD6, maresin (MaR)2, and
RvE1 in a CB2-dependent manner, modulation of gene expression of SPM enzymes
involved in formation and further metabolism of SPMs such as 5-lipoxygenase and
15-Prostaglandin dehydrogenase, enhancement of efferocytosis in human
monocyte-derived macrophages (MoDs) in a CB2- and GPR18-dependent manner; in the
choroid plexus, modulated gene expression, enhanced extracellular release of
miRNA localized in extracellular vesicles (EVs), upregulation in males of
apolipoprotein A (Apoe), ATPase Na+/K+ Transporting Subunit Alpha 2 (Atp1a2),
Collagen Type II Alpha 1 Chain (Col2a1), Complement C3 (C3), Eukaryotic
Translation Elongation Factor 1 Alpha 1 (Eef1a1), FAU Ubiquitin Like And
Ribosomal Protein S30 Fusion (Fau), Fibrinogen Alpha Chain (Fga), Haptoglobin
(Hp), Heat Shock Protein Family A Member 5 (Hspa5), mtDNA Haplogroup H2a1
(H2a1), Megakaryocyte-Associated Tyrosine Kinase (Matk), Moesin (Msn), PZP
Alpha-2-Macroglobulin Like (Mug1), Myosin Heavy Chain 9 (Myh9), Proteasome 20S
Subunit Alpha 4 (Psma4), Proteasome 20S Subunit Beta 4 (Psmb5), Ribosomal
Protein L6 (Rpl6), Ribosomal Protein L19 (Rpl19), Ribosomal Protein L36a
(Rpl36a), Serpin Family A Member 1 (Serpina1), Solute Carrier Family 25 Member 4
(Slc25a4), Spondin 1 (Spon1), Transglutaminase 2 (Tgm2), Thy-1 Cell Surface
Antigen (Thy1), and Vimentin (Vim), proteins associated with cellular signaling
mechanisms, protein phosphorylation and expression, receptor activation,
neurodegenerative disease states, immune signaling, apoptosis, metabolism,
vesicle trafficking, and mitochondrial function, and in females upregulation of
Aggrecan (Acan), Barrier To Autointegration Nuclear Assembly Factor 1 (Banf1),
Brain Abundant Membrane Attached Signal Protein 1 (Basp1), CD59 Molecule (CD59
Blood Group) (Cd59), Contactin 1 (Cntn1), Cystatin C (Cst3), Cytochrome C,
Somatic (Cycs), Fga, Hemoglobin Subunit Beta (Hbb), Milk Fat Globule EGF And
Factor V/VIII Domain Containing (Mfge8), Musculoskeletal, Embryonic Nuclear
Protein 1 (Mustn1), Natriuretic Peptide C (Nppc), Spondin 1 (Spon1), Thymosin
Beta 4 X-Linked (Tmsb4x), Vimentin (Vim), and Yip1 Domain Family Member 3
(Yipf3), and downregulation of Annexin A2 (Anxa2), ELKS/RAB6-Interacting/CAST
Family Member 2 (Erc2), H1.5 Linker Histone, Cluster Member (H1-5), H4 Clustered
Histone 2 (H4c2), Keratin 14 (Krt14), Myelin Basic Protein (Mbp), Ribosomal
Protein L7a (Rpl7a), and Ribosomal Protein 23) Rpl23, associated with
neurodegenerative processes, protein phosphorylation, homeostatic pathways,
inflammatory pathways, and synaptic signaling mechanisms, in both sexes
activation of the nitric oxide pathway and inhibition of inflammatory processes
in cerebrospinal fluid (CSF); increased Aβ degradation endopeptidase neprilysin;
attenuation of Aβ-induced reductions in calbindin and tubulin; improved memory
impairment at advanced stages of the Alzheimer's Disease (AD) pathology; rescue
of synaptic function via reduction in metabotropic glutamate receptor 2/3 and
increased levels of GABA-A Rα1; nicotinamide adenine dinucleotide
(NAD+)-dependent inhibition of amyloid-beta and p-Tau aggregation; reduced
relative expression of glucocorticoid activated kinase (SGK), AIF1, NFκBIA
(encoding NFκB inhibitor alpha) and genes via reduced tissue inhibitor of
metalloproteinase 3 (TIMP-3); increased neurogenesis via upregulation of c-Jun
N-terminal
kinase (JNK) by increased N-acyl
phosphatidylethanolamine phospholipase D (NAPE-PLD); increased hippocampal
neurogenesis via direct action on CB1R in neural stem/progenitor cells
(NSC/PCs), as marked by increased nestin, doublecortin (DCX), class III
β-tubulin (TuJ-1) and glial fibrillary acidic protein (GFAP); promotion of
neuronal differentiation via transcription factor B-cell lymphoma/leukemia 11B
(BCL11B), transmembrane protein deleted in colorectal cancer (Dcc) and a reduced
level of UNC-5 netrin receptor C (Unc5C); increased gap 1 phase (aka growth 1
phase)/synthesis phase (G1/S) progression via upregulation of Ccne2 and Cdk2
genes, net activation of chromosome segregation, mitotic cell cycle phase
transition, mitotic nuclear division, nuclear chromosome segregation, regulation of cell cycle phase transition and of chromosome organization;
increased neuronal proliferation during differentiation of neural
stem/progenitor cells (NSPCs) with upregulation of nestin via adenosine A1
receptor, increased ERK1/2 phosphorylation, and ATP levels; increased migration
and differentiation via DCX, supported by levels of β-tubulin isoform III
(Tuj-1), indicating neuron survival; increased transendothelial electrical
resistance and upregulated tight junction proteins, reduced vascular cell
adhesion molecule-1 (CADM1) and intercellular adhesion molecule-1 (ICAM1)
surface expression in brain microvascular endothelial cells, attenuated
leukocyte adhesion in surface pial vessels and in deep ascending cortical
postcapillary venules; in glioma cells, inhibitor of DNA binding-1 (ID-1),
formation of biomolecular condensates (BMC), elevated cytotoxic
granule-associated RNA binding protein tiar-1 (TIAR-1), expression of eukaryotic
initiation factor-2α (eIF2α) and p-eIF2α, cannabiniol (CBN)-induced inhibition
of cell proliferation as characterised in A172 cell lines, and of the ERK1/2
pathway, modulation of the level of cannabinoid receptors, including GPR18, CB2
and GPR55 [G protein-coupled receptor], cannabinoid triggering of a transient
vanilloid receptor type 4 (TRPV4) signalling pathway including: activating
transcription factor (ATF4), DNA damage inducible transcript 3 (DDIT3), tribbles
pseudokinase 3 (TRB3 or TRIB3), Akt and mammalian target of rapamycin (mTOR or
mechanistic target of rapamycin)-mediated mitophagy, and via reduction of VEGF,
VEGFR2, angiopoietin-2, and matrix metalloproteinase-2 in glioma tumours;
antigliomagenic action via suppression of solute carrier family 7 member 11
(SLC7A11), increased microtubule-associated protein light chain 3 II (LC3 II),
autophagy related 7 (ATG7) and beclin-1 (BECN1), enhancement of the expression
of transferrin receptor (TFRC) favouring ERK-driven autophagy and ferroptosis
via glutathione peroxidase 4 (GPX4) reducing of hydroperoxy groups of complex
lipids and silencing of lipoxygenases; GPX4-mediated alleviation of radiation
enteritis, enhancement of chromatin compaction, of fertility via mitochondrial
sheath formation in spermatozoa, and dampening (with GPX1) of phosphorylation
cascades; in skeletal muscle, diminished fibrotic area, down-regulated collagen
type I/ІІІ mRNA, augmented multinucleated regenerating myofibers in injured
muscle attributable to decreased mRNA levels of transforming growth factor beta
1 (TGF-β1), alternative splicing of extra domain A of fibronectin (FN-EIIIA) and
alpha-smooth muscle actin (α-SMA or ACTA2), reduced accumulation of
myofibroblasts, and increased mRNA levels of matrix metalloproteinase-1/2;
CBR-independent neuroprotection against ferroptosis; reduced neoplasticity via
inhibition of phosphodiesterase-5 (PDE5); a reduced burden of breast cancer via
modified expression of tumor development markers Ki67, Bcl2 and P53, via reduced
aromatase and reduced expression of estrogen receptors alpha (ERα) and beta
(ERβ), with reduced angiogesis via nitric oxide (NO) and matrix
metalloproteinase-1 (MMP-1) inhibition, downregulation of VEGF-A and -B,
hypoxia-inducible factor-1α (HIF-1α), connective tissue growth factor (CTGF),
midkine (MDK or neurite outgrowth-promoting factor 2), inhibitor of DNA binding
3 (ID-3 or inhibitor of differentiation 3), placental growth factor (PlGF),
angiopoietin 2 (ANG-2 or ANGPT2) and its receptor tyrosine kinase with
immunoglobulin-like and epidermal growth factor (EGF)-like domains 1 tyrosine
kinase with immunoglobulin like and EGF like domains 1 (TIE-1), and HO-1, and
upregulation of type I procollagen α1 chain (COL1A1), antiproliferative action
via modulation of JunD Proto-Oncogene, AP-1 Transcription Factor Subunit (JunD)
by upregulation of gene expression and by protein translocation to the nuclear
compartment, via cyclin-dependent kinase inhibitor p27 and the tumour suppressor
gene testin and via stress-regulated protein p8 mediated upregulation of
endoplasmic reticulum stress-related genes in a JunD-independent manner,
inhibition of filopodia formation, migration, and invasion via reduced
expression of focal adhesion kinase (FAK or PTK2 protein tyrosine kinase 2),
serine/threonine kinase 1 (Akt), phospho-p44/42 MAPK (P-p42/44 or ERK 1/2),
mitogen-activated protein kinase P38 alpha (p38MAPK or MAPK14), and nuclear
factor kappa light chain enhancer of activated B cells (NFκB, NF-κB, NFkB,
NF-kB) upstream pathways, and inhibition of the RAC family small GTPase 1
(Rac1), and cell division cycle 42 (Cdc42) downstream pathways, inhibition of
the mTOR pathway, and induction of apoptosis via the Bcl-2/caspase-3 pathways;
reductions in colorectal cancer via suppression of M2-like macrophages and
promotion of M1-like macrophages, rebalancing of the metabolic process from
oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting
the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and
downstream targets, enhanced response to anti-programmed cell death protein-1
(PD-1), cleaved poly [ADP-ribose] polymerase 1 (PARP-1), receptor-interacting
serine/threonine-protein kinases 1 and 3 (RIP1 and RIP3), regulation of
intracytoplasmic vesicle formation by modulation of peroxisome proliferator
activated receptor γ (PPARγ) and clathrin expression, inhibition of suppression
