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. agreeableness, extraversion, and self-esteem; 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 15 September 2025.