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, antiparasitic, antioxidant, antihypertensive,
antisteatotic, anti-ischemic, cardioprotective, myelinogenic, antiamyloidogenic,
antigliomagenic, anti-epileptic, neuroprotective, geroprotective,
antifibrogenic, anti-arthritic, osteogenic, antiosteopenic, antiosteonecrotic,
proconceptive, pro-hematopoietic, antipyretic, antinociceptive, antiallodynic, antitussive,
antibiotic, probiotic, antipruritic, antixerotic, anti-emetic, antidiarrheal,
anti-choleric, antidysenteric, antidepressive, anxiolytic, antipsychotic,
neurogenic, nootropic, anti-aging, anti-addiction (cocaine, alcohol,
methamphetamine, 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); in urothelial cancer, cell cycle arrest
and cell apoptosis, inhibition of cell migration and disintegration of F-actin;
reduction of alcohol craving via lower bilateral cue-induced nucleus accumbens
(NAc) activation; reduction of alcohol intake via neuropeptide S receptor
(NPSR), and chemokine receptor type-4 (CXCR4); reduction of obsessive craving in
addiction withdrawal and of alpha-synucleopathies via inhibition of
alpha-synuclein (aSyn, formerly NACP, non-amyloid component of plaque),
preventive effects on the reinstatement of reward-seeking behavior via D2-like
dopamine receptors in the CA1 region of the hippocampus, with shortened
extinction period; 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, restoration of splicing defects induced by Aβ in differential alternative
splicing events (DASEs); via up-regulated nicastrin (Nct) expression and
enhanced Notch-1 signaling increased IQ via resistance to inter alia
neurofluorosis, plus reduced T-cell acute lymphoblastic leukemia via activating
transcription factor (ATF4)-C/EBP Homologous Protein (CHOP)-ChaC glutathione
specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling by Ca2+ depletion
and ER stress, cerebral autosomal-dominant arteriopathy with sub-cortical
infarcts and leukoencephalopathy (CADASIL), multiple sclerosis (MS), tetralogy
of Fallot (TOF, formerly Steno-Fallot tetralogy), Alagille syndrome and
amelioration of other conditions of Notch aberration; anti-Aβ aggregation
activity via direct THC interaction with Aβ peptide fibril formation and
aggregation, and by CBD via the ROS scavenging activity of its phenolic hydroxyl
groups; 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; in AD prevention or treatment via anti-AChE and
anti-butyrylcholinesterase (BuChE) activity, reduced hepatotoxicity,
gastrointestinal disorders compared with Rivastigmine and Galantamine, avoidance
of human ether-a-go-go-related gene (hERG) inhibition and therefore reduced
ventricular arrhythmia compared to Donepezil, and lower LD50 than all three
drugs; 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 polyunsaturated fatty acids (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; in
autism spectrum disorder (ASD), CB1R-activated amelioration of synaptic
dysfunction, including neuronal complexity, spine density, dendritic integrity,
synaptic protein expression, neuronal damage, and enhanced expression and
current density of Kir4.1, enhanced social responsiveness and reduced disruptive
behaviour and psychomotor agitation; a 19% reduction in long term cognitive decline measured by IQ; a 96%
reduction in subjective cognitive decline (SCD); in Rett Syndrome, improved
Clinical Global Impression-Improvement (CGI-I) total score, communication
skills, mental alertness, socialisation/eye contact, attentiveness, and anxiety,
Clinical Global Impression-Severity (CGI-S) score, RTT Behaviour Questionnaire
(RSBQ) total score, general mood, breathing problems, repetitive face movements,
fear/anxiety, ability to communicate choices in RTT-Domain-Specific
Concerns-Visual-Analog Scale (RTT-DSC-VAS), Impact of Childhood Neurological
Disability/Quality of Life (ICND+QoL) total score, cognition, and total score on
RTT-Caregiver Burden Inventory (RTT-CBI); 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); in spinal injury, decreased proinflammatory
cytokines, and suppression of astrocyte/microglia glial fibrillary acidic
protein and ionized calcium-binding adapter molecule 1 (GFAP/Iba1) activation,
proapoptotic proteins Bax and caspase 3, promotion of microglial polarization
toward the anti-inflammatory M2 phenotype, regulation of excitatory and
inhibitory neuronal balance, increased anti-apoptotic protein Bcl-2, enhanced
antioxidant defense via upregulated superoxide dismutase (SOD), and glutathione
(GSH), lower malondialdehyde (MDA), activation of nuclear factor erythroid-2
related factor 2 (Nrf2) signaling pathway, and improved motor function;
increased Aβ degradation by endopeptidase neprilysin; prevention of AD via
downregulated expression of proteins involved in tau phosphorylation and Aβ
production in mesenchymal stem cells (MSCs); anti-AD effects via reduction of
triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E4
(APOEε4), and direct interaction with Tau;
competition with heparin at VQIINK/VQIVYK motifs, rescue of Wnt/β-catenin
signaling, attenuation of Aβ-induced reductions in calbindin and tubulin;
decreased expression of genes
related to the formation of the γ-secretase complex including aph-1 homologue A
(APH1A), presenilin 1 and 2 genes (PSEN1 and PSEN2), presenilin enhancer
(PSENEN), nicastrin (NCSTN), and beta-secretase 1 (BACE1),
giving anti-early and late onset Alzheimer's Disease (AD) protection, and of
proteasome subunit beta (PSMB), calpain 1
(CAPN1) and 2 (CAPN2) cyclin dependent kinase 5 (CDK5), cyclin dependent kinase
5 regulatory subunit 1 (CDK5R1) genes, AChE and BChE;
improved memory impairment at advanced stages