of interleukins 22 and 17A (IL-22, IL-17A), G1-phase cell cycle arrest via
inhibition of cellular myelocytomatosis (c-MYC), increased sub-G1 population
(apoptotic cells), downregulated protein expression of cyclin D1 (CCND1), cyclin
D3 (CCND3), CBN-mediated decreases in cyclin-dependent kinases 1 and 2 (CDK1,
CDK2) and cyclin E1 levels, other cannabinoid-mediated cyclin-dependent kinases
2, 4, and 6 (CDK2, CDK4, CDK6), increased microtubule associated protein 1 light
chain 3 beta (LC3-II or MAP1LC3B), caspase 3/7 activity, elevated expression of
endoplasmic reticulum (ER) stress proteins including binding immunoglobulin
protein (BiP), inositol-requiring enzyme 1α (IRE1α), phosphorylated eukaryotic
initiation factor 2α (eIF2α), ATF3, ATF4; anti-proliferative effects via
downregulation of monoglyceride lipase (MAGL or MGLL), induction of dual
specificity phosphatase 1 (DUSP1), upregulated ataxia telangiectasia mutated
(ATM) gene and cyclin dependent kinase inhibitor 1A (p21) protein expression,
downregulation of tumour protein p53 expression (TP53 or cellular tumour antigen
P53), reduced stimulation of phosphorylated retinoblastoma protein (P-pRb),
cyclin dependent kinases 1, 2, and 4 (CDK1, CDK2, CDK4), cyclin E1 (CCNE1),
cyclin D (CCND), growth arrest and DNA damage inducible alpha (GADD45A),
5-lipoxygenase (5-LOX), and leukotriene B4 (LTB4); pro-apoptotic stimulation of
reactive oxygen species (ROS), NADPH oxidase 4 (NOX4), increased interaction of
X-linked inhibitor of apoptosis (XIAP) with diablo IAP-binding mitochondrial
protein (DIABLO or Smac), cytochrome B-245 alpha chain (CYBA or p22phox),
stimulated Smac release, lipid rafts, recruitment of the death receptor Fas,
prostaglandin E2 (PGE2), and PPARγ; enhanced efficacy and reduced oxaliplatin
resistance via decreased NOS3 phosphorylation in oxaliplatin colorectal cancer
treatment; inhibition of specificity protein (Sp) transcription factors Sp1, Sp3
and Sp4, Sp-regulated gene products, and ying yang 1 (YY1); pro-autophagic
effects via stimulation of Akt, mammalian target of rapamycin complex 1 (or
mechanistic target of rapamycin complex 1 (MTorc1), 5'-AMP-activated protein
kinase (AMPK), RUNX family transcription factor 1 (RUNX1 or AML-1),
BCL2/adenovirus E1B 19 kd-interacting protein (BNIP), increased cytochrome-c,
465-amino acid residue E3 ubiquitin ligase (Parkin or PRKN), and cytoprotective
enzyme heme oxygenase-1 (HO-1) and reduced viability of cholangiocarcinoma cells
via activation of GPR55, with decreased actin polymerization, pMEK1/2 and pAkt;
anti-invasive and anti-metastatic effects via increased intercellular adhesion
molecule 1 (ICAM-1 or CD54) and tissue inhibitor of metalloproteinase-1 (TIMP-1)
expression, reduced expression of 70-kDa ribosomal protein S6 kinase (p70S6K),
stimulation of matrix metalloproteinases -2 and -9 (MMP-2, MMP-9), inhibitor of
basic helix-loop-helix transcription factors isopentenyl-diphosphate delta
isomerase 1 (Id-1), plasminogen activator inhibitor-1 (PAI-1), and ERK 1/2; anti
epithelial-to-mesenchymal transition (EMT) effects via reduced stimulation of
snail family transcriptional repressors 1 (SNAI1 or Snail1) and 2 (SNAI2 or
Slug), Twist Family BHLH Transcription Factor 1 (TWIST), β-catenin, mesenchymal
markers vimentin (VIM), N-cadherin (CDH2), fibronectin (FN1), and transcription
factor p63 (ΔNp63), baculoviral IAP repeat containing 3 (BIRC3) and Id-1, and
inhibition of E-cadherin (CDH-2) and cytokeratin 18 (KRT18); anti-angiogenic
action with reduced Ki67 proliferative and CD31 endothelial markers, inhibition
of ras oncogene-dependent tumor growth via CB1R, reduced stimulation of MMP-2,
HO-1) leptin, and inhibition of collagen type I alpha 1 chain (COL1A1), and
TIMP-1; positive and preventive influences in diseases of excessive or abnormal
angiogenesis; in psoriasis, decreased K6 and K16 expression, conversion of the
pro-inflammatory Th1 profile to an anti-inflammatory Th2 type expression, and
anti-proliferative properties on keratinocytes; suppression of allergic contact
dermatitis via inhibition of monocyte chemotactic protein-2 (MCP-2) chemokine,
interleukins (ILs) 6 and 8, and tumour necrosis factor alpha (TNFα), of activity
of T and B-cells-mediated response, of release of interleukins 6, 8, and 17,
TNF-α, and interferon (IFN)-γ, and modulated immune response via decreased
activity of T helper 17 cells; via substitution for alcohol a reduction in
post-prostate diagnosis mortality; reductions of up to 8.45 fewer new cases
annually per 1% shrinkage in non-cannabis-use (NCU) of prostate, head and neck
cell squamous carcinoma (HNSCC); increased HPV clearance; reductions in
hepatocellular, bladder cancer (BC), and renal cell carcinoma (RCC); in
hepatocellular carcinoma a 40% lower prevalence of gallstones; CBN-mediated
anti-proliferative effects in liver as represented by the HepG2 cell line;
limited attenuation of tobacco-related BC and RCC; a reduction of up to 2% per
year on average via alcohol-substitution of the risk of first diagnosis
pharyngeal or laryngeal carcinoma; reduced oral Fusobacterium; decreased protein
and mRNA expression of androgen receptor and prostate-specific antigen (PSA),
decreases in secreted PSA levels, protein expression of proliferating cell
nuclear antigen (PCNA), and vascular endothelial growth factor (VEGF);
inhibition of prostate cancer cell viability and proliferation, reduced
expression of cyclin D3 and cyclin-dependent kinases, inhibition of AKT
phosphorylation, reduced cell viability and invasiveness demonstrated in highly
metastatic PC-3 cells, inhibition of exosomes and microvesicles (EMV) via a
reduction in ATP production and proton leakage and suppression of mitochondrial
respiration, increased caspase activity, protein expression of E-cadherin,
expression of p53 and Bax, induction of p53-upregulated modulator of apoptosis
(PUMA) and C/EBP Homologous Protein (CHOP) expression and intracellular Ca(2+),
antagonism of transient receptor potential melastatin type-8 (TRPM8) and
down-regulation of androgen receptor (AR), p53 activation and elevation of ROS;
assistance with mitochondrial functions including redox regulation, calcium
uptake, membrane potential, bioenergetics, biogenesis, and modulation of
fusion/fission dynamics that are disrupted following induction of
oxytosis/ferroptosis; assistance with mitophagy via PTEN-induced kinase (PINK)
and non-PINK pathways; PPARγ binding and activation, reduced microgliosis and
astrogliosis via thioredoxin 2 (TRX-2) and Wnt16 substrates, up‐regulation of
proinflammatory markers such as can be induced by 3-nitropropanoic acid (3‐NPA),
increased mitochondrial biogenesis, increased mitochondrial mass in
neuroblastoma N2a cells, increased expression of Cell-Death Inducing DFFA
Effector A (CIDEA) and uncoupling protein 1 (UCP1) in peritoneal fat, browning
of inguinal white adipose tissue (iWAT), less striatal degeneration, lower
leptin, reduced leptin resistance and nocioception via channels of the transient
receptor superfamily (TRP) including transient vanilloid receptor type 1
(TRPV1), transient potential cation channel subfamily M (melastatin) member 8
(TRPM8) and transient potential of the ankyrin receptor 1 (TRPA1); reduced
glucose intolerance and insulin resistance, fine tuning of appetitive control
via hypothalamic pro-opiomelanocortin (POMC), its enzymatic products,
melanocortin-stimulating hormone (MSH) peptides, melanocortin receptors MC3R and
MC4R, glucose transporter 2 (GLUT2), mitochondrial uncoupling protein 2 (UCP2)
and (protein kinase B (PKB); dietarily and economically favourable anorexigenic
effects, reduced glycosylated hemoglobin (HbA1c), a lowered acyl-ghrelin (AG) to
desacyl-ghrelin (DAG) ratio, increased insulin-induced glucose uptake and a
decreased rate of adipogenesis, decreased abundance of adipocyte-specific fatty
acid–binding protein (aP2), acyl-CoA synthase (ACS), CD36 (cluster of
differentiation 36 or platelet glycoprotein 4), lipoprotein lipase (LPL),
hormone-sensitive lipase (HSL) and perilipin in adipocytes, lower free fatty
acid uptake, increased hepatic gene expression of the lipogenic transcription
factor Sterol regulatory element-binding protein 1c (SREBP-1c) and its targets
acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FAS), de novo fatty
acid synthesis, ameliorative effects in liver and kidney including reduced and
length-of-use-dependent fatty liver index (FLI), reduced liver enlargement with
a high-fat diet, hepatic triglyceride content, and steatosis score, fewer
gallstones, reduced levels of tenascin C (TNC), alanine aminotransferase (ALT),
aspartate aminotransferase (AST), alanine peroxidase (ALP), malondialdehyde
(MDA), and abundance of hepatic lipid droplets, increased levels of glutathione
peroxidase (GPX), increased reduction of glutathione (GSH), increased mRNA
transcription of fatty acid desaturase 2 (FADS2), stearoyl-CoA desaturase
(SCD-1), acyl-CoA oxidase 1 (ACOX1), PPAR-α, fatty acid transporter CD36, MMP-2
and MMP-9, and decreased expression of transforming growth factor beta 1
(TGF-β1), cyclooxygenase-2 (COX-2), cluster of differentiation 14 (CD-14), and
macrophage inflammatory protein-2 (MIP-2), decreased telomerase activity via
inhibition of the telomerase reverse transcriptase (hTERT) gene, amelioration of
liver steatosis CB2-mediated autophagy in Kupffer cells through a
heme-oxygenase-1 dependent pathway, adipogenesis and macrophage infiltration,
reduced adipocyte size, increased mRNA transcription FADS2, SCD-1, ACOX1, PPAR-α
