THE BENEDICTIONS

Cannabis and Its Components (CCx)

Metabolic / Endocrine / Obesity / Diabetes / Lipid / Hepatic

• enhanced resistance to diets with a higher than optimum n-6:n-3 polyunsaturated fatty acid ratio
• a 55% lower probability of hepatocellular carcinoma
• in refractory diabetic neuropathy
  • reduced BPI pain severity
  • BPI interference
  • Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score
  • HbA1c
  • analgesic use

Oncology / Antineoplastic / Anti-metastatic

• 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
  • increased percentage of cells in S phase and G2/M phase
  • disintegration of F-actin
• reduced T-cell acute lymphoblastic leukemia
  • via ATF4-CHOP-CHAC1 signaling by Ca2+ depletion and ER stress
• in ovarian cancer (OC) disruption of ovarian cancer stem cell (OCSC) homeostasis
  • associated Wnt/β-catenin pathway
  • aldehyde dehydrogenase (ALDH) activity
  • reduced phosphorylation of PI3K, AKT, and mTOR
  • hedgehog/GLI (HH-GLI)- and NF-κB-dependent signaling pathways
  • 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
  • mitochondrial dysfunction in OC cells
  • increased phosphorylation of PTEN
• in HER2-positive ovarian cancer
  • inhibition of HER2-tyrosine kinase

Neurology / Neuroscience / Neuroprotection / Neurogenesis / Cognition

• 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
• 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
  • 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
  • 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
  • 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
  • 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
  • anti-aging reduction of mTOR, carbohydrates, amino acids and lipid metabolism in serum and visceral fat
• lifetime use-associated 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
  • total score on RTT-Caregiver Burden Inventory (RTT-CBI)
• protection in the brain from lipopolysaccharide (LPS) neuroinflammation-induced cognitive damage
• 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
  • 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)
  • 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
  • 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
  • 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 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
• synaptic plasticity
  • via melioration of gastroparesis
• 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
  • global neuropathological score
• reduced cortical thinning in teenage alcohol users
• enhanced language development at the individual and evolutionary level
  • via upregulation of FoxP2
• 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
  • reduced corticosterone
• in dysgeusia angiotensinergic effects
  • increased ACE2 activity
  • reduced corticosterone and renin levels in the lingual parenchyma
• 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

Psychiatry / Mental Health / Mood / Anxiety / Addiction

• 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
• reduced anhedonia
  • including via CB1R agonism in the oval subnucleus of the bed nucleus of stria terminalis (ovBNST)
• 0.3 days per month less spent in poor mental health by MM and pain-motivated users
• 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
• 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 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
• 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)
  • impact of event scale – revised (IES-R)

Immunology / Inflammation / Anti-allergic / Antioxidant

• 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

Pain / Rheumatology / Anti-arthritic

• antinociceptive properties in Rlick
  • formalin-induced inflammatory pain
  • cisplatin-induced peripheral neuropathy models
• following spinal fusion surgery lower 90-day overall and medical complication rates
  • reduced 30-day high dose opioid utilization
  • reduced 2-6 month opioid dosage
• ameliorated dialysis-related peritoneal fibrosis
  • via TGF-β(1)-induced dedifferentiation of mesothelial cells and maintenance of epithelial integrity

Gastroenterology / GI Protection

• reduced healthcare expenditure
• one less death from alcohol in Slovenia per day at 50% alcohol substitution

Gerontology / Anti-aging / Longevity

• (No unique entries beyond overlaps)

Cardioprotective / Vascular (additional)

• (No unique entries beyond overlaps)

Reproductive / Sexual / Developmental

• 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
  • 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
  • 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
• 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
  • in surface epithelium cells only for IL-6
• improved EQ-5D-5L score in endometriosis
• 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)
  • avoidance of multiple side-effects via substitution for ibuprofen
• in prenatally cannabinoid exposed (PCE) neonates
  • increased Mullen score in gross motor
  • expressive and receptive language
• more sexual partners
• ~20% increased coital frequency in both sexes
  • with increased sensitivity to touch
  • increased orgasm intensity and achievability
  • more relaxed sex
• in males
  • higher sperm counts
  • testosterone
  • inhibin B
  • 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
  • a reduction in faked orgasms

Other Medical (Antipyretic, etc.)