of the AD pathology, improved scores in the Alzheimer’s Mini-Mental State
Examination (MMSE), and Alzheimer’s Disease Assessment Scale-Cognitive
(ADAS-Cog) scale; rescue of synaptic function via reduction in metabotropic
glutamate receptor 2/3 (mGluR2/3), 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 (A1AR), increased
extracellular signal-regulated protein kinases 1 and 2 (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
(TJPs), reduced vascular cell adhesion molecule-1 (CADM1), and intercellular
adhesion molecule-1 (ICAM1 or CD54) 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 (CBRs),
including GPR18, CB2, and GPR55 [G protein-coupled receptor], cannabinoid
triggering of a transient vanilloid receptor type 4 (TRPV4) signalling pathway
including: 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 induction of
ferroptosis, integrated stress response activation, and epigenetic modulation,
with 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 modulating 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
induction of a basal-to-luminal switch, suppression of stemness, reduced
invasiveness and self-renewal via CB2R activation-initiated transient chromatin
remodeling, and epigenetic reprogramming, production of a stably differentiated
state, amplifying response to tamoxifen, 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 ICAM-1 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; in
exercise induced muscle damage (EIMD) induced delayed onset of muscle soreness
(DOMS) reduced soreness per visual analog scale (VAS) score; 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), 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 IL-4, IL-6, IL-8, IL-13, IL-17, IL-18, IL-22, IL-33, and tumour
necrosis factor alpha (TNFα), of activity of T and B-cells-mediated response,
and interferon-γ (IFN-γ), and modulated immune response via decreased activity
of T helper 17 (Th17) cells; in atopic dermatitis, antipruritic effects via
TRPV1 channels, increased antioxidant effects via NADPH oxidase (NOX), xanthine
oxidase (XO or XAO), and glutathione reductase (GR aka glutathione-disulfide
reductase, GSR), increased ceramide via stimulated sphingomyelinase activity,
increased aquaporin 3 (AQP3), modulation of janus kinases 1 and 2 (JAK1/2),
tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 1, 2,
and 3 (STAT1/2/3), phosphorylated STAT3 (p-STAT3), STAT6, reduced mRNA
expression levels of IL-1β, IL-4, IL-6, IL-8, IL-13, IL-17, reduced IL-5, thymic
stromal lymphopoietin (TSLP), monocyte chemotactic protein-1 (MCP-1),
macrophage-derived chemokine (MDC), regulated on activation, normal T-cell
expressed and secreted, (RANTES, aka CCL5), reduced production of CCL2, CCL8,
CXL10, and CCL26, reduced dermatitis severity scores and visual severity,
thinner epidermal layers, and fewer mast cells, thymus and activation-regulated
chemokine (TARC), improved skin hydration, intracellular filaggrin and
involucrin, decreased intracellular ROS, MAPK activation, translocation of NF-κB
to the nucleus, NF-κB and p-NF-κB in the nucleus, p-IκBα in cytoplasm,
phosphorylated JAK1 phosphorylated STAT6, sebum level, transepidermal water loss
[TEWL], and erythema, via antimicrobial effects, and via substitution avoidance
of side-effects from corticosteroid topical treatment, and of side-effects of
JAK4 inhibitors and other systemic approaches; reversal of acne pathophysiology
via anti-inflammatory, apoptotic, and lipid-inhibitory effects, upregulation of
elastin synthesis, collagens 1 and 3, increased apoptotic area, reduced lipid
synthesis via the AMP-activated protein kinase, and sterol regulatory
element-binding protein (AMPK-SREBP-1) pathway, and reduced sebum, CXCL8, IL-1α,
IL-1β, and hyperkeratinization-related protein keratin 16 (Krt16); in rosacea
inhibition of redness, epidermal thickness, and mast cell infiltration,
suppression of key inflammatory regulators in the MAPK signaling pathway,
particularly the ERK, JNK, and p38 pathways, and reduction in proinflammatory
cytokines, and chemokines; prophylactically and post-injury accelerated wound
healing with altered timing and quantity of infiltrating immune cells, increased
infiltration of M1-macrophages and MSCs, elevated granulocyte count, and
decreased levels of inflammatory cytokines; 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; inhibition of
growth and biofilm formation of Streptococcus iniae, with DNA leakage, impaired
cell membrane integrity, hyperpolarized membrane potential, and reduced
respiratory chain dehydrogenase activity; 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), 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; reduction of Covid-induced liver
injury (CiLi) via assisted mitochondrial biogenesis; in stress-induced liver
injury, enhanced CB2R and SLC7A11 protein expression, increased SOD, and
glutathione peroxidase (GSH-Px or GPX), decreases in aspartate aminotransferase
(AST), alanine aminotransferase (ALT), IL-1β, tumour necrosis factor-alpha
(TNF-α), alpha-smooth muscle actin (α-SMA), mitigation of fibrosis, decreased
Acyl-CoA synthetase long-chain family member 4 (ACSL4), and improved
mitochondrial morphology indicating a reduction in oxidative cell death;
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, upregulation 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,
including intergenerationally via altered miR10a and tDR-Glu-CTC in F1 sons of
obese fathers who impart glucose intolerance to the F2 male descendants, 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- (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 or high-sucrose diet, hepatic triglyceride content, uric acid,