and fatty acid transporter (FATP1) in adipose tissue, ~19 more microbiome genes
per unit of body mass index (BMI) reduced, prevented or reversed increases in
the firmicutes to bacteroidetes ratio, reduced colonic inflammatory cell
infiltration and increased lamina propria Tregs, activation of a phenotypic
switch to a more tolerogenic, anti-inflammatory phenotype lowering
interleukin-23 (IL-23), interleukin-1 beta (IL-1β), and monocyte chemoattractant
protein-1 (MCP-1) and raising TGF-β1 via increased CD103 expression and
decreased CD86 expression, increasing CD40 in mesenteric lymph node (mLN)
dendritic cells (DCs) and microglia, signalling on CD103+ DCs thus upregulating
C-C chemokine receptor type 7 (CCR7); enhanced immunomodulation and intestinal
immune homeostasis and advantageously balanced pro- and anti-inflammatory
cytokines via granulocyte colony-stimulating factor (G-CSF) and signal
transducer and activator of transcription 3 (STAT3); prevention of colonic
aberrant crypt foci (ACF) formation; increased phosphorylation of ribosomal
protein S6 kinase beta-1, (p70S6K or S6K1), inhibition of nucleotide-binding
domain, leucine-rich repeat pyrin domain containing-3 (NLRP3), apoptosis
associated speck-like protein containing a CARD (ASC or PYCARD) and procaspase-1
multiprotein scaffold inflammasome, protecting against PM2.5 air pollution in
general and Ptuj's Town Smell in particular, additionally Alzheimer’s, stroke
and cardiovascular diseases, asthma, gout, inflammatory bowel disease (IBD),
non-alcoholic fatty liver disease (NAFLD), myelodysplastic syndrome,
obesity-induced inflammation, insulin resistance, type-1 and type-2 diabetes,
oxalate-induced nephropathy, graft-versus-host disease, and silicosis; in
myeloid leukemia, differentiation block override via epigenetic hypomethylation
of the transcription start site (TSS) of O-linked β-N-acetylglucosamine
transferase (OGT), CBR-independent anti-leukemic action via downregulated
Raf-1/mitogen-activated protein kinase/ERK kinase (MEK)/ERK/RSK pathway leading
to translocation of the proapoptotic protein Bcl-2 associated death promoter
(BAD) to mitochondria, and decreased BAD phosphorylation at Ser(112);
anti-myeloma activity via reduced production of cell immunoglobulins E and G
(IgE and IgG), suppressed expression of phosphorylated nuclear factor of kappa
light polypeptide gene enhancer in B-cells inhibitor alpha (p-IκBα),
phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells
(p-NFκp, p65), total NFκB protein, X-box binding protein 1 (XBP1u and XBP1s),
decreased c-Myc gene and protein expression, increased gene and protein
expression of telomere, hTERT, TP53 gene, and p53 protein expression; weight
loss, a 2-6% lower probability of obesity and a $58 (€54,52) to $115 (€108,10)
per-person annual reduction in obesity-related medical costs based on MML alone;
catestatin-mediated reduction in mean arterial pressure (MAP); reduction of
coronary diabetic complications via inhibition of aldose reductase (ALR2);
alleviation of cardiac hypertrophy via reduced gene expression of atrial
natriuretic peptides A (ANP or NPPA) and B (BNP or NPPB), and myosin heavy chain
beta (β-MHC), limitation of the enlargement of the cardiomyocyte area;
repression of miR-143 via enhanced expression of yes-associated protein (YAP or
YAP1) and catenin delta 1 (Ctnnd1), promoting cardiomyocyte proliferation and
heart regeneration after acute myocardial infarction (AMI); protection against
endoplasmic reticulum stress (ERS) and apoptosis in cardiac tissue via 78 kDa
glucose-regulated protein (GRP-78, aka heat shock 70 kDa protein 5 (HSPA5) aka
binding immunoglobulin protein (BiPS)), inositol-requiring enzyme 1 α (IRE1α),
activating transcription factor 6 (ATF6), activating transcription factor 4
(ARF4, aka tax-responsive enhancer element B67), C/EBP homologous protein (CHOP,
aka DNA damage-inducible transcript 3), CRISPR associated protein 12 (Cas-12),
Cas-8, Cas-9, and Cas-3 mRNAs, and against inflammation via TNF-α; reduction in
the brain age gap (BAG) via downregulation of TNFSF12; interference in the
development of atheromatous plaque via low-density lipoprotein (LDL) oxidation
and inhibition of foam cell formation independent of CB1R/CB2R, but related to
the action of non-canonical receptors TRPV1, TRPV4 and GPR55, decreased levels
of CD36 and oxidized LDL receptor 1 (OLR1) scavenger receptors via activation of
the NFκB pathway by oxidized LDL (oxLDL), and reduced gene expression of
proinflammatory cytokines in macrophages; attenuation of cardiac fibrosis via
reduced gene expression of collagens 1 and 3 (COL1, COL3), cellular
communication network factor 2 (CTGF or CCN2) and α-SMA regulation of redox
status, suppression of oxidative damage via increased superoxide dismutase (SOD)
and decreased interleukin-24 (IL-24, MDA or MDA7) level, nicotinamide adenine
dinucleotide phosphate (NADPH) activity, protein and gene expression of NADPH
oxidases 2 (NOX2) and 4 (NOX4), and the glycogen synthase kinase 3 beta (GSK3β),
and activation of the NAD-dependent deacetylase sirtuin-1 (SIRT1 or silent
information regulator 1) and NFE2 like BZIP transcription factor 2 (NRF2 or
NFE3L2) signalling pathways; inhibition of myocardial apoptosis via upregulation
of B-cell lymphoma 2 (Bcl-2) and caspase-3; decreased H2O2-induced endothelial
differentiation markers octamer-binding transcription factor-4 (OCT-4), fetal
liver kinase-1 (FLK-1, kinase insert domain receptor, or VEGFR2), and cluster of
differentiation 31 (CD-31); downregulation of histone deacetylase 1 (HDAC-1) and
nuclear factor of kappa light polypeptide gene enhancer in B-cells 3 inhibitor
(IKBα or NFκBIA) leading to a rise in nuclear factor of kappa light polypeptide
gene enhancer in B-cells 3 (NFKB3, V-rel avian reticuloendotheliosis viral
oncogene homolog A, RELA, RELA proto-oncogene NFκB subunit, or P65) levels; via
anti-obesogenic simulated paternal fasting stress pre-conception, reduced serum
glucose in both sexes of offspring; via hypomethylation of the paternal
insulin-like growth factor (IGF2) gene, reduced enlargement of adipocytes,
metabolic dysregulation, diabetes, rhabdomyosarcoma, glioma, obesity, and
hypomethylation in mesoderm-specific transcript (MEST), paternally-expressed
gene 3 (PEG3), and neuronatin (NNAT) differentially methylated regions) (DMRs)
in the F1 generation; via paternal alcohol substitution, no or less reduction in
activity of DNA methyltransferases, cytosine-guanine (CG) hypomethylation and
subsequent activation of normally silenced genes, even in the absence of
maternal alcohol consumption before or during pregnancy, and thereby a reduction
in fetal alcohol syndrome disorders (FASD), including reductions in facial
asymmetry and right eye misposition, prevention of increased adrenal weights,
decreased spleen weights, reductions in overall brain size, specifically in the
cerebellum, basal ganglia, and corpus callosum, preventing reduced ability to
cope with novelty and spatial learning skills and hyperreponsiveness to stress,
as well as ventricular septal defects and increased susceptibility to
Pseudomonas infection, ameliorated cognitive deficits, attenuated hippocampal
TNFα and IL-6 levels and prenatal and lactation alcohol exposure (PLAE)-induced
deficits in reference memory in the F1 generation; via paternal alcohol
substitution, other adverse effects in F1 of paternal genetic aging; alcohol
substitution associated downregulation of inflammatory cytokines including
intercellular adhesion molecule 1 (ICAM-1 or CD54), interleukin-16 (IL-16),
granulocyte/macrophage colony-stimulating factor (GMCSF), interleukin-309
(IL-309, CCL1 or C-C motif chemokine ligand 1), TNF-α, tissue inhibitor of
metalloproteinases 2 (TIMP-2), platelet-derived growth factor subunit B
(PDGF-β), macrophage inflammatory protein 1 alpha (MIP-1α), interleukin 12-p40
(IL-12-p40), interleukin-15 (IL-15) with reduction of alcohol expenditure;
stimulation of anti-depressive effects via reduced TNFα and
microbiotally-elevated interleukin-10 (IL-10); greater connectivity between the
anterior cerebellum and both hippocampus and posterior parahippocampal cortex
(pPaHC), between pPaHC cortex and lobule IV/V and vermis IV/V, and between
hippocampus and vermis IV/V and cerebellar lobule III; induction of
myeloid-derived suppressor cells (MDSCs), beneficial alterations in the
expression of microRNAs (miRNAs), specifically miRNA-18a, in lung-infiltrated
mononuclear cells (MNCs) after staphylococcal enterotoxin B (SEB) exposure via
downregulation of let7a-5p, targeting suppressor of cytokine signaling 1
(SOCS1), and downregulation of miR-34-5p, increasing expression of forkhead box
protein 3 (FoxP3/scurfin), nitric oxide synthase 1 (NOS1), and the colony
stimulating factor 1 receptor (CSF1R); suppression of inflammation and
prevention of dysbiosis, both in the lungs and the gut, through the induction of
antimicrobial peptides (AMPs) including tracheal antimicrobial peptide (TAP1),
tracheal antimicrobial peptide 2 (TAP2), lysozyme 2 (LYZ 2), and murine beta
defensin 2 (MBD2), secretory leukocyte peptidase inhibitor (SLPI), tight
junction proteins including claudin (CLDN1) and E-cadherin (CDH1), and
short-chain fatty acids (SCFAs), stabilizing a gut-lung microbial axis driving
immune homeostasis, increased beneficial Muribaculaceae and decreased pathogenic
Pseudomonas and Caulobacterlaes spp. in lung, and increased beneficial bacteria
including Lachnospiraceae and Clostridia, decreased infectivity of C.
