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, neutrophilic, anti-inflammatory, antiviral,
antioxidant, antihypertensive, antisteatotic, anti-ischemic, cardioprotective,
myelinogenic, antiamyloidogenic, antigliomagenic, neuroprotective,
antifibrogenic, anti-arthritic, osteogenic, antipyretic, antinociceptive,
probiotic, anti-emetic, 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;
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 hippocampal neurogenesis via direct action on CB1R in neural
stem/progenitor cells (NS/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
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 (GPX4); 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 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
peroxisome proliferator activated receptor γ (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 TNF-α, 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; 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); 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); 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 myocardial infarction; 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; 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); 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 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), tumour necrosis factor aplha
(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
tumour necrosis factor alpha (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 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 and reductions in their adverse effect in the GI microbiome and
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; 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; 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; 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, 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, inflammatory cell infiltration, bone destruction, and
anti-collagen type II immunoglobulin G (anti-CII IgG1) production; 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 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; inhibition of SARS-CoV-2 replication by inter alia
up-regulation of host IRE1α ribonuclease ER stress response and interferon
signaling pathways, 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,
in-hospital cardiac arrest and mortality (2.9% vs 13.5%), 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 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; protection against long Covid and improved blood-brain barrier integrity
via reduced 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; enhanced executive function;
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; 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; 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; 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; 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, and increased glucose-dependent
insulinotropic peptide; 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; 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; raised ability to
work, lower PTSD checklist score (PCL) 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 via restoration of
neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk;
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; 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, 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; 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; 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 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, 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 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), 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, and apathy; via substitution for antidepressants in
Tyr129Ser, rs1176744 HTR3 SNP subjects, reduction in cocaine addiction;
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 and
irritability, 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 5 February 2025.