alkaline phosphatase, acetyl CoA carboxylase (ACC), fatty acid synthase (FAS),
malic enzyme (ME), glucose-6-phosphate dehydrogenase (G-6-P DH), and steatosis
score, fewer gallstones, reduced levels of tenascin C (TNC), alanine
aminotransferase (ALT), aspartate aminotransferase (AST), alanine peroxidase
(ALP), malondialdehyde (MDA), reactive oxygen species (ROS), thiobarbituric acid
reactive substance (TBARS), and abundance of hepatic lipid droplets, improved
carnitine palmitoyltransferase-1 (CPT-1) level, increased levels of glutathione
peroxidase (GPX), increased reduction of GSH, 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 of 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
raised 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 AD, 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, reduced abdominal girth,
systolic and diastolic blood pressure, and total and LDL cholesterol, 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); anti-ischaemic
cardioprotective effects against heat stress via cannabinoid receptor agonism;
reduced infarct size; 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; via
substitution for statins, improved cognition; 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 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 ICAM-1, 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),
interleukins 12-p40 and -p70 (IL12-p40, IL12-p70), 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
functional connectivity (FC) between the anterior cerebellum and both
hippocampus and posterior parahippocampal cortex (pPaHC), between pPaHC cortex
and lobule IV/V and vermis IV/V, between hippocampus and vermis IV/V and
cerebellar lobule III, between subcortical and sensorimotor regions, and between
subcortical and cerebellar areas, superior performance across multiple cognitive
domains, presented concurrently across a range of brain systems, brain network
characteristics typically associated with younger brains, enhanced cognitive
abilities, with reduced oxidative stress via reduced gene expression of catalase
(CAT); TXNRD1, glutathione s-transferase mu 2 (GSTM2), peroxiredoxin 3 (PRDX3),
superoxide dismutases 1 and 2 (SOD1/2), 4-Hydroxynonenal (4-HNE), and
glycoprotein 91-kDa phagocyte oxidase (Gp91phox, aka NOX2); increased FC in the
bilateral anterior insula (bAI), 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; 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); in ulcerative colitis (UC) increased goblet cells,
colon length, colonic Gram-negative bacteria, and microbiome-independent
anti-colitic effects in enterocytes and immune cells, upregulation of Mucin 2,
oligomeric mucus gel-forming (MUC2), reduced UC-associated proxy measures of
abdominal pain and Mucin-5AC (MUC-5AC), downregulation of TH1 and TH17; antifibrotic action in
colitis via classical NF-κb pathway, Nrf2/ heme oxygenase-1 (HO-1) pathway, and
transforming growth factor beta (TGF-β)/SMAD pathway by regulation of Nrf2, via
inhibition of expression of alpha-smooth muscle actin (α-SMA), Collagen1, tissue
inhibitor of metalloproteinases (TIMP1), and other factors; 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
beta defensin 2 (MBD2), secretory leukocyte peptidase inhibitor (SLPI), tight
junction proteins including claudin (CLDN1), Zonula Occludens-1 (ZO-1), 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, Bacillus cereus, Vibrio cholerae, Escherichia coli, Staphylococcus
aureus, and Staphylococcus epidermidis 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; synergism with antibiotics in drug-resistant Acinetobacter
baumannii, reduced biofilm biomass and biofilm viability, increased DNA leakage,
extracellular protein release, protein leakage, and membrane disruption; broad
antifungal activity via membrane biogenesis and stability, pyrimidine synthesis
pathway, ergosterol biosynthesis pathway, pentose phosphate pathway, inositol
pathway, and membrane and mitochondrial proteins, efficacy against jock itch and
athlete's foot; up to 100% reduction in cell viability in protoscoleces and
cysts of Echinococcus granulosus sensu stricto; adverse effects on cell wall and
membrane structure in gram-positive bacteria Bacillus licheniformis,
Staphylococcus aureus, and Enterococcus faecium; 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; pleiotropic gene association-based reductions in
attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), bipolar
disorder (BIP), major depressive disorder (MDD), posttraumatic stress disorder
(PTSD), and schizophrenia (SCZ) via amelioration of gastroesophageal reflux
disease (GERD), (IBD), irritable bowel syndrome (IBS), and peptic ulcers disease
(PUD); 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;
anti-tumorigenic induction of pyroptosis via the caspase-3/Gasdermin E (GSDME)
axis, reduction of aerobic glycolysis through the ATF4-insulin-like growth
factor binding protein 1 (IGFBP1)-Akt pathway; 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; post-stroke
improvement in neurological deficits, reduction in body mass, decrease in blood
cells related to the immune response, and atrophy of lymphoid organs, lower
corticosterone levels, and reduced intestinal permeability, with protection
against oxidative stress and post-stroke lung inflammation; 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 chest trauma amelioration of tumor necrosis factor α, caspase-3, caspase-9,
Bcl-2-associated X protein expressions, total oxidant status, oxidative stress
index levels, decreased B-cell lymphoma expression, total antioxidant levels,
inflammatory cell infiltration, damage-related emphysema, pronounced hyperemia,