perfringens via inhibition of neuraminidase, decreased pathogenic Tenericutes
and Anaplasmataceae in gut, decreased CD4 + T cells, CD8 + T cells, Vβ8 + T
cells, and natural killer T-cells (NKT cells) in mesenteric lymph nodes (MLNs);
possible evolutionarily advantageous symbioses via horizontal gene transfer,
increased microbiotal balance favouring β-galactosidase activity denoting a
higher threshold of resistance to lactose intolerance irrespective of genetic
predisposition, more bacteria that produce butyric acid, valeric acid and
isovaleric acid, suppressing inflammation, and being (as a daily user) five
times less likely to have a BMI ≥25); in intestinal epithelial cells, increased
AMPK phosphorylation, upregulated differentiation markers, enhanced PGC1α/SIRT3
mitochondrial signaling, reduced ROS production, increased antioxidant enzymes,
levels of citrate, malate, and succinate, upregulation of pyruvate dehydrogenase
and isocitrate dehydrogenase 1, and induced metabolic and antioxidant signaling;
population-wide reduction of antibiotic resistance and its associated global
mortality burden of 4.95 million (2019) by substitution with cannabinoids with a
low innate resistance frequency value, e.g. CBD's low propensity to induce
resistance against methicillin resistant staphylococcus aureus American Type
Culture Collection (MRSA ATCC) 43300, resulting in prolonged useful life of
antibiotics, reductions in their adverse effect in the GI microbiome, prevention
of weight loss, increased survival, increased natural killer (NK) cells, immune
cell mobilization; via CBR activation prevention of a dysregulated polarization
state combining pro-inflammatory and regulatory elements, increased levels of
beneficial Lactobacillus and Bifidobacterium species, L. intestinalis, L.
gasseri, L. crispatus, protection against gastrointestinal infections caused by
Citrobacter rodentium and Alistipes species A. humii, A. finegoldii, and A.
onderdonkii, elevated Bifidobacterium shunt, 7-cyano-7-deazaguanine (preQ0)
biosynthesis pathway, L-glutamine and L-lysine biosynthesis, prevention of
microbiota-driven immune dysregulation, modulation of innate immunity, host
defense, and microbiota composition during bacterial infections, phagocytosis of
zymosan particles, enhancement of mammalian cell viability, endocannabinoid
regulation of gut homeostasis and microbiome, promotion of gut barrier
integrity, enhancement of anti-inflammatory responses, and pathogen resistance,
more potent bactericidal activity than vancomycin including in exponential- and
stationary-phase MRSA cells, via degradation of the bacterial lipid membrane and
alteration of the bacterial nucleoid; consequent downstream effects in mental
and physical wellbeing via gut permeability and transport; lower levels of
fibrinogen; interleukin-8 (IL-8, or CXCL8)-mediated thrombus resolution,
prolonged clotting time, reduced platelet adhesion and aggregate formation under
flow, reduced platelet alpha-granule secretion, reduced major precursors for
oxylipin generation docosahexaenoic acid (DHA), arachidonic acid (ARA), and
eicosapentaenoic acid (EPA), dose-dependent inhibition of aggregation, with the
same clotting times and blood counts including platelets; benefits in breast
cancer, stomach cancer, prostate cancer, hepatic ischemia/reperfusion (IR)
injury, acute liver failure (ALF), alcoholic liver disease (ALD), non-alcoholic
fatty liver disease (NAFLD), viral hepatitis, fibrosis and hepatocellular
carcinoma (HCC) via downregulation of CCL5 (aka regulated on activation, normal
T-cell expressed and secreted, RANTES); a potential ~25% reduction of nondipping
equivalent to over 500 prevalent cases in Slovenia in 2019; induction of HO-1;
antihypertensive action via inhibition of presynaptic norepinephrine release via
α2-adrenoreceptors (α2AR); anti-inflammatory action in human vascular smooth
muscle cells (hVSMC) via transcription inactivating histone 3 lysine 4
monomethylation (H3K4me1) and transcription activating H3K4 trimethylation
(H3K4me3), mediated by recruitment of HDAC4 and nuclear corepressor NCoR1 to the
chemokine (C-C motif) ligand 2 promoter (CCL2, aka monocyte chemoattractant
protein 1 MCP1 or small inducible cytokine A2); endothelium-dependent
vasorelaxant effects via GPR18; non-exposure to an increased risk of atrial
fibrillation (AF) at a rate of 18.16 patients or 29.31 diagnoses per 1% of NCU
in Slovenia annually; between 9.62 and 27.19 fewer hospitalizations for heart
failure in Slovenia annually per 1% of population cannabis use (PCU);
non-exposure to an increased risk of death from acute heart failure (AHF) at a
rate of 5.85 per 1% of NCU at 18% PCU, and 9.74 deaths per 1% at 30% PCU in
Slovenia annually; in hospitalized AHF patients, a lower prevalence of
hypertension, dyslipidaemia, diabetes, chronic kidney disease (CKD), prior
coronary artery bypass grafting (CABG), intra-aortic balloon pump (IABP) use,
history of percutaneous coronary intervention (PCI), family history of coronary
artery disease (CAD), peripheral vascular disease (PVD), and lower Charlson
Comorbidity Index (CCI) group ≥3, and following AMI lower odds of atrial
fibrillation (AF), ventricular fibrillation, cardiogenic shock, acute ischaemic
stroke, cardiac arrest, and all-cause mortality; in Podravska, 6.09 fewer
in-hospital AHF patient mortalities per year per 1% NCU at 72% cohort NCU; in
trauma patients, 21% reduced mortality including in younger and ICU patients; in
chronic liver disease (CLD), usage-dependent lower prevalence of cirrhosis, with
lower unfavourable discharge disposition, and total healthcare cost; in
cirrhosis, regression of fibrosis with apoptosis of hepatic myofibroblasts,
reduced hepatorenal syndrome, ascites, mortality, and length of hospital stay;
72% lower mortality in co-infected HIV/HCV patients with regular/daily use; in
an overall in-hospital mortality odds ratio of 0.41; in cancer patients, an
in-hospital mortality odds ratio of 0.44; protection of NSCs and astrocytes from
ionizing radiation; attenuation via MyD88 pathways of toll-like receptor
(TLR3)-induced C-X-C motif chemokine ligand 10 (CXCL10) and IFN-β protein
expression in PBMCs, downregulation of CXCL10 and CXCL11 expression in
thyrocytes, chemokine receptor CXCR3 and chemokine ligand 9 (CXCL9) in
endothelial cells, and inhibition of angiogenesis; via inhibition of
angiogenesis, health benefits in respect of cancer, infectious diseases
including AIDS, autoimmune disorders, blood vessels, in adipose tissue, the
skin, eye, lung, intestines, reproductive system, and in the musculoskeletal
system; in cancer patients, improved reaction times in the Stroop Task;
inhibition of transforming growth factor beta (TGF-β), HA and hyaluronan
synthase 3 (HAS3) in myoblasts; promotion of adaptive immunity via the
proliferation and function of Tregs and suppression of the differentiation and
function of T-helper-17 (Th17) cells, induction of apoptosis of Th cells via
inhibition of the expression of B-cell lymphoma 2 (Bcl-2); antineoplastic
effects on lung cancer cells by various mechanisms mediated by cannabinoid
receptors or independent of them; vasodilatory effects via activation of
Transient receptor potential cation channel, subfamily A, member 1 (ANKTM1, aka
transient receptor potential ankyrin 1, TRPA1, the wasabi receptor); blocking
calcium release activated calcium (CRAC) currents, inhibition of store-operated
calcium entry (SOCE), decreased nuclear factor of activated T-cells (NFAT)
activation and interleukin 2 (IL-2) production in human T lymphocytes; reduced
lymphocyte activation, expression of miR-21, and of Th1/Th17 lineage commitment
in delayed-type hypersensitivity; remyelination and axon preservation, increased
action potential conduction, reduced chondroitin sulfate proteoglycans (CSPGs),
preferential oligodendrocyte precursor cell (OPC) differentiation and prevention
of demyelination by diminished excitotoxicity in oligodendrocytes, via
activation of phosphatidylinositol 3-Kinase (PI3K)/AKT and the mammalian target
of rapamycin (MTOR) pathways, and prevention of axonal demyelination of neurons
and axonal injury; via reduced obesity, a reduced prevalence of multiple
sclerosis; in multiple sclerosis, suppression of Th17 cell differentiation via
suppression of miR-21 expression and induction of mothers against
decapentaplegic homolog 7 (SMAD7), downregulation of IFN-γ inhibitor miR-29b,
miR-155, and miR-31, reduced pro-inflammatory cytokines IL-1, IL-2, IL-12,
IL-17, IL-22, IFN-γ, and TNF-α, and a 50% reduction in relapse rate; a decrease
in the production of autoantibodies; a lowering of
12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), promotion of the
differentiation of M2 phenotype of macrophages and the tolergenic dendritic
cells (DCs), and longer but not too long telomeres; induction of apoptosis of
synovial cells; repression of the nuclear factor-κB signaling pathway in
fibroblast-like synoviocytes and inhibition of the migration and proliferation
of FLSs, assistance to FLS apoptosis, prevention of hyperplasia in rheumatoid
arthritis synovium, reduction of joint and cartilage erosion, inhibition of
interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3, aka stromelysin-1), and
CCL2 in FLSs, and osteoclastogenesis of peripheral blood monocytes, reduced
arthritis score, pain, fatigue, stiffness, inflammatory cell infiltration, bone
destruction, and anti-collagen type II immunoglobulin G (anti-CII IgG1)
production; in hypermobility spectrum disorder (HSD) and hypermobile
Ehlers–Danlos syndrome (hEDS), improved scores in Short-Form McGill Pain
Questionnaire 2 (SF-MPQ-2), pain visual analog scale score (Pain-VAS), Brief
Pain Inventory (BPI), five-level EQ-5D (EQ-5D-5L), Single-Item Sleep Quality
Scale (SQS), General Anxiety Disorder Seven-Item Scale (GAD-7), and Patient
Global Impression of Change; suppression of TGF-β-induced collagen gene expression,
differentiation of myofibroblasts, Smad-dependent promoter activity in
fibroblasts, and inhibition of the proliferation and viability of fibroblasts
while inducing the apoptosis of fibroblasts; anti-osteopenic effects via
modulation of receptor activator of the nuclear factor-κB (RANKL or TNF
Superfamily Member 11) and osteoprotegerin (OPG or TNF Superfamily Member 11b),
maturation of preosteoclasts, phosphorylation of ERK1/2, release of transforming
growth factor-β1 (TGF-β1), binding of TNF receptor-associated factors (TRAFs),
increased MAPK, cyclic adenosine monophosphate (cAMP) response element-binding
protein transcription, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1),
amplification of c-Fos expression, interacting with nuclear factor of activated
T-cells cytoplasmic 1 (NFATc1) triggering transcription of the osteoclastogenic
gene, decreased bone resorption via decreased expression of cytokines, TNF, and
IL-1, and increased expression of IL-1 receptor antagonist; in fracture healing,
upregulated osteoblastic mRNA levels of the lysyl hydroxylase PLOD2, transient
enhancement of cartilaginous callus resorption and increased work-to-failure;
suppression of the interleukin 1-beta (IL-1β) and NFκB signaling pathways in
salivary gland epithelial cells (SGECs) and inhibition of the apoptosis of
SGECs; inhibition of the IL-1β pathway in lacrimal gland acinar cells;
therapeutic and prophylactic reduction of PD-1 in T-cells, anti-programmed cell
death protein-1 ligand 1 (PD-L1), IL-1β and decreased malignancy markers in
breast cancer cells, thereby protective against particulate matter measuring
≤2.5 μm (PM2.5); cannabiniol (CBN)-induced decrease in proliferation and
suppression of the Akt pathway as represented by its action in HCC1086 cell
lines, decreases in the levels of interferon gamma and interleukin-6 (IL-6),
tumour necrosis factor alpha (TNF-α) and IL-1β accompanied by an increase the
level of interleukin-4 (IL-4) in the serum, by which the peroxisome
proliferator-activated receptor gamma (PPAR-γ or PPARG) agonist inhibits
inflammatory reactions, modulates the balance between immune cells and protects
the target organs in autoimmune diseases; reduced cell senescence via
upregulation of peroxisome proliferator activated receptor alpha (PPARα or
PPARA) and its target gene carnitine palmitoyltransferase 1C (CPT1C); improved
nuclear architecture and mRNA levels of cell cycle regulators and genes involved
in extracellular matrix (ECM) production, increased rejuvenation and reduced
senescence in dermal fibroblasts as measured by beta-galactosidase (GLB)
activity, via amelioration of elastin (ELN), Cyclin D1, proliferating cell
nuclear antigen (PCNA), and pro-apoptotic protein Bcl-2 homology 3
interacting-domain death agonist (BID) protein levels altered by stress-induced
premature senescent (SIPS) cells, with increased SIRT1 and SIRT6, and
(nonsignificantly) SIRT3 and SIRT4; reduced senescence-related vascular
disorders, reduced deposition of hepatic triglyceride (TG), AD, and insulin
resistance via the receptor for advanced glycation end product (RAGE)/PPARα
axis; selective COX2 inhibition overall, favourable modulation of the
arachidonic acid cascade, inhibiting production of series 2 prostaglandins and
series 4 leukotrienes; anti-viral and antibacterial infectivity via inhibition
of C. perfringens and influenza A (H5N1) neuraminidases and SARS-CoV-2 main
protease and spike protein–human ACE2 interaction; inhibition of SARS-CoV-2
replication by inter alia upregulation of host IRE1α ribonuclease ER stress
response and interferon signaling pathways, via upregulated
interferon-stimulated gene 15 (ISG15), interferon induced protein with
tetratricopeptide repeats 1 (IFIT1), IFIT3, suppressor of cytokine signaling 1
(SOCS1), and 2’-5’-oligoadenylate synthetase 1 (OAS1), leading to activation of
RNase L and RNA degradation, especially in the presence of the virus, lowering
of the titer this facilitating the innate immune response, suppression of
SARS-CoV-2-induced changes in gene expression and eradication of viral RNA
expression in the cells, including RNA coding for spike, membrane, envelope and
nucleocapsid proteins; a 0.77 population causal odds ratio of Covid
hospitalization using inverse-variance weighted (IVW) linear regression, and
0.87 and 0.97 causal odds ratios of severe respiratory symptoms and
hospitalization respectively using weighted median (WM); upon hospital admission
for Covid-19, lower levels of C-reactive protein, ferritin, D-dimer, and
procalcitonin, inhibition of spike protein-mediated membrane fusion, improved
outcomes reflected in lower Covid NIH score, a one third shorter hospitalization
time, approximately two thirds lower ICU admission rate, also two thirds less
need for mechanical ventilation, and 6-36% lower intubation rate, with reduced
rates of acute respiratory distress syndrome (ARDS), acute respiratory failure,
severe sepsis with multiorgan failure, extracorporeal membrane oxygenation
(EMCO), GI bleeding, in-hospital cardiac arrest and mortality (2.9% vs 13.5%),
with up to 83.97% lower odds of death compared to those in a no active cannabis
use group, and up to 2.75 fewer hospitalizations per day in Slovenia during a
pandemic episode; prevention and/or amelioration of Covid, reduced disease
sensitivity via downregulated ACE2 gene expression, blocked replication of
SARS-CoV-2 and expression of viral genes, reduced SARS-CoV2 entry into host
cells via downregulation of serine protease TMPRSS2, triggering of interferon
expression and activation of the antiviral signaling pathway, increased serum
apelin, accompanied by an increase in oxygen level in the lungs, formation of
allosteric and orthosteric ligands with spike protein, prevention of SARS-CoV-2
cell entry, blockade of SARS-CoV-2 fusion, inhibition of SARS-CoV-2 spike
protein-mediated membrane fusion, and via inhibition of the expression of IL-1b,
dual specificity phosphatase 2 (Dusp2), chemokine (C-C motif) ligand 12 (CCL12),
chemokine (C-C motif) ligand 9 (CCL9), endothelin 1 (EDN1), interferon beta 1
(IFNB1) chemokine (C-C motif) ligand 7 (CCL7), CD69, formyl peptide receptor,
related sequence 2 (FPR-RS2), IL-1a, interleukin 4 induced 1 (IL4i1);
interleukin 27 (Il27), paired immunoglobin-like type 2 receptor alpha (PILRA),
matrix metalloproteinase 13 (MMP13) and chemokine (C-C motif) ligand 2 (CCL2),
enhanced effect on LPS-upregulated genes growth differentiation factor 15
(GDF15), sequestosome 1 (SQSTM1 aka P62), solute carrier family 7 (cationic
amino acid transporter, y+ system) member 11 (SLC7A11), aquaporin 9 (AQP9),
mucolipin 2 (MCOLN2 aka TRPML2), dual specificity phosphatase 1 (DUSP1 aka
MKP-1), DUSP8, prostaglandin I receptor (PTGIR), cyclin-dependent kinase
inhibitor 2B (CDKN2B aka P15), homocysteine-inducible, endoplasmic reticulum
stress-inducible ubiquitin-like domain member 1 (HERPUD1), C-type (calcium
dependent, carbohydrate recognition domain) lectin (CLECSF9), and villin 2 (VIL2
aka ezrin), and via the MAPK pathway, the JAK/STAT regulatory molecules:
suppressor of cytokine signalling 3 (SOCS3), cytokine inducible SH2 containing
protein (CISH), signal transducer and activator of transcription 1 (STAT1), and
the cell cycle related genes growth arrest and DNA damage inducible alpha
(GADD45A), cyclin dependent kinase inhibitor 1A (CDKN1A aka P21), the nuclear
factor (erythroid-derived 2)-like 2/heme oxygenase 1 (NRF2/HMOX1) axis and the
NRF2/ATF4-TRIB3 pathway; pro-apoptotic action in ARDS via elevated serum
concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and
propionyl L-carnitine, downregulation of miR-185, and dampening of the cytokine
storm; regulation of macrophage inflammatory and repair function in the lung
after viral injury via peroxisomes; protection against long Covid and improved
blood-brain barrier integrity via reduced IFN-γ, MCP-1, tumor necrosis
factor-alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6),
interleukin-8 (IL-8), interleukin-17 (IL-17), interferon-gamma (IFNγ),
myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), nitrogen dioxide
(NO2), prostaglandin E2 (PGE2), phosphorylation levels of T cell receptor (TCR)
signaling proteins Lck and Zap70, and reactive oxygen species (ROS); reduced
hyperthermia and improved thermoregulation via substitution for antimicrobials,
nonsteroidal anti-inflammatory drugs (NSAIDs), first generation anticonvulsants,
atypical antipsychotics, beta-blockers, and tricyclic and selective serotonin
reuptake inhibitor (SSRI) antidepressants; gastric protection against ethanol,
NSAIDs, proton pump inhibitors (PPIs) and stress-induced mucosal damage;
prevention of the inflammatory response in intestinal mucosa via increased GPX;
reduced acute and chronic pancreatitis; in acute pancreatitis, lower morbidity
and hospitalization costs, a sixfold lower mortality risk; against pancreatic
cancer, decreased expression of epidermal growth factor receptor (EGFR),