and increased septal tissue thickness; 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; reduced HIV anti-retroviral drug
resistance mutations and lower odds of high viremia; 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 peripheral blood
mononuclear cells (PBMCs), inhibition of TLR7/8-induced nuclear factor of kappa
light polypeptide gene enhancer in B-cells inhibitor alpha [IκB-α aka NFKBIA]
degradation and phospho-p38 in macrophages, upregulation of interferon regulator
factor 7 (IRF7), 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; reduced obesity via nucleobindin-2
(NUCB2), and nesfatin-1; via reduced obesity, a reduced prevalence of MS; in MS,
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, improvements in spasticity, urine bladder
dysfunction, disability progression rate per the Modified Ashworth Scale (MAS),
the Post Void Residual (PVR) volume, and the Expanded Disability Status Scale
(EDSS); 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; antiosteoarthritic via
inhibition of nuclear factor erythroid 2-related factor/heme oxygenase-1
(Nrf2/HO-1) signaling pathways by binding to NF-κB essential modulator/inhibitor
of κB Kinase subunit beta (NEMO/IKKβ), and kelch-like ECH-associated protein 1
(Keap1) target proteins, suppression NF-κB signaling pathway activation via
activation of Nrf2 in chondrocytes, inhibition of bone anabolism, mitigation of
articular cartilage hyperplasia and wear, and reduced Mankin score; 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 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 fibromyalgia increased tolerance to pressure in kgf/cm2,
increased tolerance and lower perception threshold to electrical pain, improved
modified-modified Schober test of lumbar flexion, improved scores in
Fibromyalgia Assessment Status (FAS), Fibromyalgia Impact Questionnaire
(FIQ) and its revised (FIQR) and Italian versions,
Fibromyalgia Symptom Severity (combining widespread pain index (WPI) and
(Symptom) Severity Score (SS/SSS), Quality-of-Life Impairment by Pain (QLIP),
Oswestry Disability Index (ODI), Functional Assessment of Chronic Illness
Therapy (FACIT), Patients' Global Impression of Change (PGIC), General Anxiety
Disorder Scale (GAD-7), Pain Disability Index (PDI), 6-point Verbal Rating Scale
(VRS-6) for pain intensity, Pain by Visual Analogue Scale (VAS), stiffness by
VAS, relaxation by VAS, somnolence by VAS, perception of well-being by VAS,
11-point Numeric Rating Scale (NRS), Zung Self-Rating Anxiety Scale (ZS-RA),
Zung Self-Rating Depression Scale (ZS-RD), Hospital Anxiety and Depression Scale
(HADS), Health-Related Quality of Life Measure with EuroQol 5 Dimension, Medical
outcome survey short form (MOS SF-36), McGill Pain Questionnaire (MPQ), Adjusted
Short-form Profile of Mood States/Leeds Sleep Evaluation Questionnaire (LSEQ),
Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Quality of
Life on the Likert scale, global assessment on the Likert scale, with decreased
number of positive tender points, and standard analgesic treatment; in fibromyalgia-associated upper and lower gastrointestinal (GI)
symptoms, reduced log-transformed FIQR score, epigastric pain, epigastric burning, abdominal pain, abdominal
distension, and bloating; 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), and PGIC; 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; anti-osteosarcomogenic activity via
TNF-α/NF-κB/CCL5 axis disruption with direct binding of p65, attenuated
NF-κB-mediated transcriptional activation of CCL5, abrogation of the p65-CCL5
positive feedback loop; in periodontitis, enhanced bone remodeling, osteogenic
differentiation via activation of ERK1/2; in fracture healing, upregulated
osteoblastic mRNA levels of the lysyl hydroxylase PLOD2, transient enhancement
of cartilaginous callus resorption, and increased work-to-failure; protection of
bone marrow against ionizing radiation via restored reconstitution capacity of
hematopoietic stem cells, increased expression levels of stemness-related genes
in Wnt and BMP signaling pathways, via upregulation of activating transcription
factor 2 (ATF2), and low-density lipoprotein receptor-related protein 6 (LRP6);
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); pre-emptive amelioration of inflammaging induced by
microplastics and nanoplastics (MNPs), and by per- and polyfluoroalkane
substances (PFAS) via interleukin-18 (IL-18), IL-1β, TNF-α, and IL-6;
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, 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 angiotensin converting enzyme 2 (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 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 (CRP), ferritin, D-dimer, and procalcitonin
(PCT), 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-1β, IL-18, 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), 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), IL-6, phosphorylation of STAT3,
phosphorylation of tyrosine kinase-2 (TYK2), 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); suppression of toll-like receptor
(TLR) 7– and TLR8-mediated interleukin-1β production by CD16+ monocytes via
inhibition of post-translational maturation; improved long Covid, cancer, and
diabetes outcomes via elevated soluble interleukin-6 receptor (sIL-6R)
activation by β-receptor glycoprotein 130 (gp130, bound as spg130), and elevated
Src homology 2 domain-containing tyrosine phosphatase 2 (SHP1); based on inverse
molecular docking fingerprinting potential prophylactic and ameliorative
activity in cancer, AD, Parkinson's disease (PD), inflammation,
arthritis, diabetes, coagulopathies, disorders of phagocytosis, and
complement-driven diseases via hematopoietic cell kinase (HCK), GTPase Kras,
serine/threonine-protein kinase (PIM-1), ubiquitin-conjugating enzyme E2 N
(UBE2N), cAMP-specific 3',5'-cyclic phosphodiesterase 4B (PDE4B),
cyclin-dependent kinase 2, estrogen receptor, histone-lysine N-methyltransferase
(EHMT1, aka euchromatic histone methyltransferase 1 or GLP (G9a-like protein)),
coactivator-associated arginine methyltransferase (CARM1), N-lysine
methyltransferase (KMT5A), pyruvate kinase isozyme M2 (PKM2), glycogen
phosphorylase liver form (PYGL), fructose-1,6-bisphosphate 1 (FBP1),
interstitial collagenase (MMP1), collagenase 3 (MMP13), stromelysin-1 (MMP3),
matrix metalloproteinase-9 (MMP9), E-cadherin, macrophage metalloelastase
(MMP12), amine oxidase (flavin-containing) B (MAO-B), beta-secretase 1 (BACE1),
coagulation factor X (FX aka Stuart factor), and complement factor D (FD);
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; in Tourette's
Syndrome, improved scores for Yale Global Tic Severity Scale (YGTSS),
Premonitory Urge for Tics Scale (PUTS), and Yale-Brown Obsessive Compulsive
Scale (Y-BOCS); in obsessive compulsive disorder (OCD), improved quality of
life, general health, mood/depression, and sleep quality, reduced anxiety per
GAD-7; 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, suppression of motif
chemokine receptors 4 and 7 (CXCR4/CXCR7) expression, and of matrix
metalloproteinases (MMP-2/9), reduced migration and invasion in MIA PaCa-2,
PANC-1, and AsPC-1 cells, reversal of CXCL12-induced epithelial–mesenchymal
transition (EMT) via downregulation of mesenchymal markers and restoration of
epithelial markers, inhibition of expression of metastasis associated lung
adenocarcinoma transcript 1 (MALAT1, aka nuclear-enriched abundant transcript 2
(NEAT2)), activation of the PI3K/Akt/mTOR pathway, decreased expression of
Bcl-2, epidermal growth factor receptor (EGFR), MIAPaCa-2, and mTOR protein,
nitrite, INF-γ, IL-10 in peritoneal macrophages, inhibition of cell viability
and clonogenic growth, reduced phospho-Akt (pAkt), total Akt, and decreased
phosphorylation, regulation of cell death pathways including apoptosis and
ferroptosis, and induction of the intrinsic apoptotic pathway via upregulation
of Bax; 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, via
disruption of the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 interaction,
and by inter alia β-caryophyllene (BCP)-induced reduction of oxidative stress,
neuroinflammation and apoptosis, and thereby also cardioprotective effects; in
PD improved results in Montreal Cognitive Assessment (MoCA) test, Insomnia
Severity Index (ISI), and Epworth sleepiness scale (ESS); in Huntington's
Disease (HD) restoration of structural synaptic alterations and impairment in
spatial, recognition and working memory; enhanced autophagosome expression via
GABA(A) receptor-associated protein (GABARAP/GABARAPL2/GATE-16 family) per
nematode ortholog LGG-1; 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 (CBF) (attenuated by
CBD), THC-driven increased cortical-hippocampal and cortical-striatal
connectivity, increased 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 multiple concussions (MCC), decreased mRNA expression of
PERK, eIF2α, and CHOP, and protein expressions of PERK, eIF2α, ATF4, CHOP,
TRIB3, p-AKT, and pro-caspase-3 in the cerebral cortex, and increased expression
of p-Akt; 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 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; promotion of
resilience via astrocytic cannabinoid receptor 1 dampening of stress-induced
blood–brain barrier alterations; 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; increased sleep duration, more slow-wave sleep, reduced
insomnia and better quality sleep with increased REM latency; in hypertension,
improved Epworth sleepiness scale (ESS); via improved sleep or other mechanisms,
a 26% lower prevalence of cardiovascular disease, increased longevity, reduced
adverse effects on circadian rhythms via genes period circadian protein homologs
1, 2, and 3 (PER1, PER2, PER3), cryptochrome circadian regulator 2 (CRY2),
circadian locomotor output cycles kaput (CLOCK), nuclear receptor subfamily 1
group D member 1 and 2 (NR1D1, NR1D2), retinoic acid-related Orphan Receptor A
(RORA), deleted in esophageal cancer 1 (DEC1), casein kinase I isoform epsilon
(CSNK1E), sleep homeostasis via IL6, signal transducer and activator of
transcription 3 (STAT3), Potassium Voltage-gated channel modifier subfamily V
member 2 (KCNV2), calcium/calmodulin dependent protein kinase II delta (CAMK2D),
oxidative stress via peroxiredoxins 2 and 5 (PRDX2, PRDX5), and metabolism via
solute carrier family 2 members 3 and 5 (SLC2A3, SLC2A5), ghrelin, and obestatin
prepropeptide (GHRL), and ATP-binding cassette transporter 1 (ABCA1), affecting
chromatin modification, gene-expression regulation, macromolecular metabolism,
and inflammatory, immune and stress responses; protection against sleep apnea,
with reduced anxiety, appetite lack, depression, disturbed sleep, fatigue,
nausea, pain, vomiting, and mortality; in refractory epilepsy, improved
health-related quality of life (HRQoL) patient-reported outcome measures
(PROMs); in temporal lobe epilepsy, suppressed formation of neurotoxic reactive
astrocytes, mitigation of gliosis, and reduced neuronal loss; reduced seizures
in Lennox-Gastaut syndrome (LGS), and Dravet syndrome (DS); protection against
cadmium and lead toxicity via improved levels of oxidation markers GSH, CAT,
myeloperoxidase (MPO), and inflammatory cytokines TNF-α, IL-1β, and IL-6,
ameliorated Cd-induced tissue damage in liver and kidney; reduction in