MIAPaCa-2, and mTOR protein expression, reduced phospho-Akt (pAkt), total Akt,
and decreased phosphorylation; in burns patients, an in-hospital mortality rate
fourfold lower vs. drug-negative, and eightfold lower vs. alcohol-positive
patients, shorter ICU stay and lower hospital costs than drug- and
alcohol-negative patients; antinociceptive, bronchodilatory, antipyretic and
antirheumatic effects via antagonism of platelet activating factor (PAF) by
delta-9 tetrahydrocannabinol (Δ9-THC or D-9-THC) metabolite
tetrahydrocannabinol-7-oic acid and inhibition of cyclooxygenase and
5-lipoxygenase (ALOX5) activities; anti-Parkinsonian effects via enhancement of
Akkermansi municiphilia and F. prausnitzii dependent SCFAs, reduction of
alpha-synuclein, reduced gut permeability, attenuated loss of tyrosine
hydroxylase (TH)-containing neurons in the substantia nigra (SN), THC-inhibition
of divalent metal transporter 1 (DMT1) via blockade of phosphorylation of serine
43 and prevention of iron (Fe) absorption, and by inter alia β-caryophyllene
(BCP)-induced reduction of oxidative stress, neuroinflammation and apoptosis and
thereby also cardioprotective effects; post-injury and everyday anti-depressive
effects via attenuation of metalloproteinase-9; prevention and alleviation of
age- and lipoxin A4 (LXA4)-dependent cognitive deficits; restored cognition in
old age; ameliorated presynaptic GABA release onto cerebellar Purkinje neurons
and reduced frequency of inhibitory postsynaptic currents through a protein
kinase A-dependent pathway; upregulated CD11b+Gr-1+ myeloid-derived suppressor
cells (MDSC), glial fibrillary acidic protein (GFAP) intermediate filament
protein and ionized calcium-binding adapter molecule 1 (IBA1, a.k.a. allograft
inflammatory factor 1 (AIF1)) expression, granulocyte colony-stimulating factor
(G-CSF), brain derived neurotrophic factor (BDNF) and glial-derived neurotrophic
factor (GDNF) in hippocampus (HP), cerebral cortex, and striatum subsequent to
traumatic brain injury, with increased cerebral blood flow, neurobehavioral
function, and working memory performance, and decreased neurological deficit and
enhanced motor functions through down-regulation of pro-inflammatory markers
correlating with reduced levels of detrimental neural protein, oedema formation
and blood–brain barrier permeability, prevention of neuronal cell loss and
up-regulation of adherence junction proteins; in ischemia, attenuation of
cognitive and emotional impairments, hippocampal neurodegeneration and white
matter (WM) injury, reduced glial response, increased hippocampal BDNF protein
levels, promotion of neurogenesis and dendritic restructuring in the
hippocampus; increased dendritic spine density in the posterior dorsomedial
striatum; atypical coupling of neuronal CB1R to heterotrimeric G12/G13 proteins
triggering rapid and reversible non-muscle myosin II (NM II) dependent
contraction of the actomyosin cytoskeleton, via Rho-GTPase and Rho-associated
kinase (ROCK), induction of rapid neuronal remodeling, retraction of neurites
and axonal growth cones, elevated neuronal rigidity, reshaping of
somatodendritic morphology, prevention of excessive corticofugal axon growth
into the sub-ventricular zone, transformation of the neuronal cytoskeleton via
actomyosin contractility, resulting in cellular remodeling events ultimately
able to affect the brain architecture and wiring; improved tracer migration from
lymphatic vessels to dCLNs and modification of aquaporin-4 polarization, higher
rate of discharge home vs other care settings, lower discharge modified Rankin
scale (mRS), and shorter duration of hospital stay; increased resilience to
everyday stress and in post-traumatic stress disorder (PTSD) via FK506 binding
protein 5 (FKBP5), reduced neuropeptide Y (NPY) receptors in the basolateral
amygdala (BLA) and infralimbic prefrontal cortex, and a fall in the positive
diagnostic criteria rate at one year; supported cerebellar volumes in aging,
particularly in lobules I–V of the cerebellum; increased hippocampal, NAc and
putamen volumes; fewer motor deficits; elevated or normalised hedonic tone;
assisted regulation of social reward via oxytocin-dependent endocannabinoid
signalling in the NAc; more slow-wave sleep, reduced insomnia and better quality
sleep with increased REM latency; via improved sleep or other mechanisms, a 26%
lower prevalence of cardiovascular disease, increased longevity, reduced adverse
effects on circadian rhythms via genes PER1, PER2, PER3, CRY2, CLOCK, NR1D1,
NR1D2, RORA, DEC1, CSNK1E, sleep homeostasis via IL6, STAT3, KCNV2, CAMK2D,
oxidative stress via PRDX2, PRDX5, and metabolism via SLC2A3, SLC2A5, GHRL, and
ABCA1, affecting chromatin modification, gene-expression regulation,
macromolecular metabolism, and inflammatory, immune and stress responses;
protection against sleep apnea; in attention deficit hyperactivity disorder
(ADHD), reductions in poor tolerance to frustration, outbursts of anger,
boredom, and problems related to concentration, and via cannabinoid effects such
as neurotransmitter release inhibition in the ventral tegmental area (VTA), an
unknown and unknowable mixture of net positive up- or down-regulations of genes
associated with psychoactive disorders, or placebo effects, as supported by
majority belief; in bipolar disorder, increased effortful motivation, reduced
impulsivity and risky decision making via regulation of the glutamate-glutamine
cycle; reduced workplace injuries and fatalities; reduced pedestrian fatalities;
reduced vehicle insurance premiums; lower health insurance premiums; reduced
opioid use, including fewer prescriptions and fewer units, lower opiate
mortality and accidental poisoning rates; in an RML vs. no-RML paradigm improved
crime clearance and reduced school expulsions; improved visual contrast
sensitivity under low-light conditions; reduced intraocular pressure; relief of
tinnitus symptoms including dizziness, pain and sleep disturbance, improved
audio gating ratio; added longevity and protection against acetaminophen-induced
hepatotoxicity via suppression of interleukin-11 (IL-11); added longevity via
self-regulation of circadian rhythms; added longevity and prevention of
methylglyoxal-mediated cellular damage through enhancement of the neural
glyoxalase pathway; added longevity concomitant with reduced IL-23R; a more
compressed morbidity with added longevity via actions on pathways corresponding
to abnormal dauer formation protein-2 (DAF-2), consistent with reductions in
protein carbonyl (PCO), 8-hydroxy-2'-deoxyguanosine (8-OHdG), lipid
hydroperoxide (LHP), malondialdehyde (MDA) and interleukin-6 (IL-6), nuclear
factor κβ (NF-κβ) cell number, elevated thiol fraction, mRNA expression of
Krüppel-like factor-4; prevention and attenuation of diabetic retinopathy via
inhibition of uptake of adenosine by equilibrative nucleoside transporter 1
(ENT1) in microglia, synergistic enhancement of adenosine’s TNF-α suppression,
decreased TNF-α production in serum, decreased retinal inflammation by blocking
of p38, MAP kinase activation, and microglial activation, and preservation of
the blood-retinal barrier (BRB); comparable binding affinity to sitagliptin with
dipeptidyl peptidase-4 (DPP-4), and higher binding affinity with α- glucosidase,
α-amylase and invertase than acarbose; amelioration of impaired redox status of
diabetic kidney and immunomodulation; prevention of renal atrophy, attenuation
of renal fibrosis, and amelioration of functional loss and damage in kidney
inflammation via inhibition of apoptosis through blocking of caspase-3 activity
and subsequent cleavage of poly ADP-ribose polymerase 1 (PARP1) and inhibition
of transient receptor potential cation channel subfamily M member 7 (TRPM7);
reduced adiponectin, apolipoprotein, resistin (aka adipose tissue-specific
secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted
cysteine-rich protein (XCP1)), and increased glucose-dependent insulinotropic
peptide (GIP); in obesity, lower plasma fasting insulin (FINS) and homeostasis
model assessment of insulin resistance (HOMA-IR); reduced waist circumference;
reduced discrimation against women in diabetes prophylaxis; fewer migraines and
cluster headaches via suppression of calcitonin gene-related peptide (CGRP)
release from trigeminal sensory fibers, inhibition of 5HT release from
platelets, CB1 receptor activation, descending modulation of pain at the spinal
level through periaqueductal gray matter (PAG) and rostral ventrolateral medulla
(RVM) connections, modulation of descending cutaneous-evoked C-fiber spinal
nociceptive responses from the brainstem regions including the ventrolateral PAG
and RVM, inhibition of dural trigeminovascular nociceptive responses, descending
attenuation and modulation of dural-evoked nociceptive trigeminovascular
processing and transmission in the PAG, including Aδ-fiber and C-fiber
responses, and basal trigeminal neuronal tone in the trigeminocervical complex
resulting in reduced frequency and duration; resolution of neuropathic pain via
activation of spinal cord adenosine A2A receptors and inhibition of
voltage-gated sodium (Nav) channel Nav1.8; amelioration of gastroparesis;
reduced healthcare expenditure; 0.3 days per month less spent in poor mental
health by MM and pain-motivated users; one less death from alcohol in Slovenia
per day at 50% alcohol substitution; one less suicide per 15 days in an MML vs.