cobalt-triggered epileptic seizures; in chronic conditions, improvements in
Health-related quality of life (HRQL), and Short Form-36 Health Survey (SF-36)
score, pain, fatigue including on SF-36, sleep including on Pittsburgh Sleep
Quality Index (PSQI) score, anxiety, depression including Beck Depression
Inventory (BDI) score, and motor function; 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, and on the Barratt Impulsiveness
Scale (BIS-11); reduced workplace injuries and fatalities; reduced odds of motor
vehicle collisions; via substitution for alcohol, fewer hospital admissions in
6-hour post traffic accident ER visits with blood sample; 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 (IOP) via
CB1R activation, a pertussis toxin (PTx)-sensitive increase in phosphorylated
extracellular signal-regulated protein kinase (pERK), with a net inhibitory
inter-regulation of IOP with negative b2-adrenoceptor (b2AR) response,
neuroprotective, anti-inflammatory, and immunosuppressive effects on
autoimmunity in glaucoma, effects in glaucomatous neurodegeneration via
epigenetic changes in immune cells associated with autoimmunity, and effects via
the gut-retina axis, and Wnt signalling; relief of tinnitus symptoms including
dizziness, pain, and sleep disturbance, improved audio gating ratio; in
temporomandibular disorder (TMD) reduced pain, anxiety, and improved sleep;
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 via beclin-1 (BECN1), and sequestosome-1 (SQST-1, aka
ubiquitin-binding protein p62) gene-dependent promotion of autophagic flux in
hippocampal neurons; 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), IL-6, and 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)),
increased glucose-dependent insulinotropic peptide (GIP), and binding to
glucagon-like-peptide-1-receptor (GLP-1R); in obesity, lower plasma fasting
insulin (FINS), and homeostasis model assessment of insulin resistance
(HOMA-IR); antidiabetogenesis via high-calorific diet (HCD)-ameliorating reduced
body weight and food intake but increased fluid consumption, modified expression
for GPR55 receptor, glucagon, insulin and v-maf musculoaponeurotic fibrosarcoma
oncogene homolog A (MafA), decreased glycaemia, insulinaemia, islets relative
area, GPR55-positive cells, pancreatic and duodenal homeobox factor-1 (PDX-1);
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; in
allodynia reduced thermal, mechanical, and cold sensitivity; via CB1R
activation, modulation of pro-analgesic hyperpolarization-activated cyclic nucleotide-gated
channels 1 and 2 (HCN1, HCN2) in sensory neurons of the dorsal root ganglia
(DRG), reduced neuronal excitability, depletion of neurotransmitter release in
sensory neurons, stimulation of inhibition by GABAergic interneurons, or by
action on other channels; via GPR55 activation
ameliorated cognitive dysfunction, attenuated hippocampal neuroinflammation,
preserved synaptic plasticity, with shifted microglial polarization toward the
neuroprotective M2 phenotype, mitigation of neuroinflammatory cascades,
alleviating neuropathic pain-associated cognitive dysfunction through a
mechanism involving the calcium/calmodulin-dependent kinase beta
(CaMKKβ)/AMPK/SOCS3 signaling pathway;
amelioration of gastroparesis; antinociceptive properties in Rlick,
formalin-induced inflammatory pain, and cisplatin-induced peripheral neuropathy
models; 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, including via CB1R agonism in the oval
subnucleus of the bed nucleus of stria terminalis (ovBNST); 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 score, 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, higher placental
weight, placental-to-birth-weight ratio (PBWR), 2-fold neonatal intensive care
unit (NICU), placental weight, and umbilical cord length, 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; in pregnancy without substitutive use and via
reduction of stress acceleration, IL-6-inversely-associated higher socioeconomic
status (SES), lower neonatal corticospinal fractional anisotropy (FA), and
uncinate axial diffusivity (AD), IL-10-inversely associated lower FA and higher
radial diffusivity (RD) in corpus callosum and corticospinal tracts, higher
optic radiation RD, lower uncinate AD, lower FA in inferior fronto-occipital
fasciculus and anterior limb of internal capsule tracts, SES-moderated maternal
TNF-α levels during gestation and neonatal white matter diffusivity,
TNF-α-inversely-associated inferior cingulum AD; in neonatal hypoxia-ischemia
(HI) improved sensorimotor and neurodevelopmental reflex scores, hippocampal
ratio, myelin basic protein (MBP) ipsilateral-to-contralateral ratio, MBP
densitometry, white matter score in cingulum, and global neuropathological
score; 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; relief of
menstrual-related symptoms (MRS) with reduced scores on Greenhouse–Geisser
adjusted Menstrual-Related Symptom Questionnaire (MRSQ), on anxiety and stress
in Depression, Anxiety, and Stress Scale–21 (DASS-21), Brief Irritability Test
(BITe), and avoidance of multiple side-effects via substitution for ibuprofen;
in ovarian cancer (OC) disruption of ovarian cancer stem cell (OCSC)
homeostasis, associated Wnt/β-catenin pathway, aldehyde dehydrogenase (ALDH)
activity, PI3K/Akt, hedgehog/GLI (HH-GLI)- and NF-κB-dependent signaling
pathways, and BCL2- and ID-1-related processes, decreased fatty acid levels,
suppression of the transcription of genes involved in fatty acid uptake and
synthesis, activation of endoplasmic reticulum (ER) stress pathway, upregulation
of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) leading to G0-G1
phase arrest, and mitochondrial dysfunction in OC cells, and in HER2-positive
ovarian cancer, inhibition of HER2-tyrosine kinase; in prenatally cannabinoid
exposed (PCE) neonates, increased Mullen score 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,
reduction of generalisation via deactivation of GABAA receptors on pyramidal
neurons; fine-tuning of regulation of olfactory circuits and functional
discrimination in the retrieval of positively and negatively motivated olfactory
memories; in anosmia increased ACE2 activity and Angiotensin-(1-7), as decreased
Renin levels, decreased pro-inflammatory and increased anti-inflammatory
cytokines, reduced apoptosis and atrophy of olfactory circuitry, and reduced
corticosterone; 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, reduced avoidance, intrusions, hyperarousal,
self-care, usual activities, pain and discomfort, anxiety and depression,
patient global impression of change (PGIC), and impact of event scale – revised
(IES-R); higher educational attainment, directly and via substitution for
alcohol use; 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, with proconceptive
effects via prevention of untimely capacitation and acrosome reaction; 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) score, 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; extension of cellular lifespan,
with delayed exhaustion of proliferative potential, increased cumulative
population doublings, and decreased population doubling time, delayed onset and
reduced senescence, decreased beta-galactosidase (βgal) activity, reductions in
p21, and cyclin-dependent kinase inhibitor (p16), increased proliferating cell
nuclear antigen (PCNA), and retinoblastoma protein (pRB or Rb), preserved
telomere length, higher survival, phenotypic improvements in hair growth and
reductions in white hair; increased balance between senders and receivers of
neural signals; 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 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 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; enriched reactome pathways
related to axon guidance, cellular responses to stress, and cellular responses
to stimuli, including metabolism of RNA, cellular responses to stimuli,
Cap-dependent translation initiation, eukaryotic translation initiation,
cellular responses to stress, formation of a pool of free 40S subunits,
L13a-mediated translational silencing of ceruloplasmin expression,
guanosine-5'-triphosphate (GTP) hydrolysis and joining of the 60S ribosomal
subunit, axon guidance, eukaryotic translation elongation, peptide chain
elongation, processing of capped intron-containing pre-mRNA, nervous system
development, response of eukaryotic translation initiation factor 2 alpha kinase
4 (EIF2AK4 or GCN2) to amino acid deficiency, SRP-dependent cotranslational
protein targeting to membrane; 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 tropomyosin receptor kinase B (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, enhanced long
term memory via increased neuronal activation-induced expression of
immediate-early genes (IEGs) via upregulation of cyclin-dependent kinase (CDK7),
reduced Tau phosphorylation at Thr212 and Ser396 via inhibition of dual
specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), 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, enhanced DNA replication, axon guidance,
synaptic vesicle cycle, neurotransmitter release, plasticity, learning, memory
and cognition, improved visual memory consolidation and recall, increased
phosphorylation of the BDNF receptor TrkB, and AKT at Ser473, allosteric binding
to TRKB, BDNF upregulation but not TNF-α suppression via activation of aryl
hydrocarbon receptor (AhR), 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, relaxation of prior predictions via increased bottom-up information
flow, epigenetic modulation, ameliorated impairment of hypothalamic and
brainstem circuits responsible for satiety and reward processing, inhibition of
indoleamine 2,3-dioxygenase (IDO1), and tryptophan 2,3-dioxygenase (TDO),
restoration of gut barrier function via reduction of kynurenine production, and
decreased hippocampal kynurenine/5-HT ratio, decreased the gut microbiome
Shannon alpha diversity, and prevention of decreased Firmicutes:Bacteroidetes;
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,
restoration of vascular reactivity, and 5-HT-independent allosteric enhancement
of BDNF signalling; in Parkinson's Disease (PD), improved score in Movement
Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) non-motor
and motor symptoms, cognitive domains in Paired Associates Learning, Spatial
Working Memory, Probabilistic Reversal Learning, and MoCA test; 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;
greater hearing sensitivity and levels of state absorption, 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;
in PTSD/TBI EEGs reduced delta dominance particularly in frontal and temporal
regions, weakening of delta-beta correlations, improved filtering of irrelevant
stimuli and enhanced vigilance, of theta–alpha connectivity in cognitive and
emotional processing, of memory integration and affective regulation, improved
emotional regulation and processing control, normalisation of theta activity,
decreased alpha power in frontal and central regions, heightened attention and
improved cognitive processing directed towards emotional information, increased
beta band power in frontal and parietal regions, increased beta-band spatial
variance across electrodes, greater inter-band segregation from delta activity,
reorganisation of beta activity within frontal-parietal networks, improved