prohibition paradigm, in anticipation of yet fewer YPLL to suicide in RML
conditions; reduced attempted or completed suicide via substitution for
benzodiazepines, the antidepressants sertraline, fluoxetine, paroxetine,
venlafaxine, fluvoxamine, duloxetine, and clomipramine, and antipsychotics
including aripiprazole, risperidone, haloperidol, flupentixol, and
zuclopenthixol; reduced anhedonia; via substitution for benzodiazepines, reduced
withdrawal symptoms including low energy, poor concentration, memory loss,
anxiety, sleep disturbances, sensitivity to sights and sounds, dysbiosis, muscle
weakness, aches and pains; in offspring via substitution for antidepressant use
during pregnancy, higher platlet 5-HT levels, more mature fetal movement
quality, improvements in Brazelton Neonatal Behavioral Assessment Scale (NBAS),
orientation, reflexes, gestational age, Activin-A, cord blood level of cortisol,
thyroid-stimulating hormone and reelin levels, a reduced incidence of pre-term
birth, urogenital, eye, ear, face and neck, digestive and central nervous system
anomalies, dysbiosis and constipation, speech/language disorders, low Apgar
scores, poor brain connectivity, behavioural symptoms such as increased
irritability and decreased sleep time, clubfoot, Hirschsprung’s disease, EEG
anomalies, ADHD, ASD via prenatal inhibition of P450 enzymes and amelioration of
maternal immune activation (MIA), hydrocephalus, respiratory problems,
persistent pulmonary hypertension of the newborn, cardiovascular risk, low birth
weight, altered birth length, head circumference below the 10th percentile, long
hospital stay, omphalocele, Chiari I risk, less (primarily cortcolimbic) gray
matter, altered pattern of volumetric development in amygdala and fusiform gyrus
in ages 7-15, psychiatric disorders, and reduced disorders of gut-brain
interaction (DGBI) driven by functional constipation; reduced cortical thinning
in teenage alcohol users; ameliorated dialysis-related peritoneal fibrosis via
TGF-β(1)-induced dedifferentiation of mesothelial cells and maintenance of
epithelial integrity; reduced endometriosis with reduced serum total oxidant
status (OS), oxidative stress index (OSI), peritoneal fluid OSI, IL-6, TNF-α,
increased total antioxidant status (TAS), in serum and peritoneal fluid, lower
mean intensity in both surface epithelium and stromal cells for VEGF, and in
surface epithelium cells only for IL-6; in prenatally cannabinoid exposed (PCE)
neonates, increased Mullen scores in gross motor, expressive and receptive
language; in PTSD, reduced nightmares, control of exaggerated fear response via
inhibition of adenylate cyclase, cAMP and adrenergic pathways; suppression of
non-advantageous startle via heterosynaptic long-term depression of inhibition
(iLTD) via activation of group I metabotropic glutamate receptors (mGluR1 or
mGluR5) in postsynaptic neurons, activation of CB1R on inhibitory terminals
inducing long-lasting reduction of presynaptic GABA release probability; raised
ability to work, lower PTSD checklist (PCL) score for both arousal and
re-experience; higher educational attainment, directly and via substitution for
alcohol use; increased functional connectivity in the bilateral anterior insula
and anterior cingulate cortex (ACC), including its anterior middle (aMCC) and
posterior portion (pACC), raised score in the Cognitive and Affective Empathy
Test, a greater understanding of others' emotions, less verbal hostility,
enhanced prosociality, emotional comprehension, and empathic predisposition to
others' situations; more sexual partners; ~20% increased coital frequency in
both sexes, with increased sensitivity to touch, increased orgasm intensity and
achievability, and more relaxed sex; in males, higher sperm counts,
testosterone, inhibin B and sex hormone binding globulin (SHBG), increased
overall International Index of Erectile Function (IIEF) erectile, orgasm,
intercourse satisfaction and overall satisfaction domains; in females reporting
orgasm difficulty, increased orgasm frequency, improved orgasm satisfaction,
easier orgasm; in females, compression of the luteal phase, higher Female Sexual
Function Index (FSFI) scores, more sexual desire, more arousal, double the
female orgasms, more satisfaction with better sex, and a reduction in faked
orgasms.
In the case of classical psychedelics the Benedictions
proposed by the Defence include increased longevity via lower odds of heart
disease and diabetes, via increased problem-solving, via flattening of the brain
energy landscape, via ten-eleven translocation methylcytosine dioxygenase 1
(TET1), chromatin organisation, vesicle mediated transport in synapse and
cell-cell adhesion gene ontology (GO) categories, and via overall reduction of
the allostatic load; activation of 5HT2A-R and protection against reactive
oxygen species (ROS) and stimulation of mitochondrial biogenesis increasing
availability of adenosine triphosphate (ATP) via upregulation of Sirtuin-1
(SIRT1); sympathovagal coactivation; long-lasting antidepressive action via
reduced metalloproteinase-9 (MMP-9); amelioration of AD, TBI and ischemia via
restoration of neuronal Sigma-1 receptor-mediated endoplasmic
reticulum-mitochondria crosstalk, 5-HT, dopamine, adrenergic, and trace amine
receptors; anti-inflammatory action and protection against (inter alia) fluorosis-induced
metalloproteinases -2 and -9 via TIMP2; anti-inflammatory inhibition of TNF-α
and IL-1β, lowered IL-6 and COX-2 concentrations in macrophage cells, and
increased IL-10; anti-allergenic and anti-inflammatory reduction of arginase 1
(Arg1) and chitinase; enhanced chromatin accessibility, energy homeostasis, and
DNA damage repair via increased expression of metallothionein (MT) family genes,
elevated nuclear ubiquitous casein and cyclin-dependent kinases substrate
(NUCKS1); actin binding activity regulating the actin-myosin interaction of
smooth muscle via myosin light chain kinase 2 (Myl2); reduced infection,
infectivity and death due to SARS-Covid via inhibition of Mprotease and IL-6 by
psilacetin, psilocin, and psilocybine; decreased network modularity and
decreased axial diffusivity in prefrontal-subcortical tracts; weakened
hierarchicalism in directed connectivity with increased balance between senders
and receivers of neural signalling; anti-diabetogenic action via or associated
with elevated connectivity in the precuneus/posterior cingulate cortex and a
higher default mode network resting-state, and via suppression of TNF-α and
other cytokines such as IL-6 and IL-12; increased markers of neuroplasticity
growth associated protein 43 (GAP43), postsynaptic density protein 95 (PSD95),
synaptophysin, and synaptic vesicle protein 2A (SV2A); increased neuroplasticity
via reduced binding to receptor-type tyrosine-protein phosphatase S (PTPσ) in
somatic, dendritic and initial segments of parvalbumin (PV+) containing
interneuron axons, reduced TRKB endocytosis via inhibition of interaction of
adaptor protein-2 (AP-2) with TRKB, increasing translocation of TRKB to the
plasma membrane; increased synaptic plasticity via inhibition of glycogen
synthase kinase-3-beta (GSK3β); neuroplastogenic effects in brain areas with high 5-HT2A
receptor density, a decrease of cell surface-located 5-HT2A receptors first in
the axonal followed by the somatodendritic-compartment, increased excitatory
postsynaptic potential (EPSP), elevated miniature excitatory postsynaptic
currents (mEPSCs) from pyramidal neurons, 5-HT2A receptor internalization and
redistribution in human cortical neurons, upregulation of neocortical
plasticity-related genes, enhanced long term memory via increased neuronal
activation-induced expression of immediate-early genes (IEGs) via upregulation
of cyclin-dependent kinase (CDK7), promotion of the growth of synapses, branching,
stability, and long-lasting dendritic spine density, increased plasticity in the
prefrontal cortex (PFC), enrichment of significantly affected genes in many
ontologies and pathways associated with axonal growth and synaptic remodeling,
plasticity and learning, memory and congnition, increased phosphorylation of the
BDNF receptor TrkB, and AKT at Ser473, increased total neurite length, increased
glutamate signaling in the PFC, antinociceptive action via upregulation of genes
that suppress inflammation via tumour necrosis factor alpha (TNF-α), ameliorated
stress-related behavioral deficit via secretion of corticotropin-releasing
factor (CRF), HPA-axis activation, transient elevation of plasma
glucocorticoids, and changes in glucocorticoid concentration profiles over time,
upregulation of the Arc gene in the whole cortex, as well as in the parietal
cortex specifically, upregulated c-Fos in most cortical regions including
sensory visual, auditory, somatosensory, and gustatory areas, motor and
association areas, the anterior cingulate cortex (ACC), and the insula, in the
claustrum, locus ceruleus, lateral habenula and some areas of the thalamus,
amygdala, and brainstem; potential amelioration of compulsive eating via
selective effects on deep-layer cortical neurons in the context of predictive
coding of expectations about sensory experience including stimulus-reward
predictions; direct antinociceptive action of CBD via S296 in the
third transmembrane domain of α3 glycine receptors (GlyR), with reduced
downstream ADAM metallopeptidase domain 17 (ADAM17), increased surface
expression and activation of TNFα receptor 1 (TNFR1) and associated NF-kB