symmetry in temporal lobes’ theta power, improved emotional processing and
information encoding, increased beta power parietal lobes indicating improved
attention, visual processing, and multisensory integration; 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, non-5-HT2AR-mediated antidepressive effects, increased
divergent thinking and symbolic thinking; anti-suicidality via
5-hydroxytryptamine receptor 2 A (HTR2A), 5-hydroxytryptamine receptor 2 C
(HTR2C), 5-hydroxytryptamine receptor 7 (HTR7), and cAMP-dependent protein
kinase catalytic subunit alpha (PRKACA); in post-traumatic stress of child
maltreatment subtypes neglect and emotional abuse, reduced internalized shame
and complex trauma symptoms; improved wellbeing in anorexia nervosa via 5-HT2a
serotonin receptor agonism, and increased BDNF concentrations, restoration of
gray matter and cortical neuroplasticity in areas responsible for emotional
regulation, decreased DMN and ACC activity, increased insula activity, breakdown
of cognitive rigidity and ruminative tendencies, including via direct
stimulation of the vagus nerve and interaction with the microbiota–gut–brain
axis, reduced negative beliefs about body image, and pathological avoidance of
social situations, improved reward system regulation, and ability to surpass
traumatic experiences, facilitating treatment of psychiatric comorbidities of
AN; 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'; including but not only via
substitution for escitalopram, increased optimism on the Revised Life
Orientation Test (LOT-R), and Prediction of Future Life Events task (POFLE),
achievement, flourishing on the Flourishing Scale (FS), and self-control, and
reduced dependency on the Dysfunctional Attitudes Scale (DAS-24); improved
scores on NEO Five-Factor Inventory-3 (NEO-FFI-3), Mystical Experiences
Questionnaire (MEQ-30), Posttraumatic Growth Inventory (PTGI), Emotional
Breakthrough Inventory (EBI), and reduced neuroticism; in terminal illness
reduced scores in Hospital Anxiety and Depression Scale (HADS), Beck Depression
Inventory-II (BDI-II), State-Trait Anxiety Inventory – State version (STAI-S),
Death Attitudes Profile (DAP-R), Hopelessness Assessment Inventory (HAI), and
Demoralization Scale II (DS-II), increased WHO Quality of Life Scale
(WHOQOL-BREF), MEQ, Persisting Effects Questionnaire (PEQ) positive mood scores,
and spiritual well-being); 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 on the
Meaning of Life Questionnaire (MLQ), 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 smell and taste, enhanced executive function and improved performance
in the Wisconsin Card Sorting Test (WCST), downregulation of Tau and Aβ
deposition, increased synaptic plasticity via increases in mTOR activity,
inhibition of glycogen synthase kinase-3-beta (GSK3β), promotion of Tau
dissociation from microtubules, decreased insoluble and increased soluble Tau
levels; improved scores on longitudinal improvements in anxiety and depression
on GAD-7, and Patient Health
Questionnaire (PHQ-9), PTSD Checklist for DSM-5 (PCL-5), and reduced
neuroticism; increased forgiveness, gratitude, humility, sense of connection,
self-transcendence; lower laughter threshold, health benefits of laughter
including vasoactive effects of pituitary gland released endorphin-activated
opiate receptors in the vascular endothelium, production of nitric
oxide-dependent cardioprotection, vasodilation, reduced vascular inflammation,
reduced IL-6, IL-10, and tumor necrosis factor (TNF)-alpha, improved peak oxygen
uptake (VO2peak), vascular cell adhesion molecule (VCAM), and ICAM; 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; in PD improved
results in the MoCA test; faster and more responsive positive hedonic effects
than antidepressants; via substitution for antidepressants, avoidance of
increased pain sensitivity subsequent to adolescent use, 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;
elimination of accidental death or injury in CaPs-related vehicular fleeing; 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; rescue of alcohol-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 including epigenetic
transgenerational effects of hypomethylation of HRAS and hypermethylation of
Tumor Protein TP53 (aka Transformation-Related Protein 53 or Antigen NY-CO-13),
histone post-transcriptional chromatin modifications in liver, brain, and
impaired chromatin condensation in sperm, adverse effects in noncoding microRNAs
(miRNAs) Transfer RNA Glutamic Acid 6 (aka Anticodon CUC or tRNA-Glu-CTC), and
TRG-GCC6-1 (Transfer RNA Glycine 12 aka Anticodon GCC or tRNA-Gly-GCC);
alcohol-substitution-mediated reductions in pre- and post-conception teratogenic
effects including intergenerational autism and psychosis, reduced glucose
intolerance intergenerationally via altered miR10a and tDR-Glu-CTC in F1 sons of
obese fathers who impart glucose intolerance to the F2 male descendants,
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; elevated SIRT1, GADD45a, Nox4, and and Nrf2; 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 coping with chronic stress including a
politically and media driven stress cycle agenda via EGFR expression in amygdala
astrocytes, inhibition of a stress-induced, pro-inflammatory signal-transduction
cascade facilitating neuron–glial crosstalk and stress-induced fear behaviour
via orphan nuclear receptor NR2F2 in amygdala neurons, and recruitment of
meningeal monocytes during chronic stress; resilience via N-methyl-d-aspartate
receptor (NMDAR)-mediated neuroprotection of parvalbumin (PV+) containing
interneurons; 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 update 14 September 2025.