pathway, increased expression in Purkinje neurons of tumour necrosis factor
TNFa, interleukin 1-b (IL-1b), high mobility group box 1 protein (HMGB1), and
glutaminase, increased extracellular glutamate, and potentiated microglial
activation via HMGB1; increased presynaptic density in both the hippocampus and
the PFC, increased dendritic spine size in frontal cortical pyramidal cells,
with elevated excitatory neurotransmission, and strengthened cortico-hippocampal
synapses; reduced low frequency oscillatory power, increased overall firing
rates and desynchronized local neural activity; the opportunity to have a
life-changing ontological shock if desired or necessary;
restoration of
executive control and reduction of alcohol craving and relapse via elevated
mGlu2; increased fear
extinction and neurogenesis; via enhancement of adult hippocampal neurogenesis
(AHN), reduced impairment with age of spatial learning, pattern separation for
memory encoding and retrieval, contextual fear conditioning, cognitive
flexibility, and mood regulation; increased neurite outgrowth, dendritogenesis,
spinogenesis and synaptogenesis, 5-HT-independent allosteric enhancement of BDNF
signalling; the ability to explore panpsychist and less materialistic
philosophical viewpoints, to increase the Lempel-Ziv complexity of cortical
activity while reducing the chaoticity of low-frequency cortical
electrodynamics, and increasing global integration in the brain; increased
musical performance ability; increased music-induced imagery via changes in
parahippocampal connectivity and increased music-evoked emotion; increased
musical appreciation with a rise of EEG alpha percentage and power in parietal
cortex, differences in the right fronto-temporal cortex on theta, and on alpha
in left occipital cortex, and via relative increases in amplitude of low
frequency fluctuations (ALFF) in the bilateral superior temporal lobes and
supramarginal gyrus, and relative decreases in the medial frontal lobes for the
resting-state; the possibility of increased creativity, novelty, surprise,
originality and semantic distances even at the expense of decreased
'organization', active coping mediated by 5-HT2AR signaling, increased divergent
thinking and symbolic thinking; in post-traumatic stress of child maltreatment
subtypes neglect and emotional abuse, reduced internalized shame and complex
trauma symptoms; improved wellbeing in anorexia nervosa; in anosmia or
microsmia, improved or restored olfaction following Covid-19 and otherwise; in
personality disorders, reduced suicidal behavior, anxiety and depression,
increased cognitive flexibility and sustained increases in cognitive
reappraisal; reopening of the social reward learning critical period
proportional to the duration of acute subjective effects, paralleled by
metaplastic restoration of oxytocin-mediated long-term depression in the NAc,
differentially expressed genes and reorganization of the extracellular matrix in
the open state versus the closed state; increased satisfaction with one's
partner and physical appearance; a metaphysical idealism-mediated link with
wellbeing; increased insightfulness; increased perceived health, inclusive
identity, mindfulness, equanimity, altruism, awe, elevation, kindness,
self-kindness, positive affect, benefit reminding, perceived support, meaning in
life, life satisfaction, improved perceived health, health-motivated behavioural
choices, and sleep; positive changes in attitudes and behavior; universal but
baseline sleep disturbance-dependent reduction in sleep disturbance and
depression; reduced delusional ideation; reduced authoritarianism, anxiety,
depression, helplessness, boredom, pain perception, pandemic fear, negative
affect, greed, envy and hate; increased nature-relatedness and ecological
concern for planetary health; increased physical activity, ecological and
dietary awareness, gardening, petition signing, philanthropic donation giving,
eco-activity, animal adoption, and environmentally-inspired career change;
enhanced search and rescue abilities.
Benedictions common to both cannabis and to classical
psychedelics at the community level additionally include enhanced executive
function and improved performance in the Wisconsin Card Sorting Test (WCST);
increased forgiveness, gratitude, humility, sense of connection,
self-transcendence; lower laughter threshold; being full of ideas, raised
hedonic tone, sensory receptivity and intelligent coping elevated via dendritic
branching and density; via alcohol reduction, amelioration or substitution,
reductions in crystalline intrusion in liver
mitochondria, impairment of mitochondrial oxidative phosphorylation,
megamitochondria, serum markers of lipid peroxidation such as conjugated dienes,
malondialdehyde (MDA), 4-hydroxynonenal and F2-isoprostanes, reduced fat liver
infiltration, focal necrosis and fibrosis, hydroxyl radicals, membrane
permeability, impaired membrane function, collapse of mitochondrial membrane
potential, onset of mitochondrial permeability transition (MPT), reduced
sensitivity of the electron transport chain to inhibition by oxidative stress
and its downstream effects upon mitochondrial DNA (mtDNA); prevention of
preconception paternal alcohol effects in offspring such as pre- and post-natal
growth reduction, delayed parturition, and degraded long-term metabolic
programming in offspring; alcohol-substitution-mediated reductions in secondhand
harms, homicide, especially drug law-related homicides, suicidality,
larceny/theft, assault, property crime, violent crime, intimate partner violence
(IPV) and other criminal behaviour, as marked by elevation of BDNF; reduced
susceptibility to dementia (AD) as marked by elevated BDNF; faster and more
responsive positive hedonic effects than antidepressants; via substitution for
antidepressants, avoidance of penile fibrosis, impotence and post-SSRI sexual
disorder (PSSD), postpartum haemmorhage, reduction or elimination of suicidal ideation, completed
suicide, homicidal ideation and homicide, anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, violence,
imprisonment, akathisia (psychomotor restlessness), hypomania, mania, gun shot
wounds, fractures, tardive dyskenesia, insomnia, screaming, apathy, and in
incident dementia faster cognitive decline, increased risk of severe dementia,
and death; via substitution for antidepressants in Tyr129Ser, rs1176744 HTR3 SNP
subjects, reduction in cocaine addiction; reduction in tobacco use, morbidity,
mortality and associated costs; increased conscientiousness; positive
differences in self-perceptions of sexual function and wellbeing, experienced
pleasure, sexual satisfaction, arousal, communication of sexual desires,
importance of sex, and body image; reduction in crime via amelioration of autism
symptomology including increased communicative skills, attention, learning, eye
contact, diminished aggression, irritability, and allotriophagy, and an overall increase in both
the patient’s and family’s quality of life; alcohol-substitution mediated
reductions in vitamins A, B, C, D, E, K, and calcium, magnesium, iron, and zinc
deficiencies; alcohol-substitution- and BMI-mediated reductions in cancer;
alcohol-substitution-mediated reductions in pre- and post-conception teratogenic
effects including intergenerational autism and psychosis; increased testicle
volume; reduced absenteeism, pro-economic effects on property damage, police and
justice services, and the medical insurance system; antinociceptive effects;
increased longevity via CR-mimesis, including deacetylation of histones and
non-histone proteins such as transcription factor nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-kB), silencing of ApoB
protein (Apolipoprotein B) resulting in lowered serum cholesterol and
low-density lipoprotein, mediating calorie-restricted (CR) life span extension
in a NAD+-dependent manner, silencing at the mating type loci, telomeres, and
rDNA loci, repressed transcription of cryptic mating type loci (HML and HMR),
enhanced long-term potentiation (LTP) via sirtuin suppression of miR-134;
enhanced sirtuin-based telomere maintenance with the help of telomere binding
proteins, increased stress resistance through regulation of the
tumour-suppressor protein p53 and the fork head box O gene FOXO3a; improved odds
of increased lifespan associated with complete blood count and telomere
investigations, and with the improved situational awareness improved acuity
brings; increased music appreciation; the in aperto foro model offers a health
regimen achievable with a strategy of the individual's own choosing, without his
or her health decisions being overruled or ruled over by commercial interests -
neither via the government or the courts - specifically those who have no
information about, stake or interest in positive individual health outcomes, and
whose often dubious advice has not been sought by the user. The user thus enjoys
the right to patient autonomy, starting with not being involuntarily designated
as a patient. With personal autonomy, resilience and responsibility for
self-maintenance are enhanced. The cost of ill health and addiction, including
addiction to pharmaceutical medicines, is reduced via both nutraceutical and
sociocultural pathways. Via enhancement of adaptability in an ever-changing
environment, the behaviour of those using these drugs is empirically determined
to be more, not less, appropriate. Finally both cannabis and psychedelics may
act via placebo effects.
Last updated 21 April 2025.