• (No unique entries)

Sociological / Psychosocial / Behavioral

• higher educational attainment
  • directly and via substitution for alcohol use

Classical Psychedelics

Metabolic / Endocrine / Obesity / Diabetes / Lipid / Hepatic

• enhancement of glycolytic flux
  • via activation of forkhead box K2 (FOXK2)
• in NAFLD/MASLD via a pleiotropic effect upon lipid hepatic metabolism and glycemic control
  • restoration of plasma and liver triglyceride levels
  • hepatic expression of genes involved in lipid localization
  • catabolic processes
  • protein expression of insulin receptor and insulin receptor substrate 1 [IRS-1]
  • phenotype of circulating NK [natural killer] cells via increased PD-1
  • decreased fasting glucose and improved diurnal glucose stability by OGTT AUC [oral glucose tolerance test area under the curve]
• anti-diabetogenic action via or associated with elevated connectivity in the precuneus/posterior cingulate cortex
  • a higher default mode network resting-state
  • via suppression of TNF-α, and other cytokines such as IL-6 and IL-12

Oncology / Antineoplastic / Anti-metastatic

• (No unique entries)

Neurology / Neuroscience / Neuroprotection / Neurogenesis / Cognition

• increased balance between senders and receivers of neural signals
• activation of 5HT2A-R
  • protection against reactive oxygen species (ROS)
  • stimulation of mitochondrial biogenesis increasing availability of adenosine triphosphate (ATP) via upregulation of SIRT1
• amelioration of AD, TBI, and ischemia
  • via restoration of neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk
  • 5-HT
  • dopamine
  • adrenergic
  • trace amine receptors
• 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
• enriched reactome pathways related to axon guidance

Psychiatry / Mental Health / Mood / Anxiety / Addiction

• long-lasting antidepressive action
  • via reduced metalloproteinase-9 (MMP-9)

Immunology / Inflammation / Anti-allergic / Antioxidant

• 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
  • increased IL-10
• anti-allergenic and anti-inflammatory reduction of arginase 1 (Arg1)
  • chitinase
• reduced infection, infectivity, and death due to SARS-Covid
  • via inhibition of Mprotease and IL-6 by psilacetin, psilocin, and psilocybine

Pain / Rheumatology / Anti-arthritic

• (No unique entries)

Gastroenterology / GI Protection

• (No unique entries)

Gerontology / Anti-aging / Longevity

• 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
  • cell-cell adhesion gene ontology (GO) categories
  • via overall reduction of the allostatic load
• extension of cellular lifespan
  • with delayed exhaustion of proliferative potential
  • increased cumulative population doublings
  • decreased population doubling time
  • delayed onset and reduced senescence
  • decreased beta-galactosidase (βgal) activity
  • reductions in p21
  • cyclin-dependent kinase inhibitor (p16)
  • increased proliferating cell nuclear antigen (PCNA)
  • retinoblastoma protein (pRB or Rb)
  • preserved telomere length
  • higher survival
  • phenotypic improvements in hair growth and reductions in white hair
• amelioration of high-glucose high lipid diet (HGHL) effects in dermal fibroblasts via 5-HT2 and 5-HT7 serotonin receptors
  • with reduced apoptosis and alleviation of HGHL-induced S phase arrest
  • reduced senescence markers
  • decreased expression of inflammatory IL-1β, IL-6, and COX-2
  • promotion of fibroblast migration
  • upregulated elastin (ELN) gene expression
• enhanced chromatin accessibility
  • energy homeostasis
  • DNA damage repair via increased expression of metallothionein (MT) family genes
  • elevated nuclear ubiquitous casein
  • cyclin-dependent kinases substrate (NUCKS1)

Cardioprotective / Vascular (additional)

• sympathovagal coactivation
• prevention of endothelial dysfunction, atherosclerosis, and thrombosis
  • via alteration of platelet aggregation pathways ameliorative of abnormal activation of peripheral 5-HT2A receptor due to chronic inflammation and lipid abnormalities

Reproductive / Sexual / Developmental

• (No unique entries)

Other Medical (Antipyretic, etc.)

• actin binding activity regulating the actin-myosin interaction of smooth muscle
  • via myosin light chain kinase 2 (Myl2)

Sociological / Psychosocial / Behavioral

• (No unique entries beyond overlaps)

Benedictions Common to Both Cannabis and Classical Psychedelics

Metabolic / Endocrine / Obesity / Diabetes / Lipid / Hepatic

• 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)

Oncology / Antineoplastic / Anti-metastatic

• alcohol-substitution- and BMI-mediated reductions in cancer including epigenetic transgenerational effects
  • hypomethylation of HRAS
  • hypermethylation of Tumor Protein TP53 (aka Transformation-Related Protein 53 or Antigen NY-CO-13)
  • histone post-transcriptional chromatin modifications in liver, brain
  • 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)

Neurology / Neuroscience / Neuroprotection / Neurogenesis / Cognition

• enhanced executive function and improved performance in the Wisconsin Card Sorting Test (WCST)
• downgregulation of Tau and Aβ deposition
• increased synaptic plasticity via increases in mTOR activity
  • inhibition of glycogen synthase kinase-3-beta (GSK3β)
  • reduction of Tau dissociation from microtubules
  • decreased insoluble and increased soluble Tau levels
• reduced susceptibility to dementia (AD) as marked by elevated BDNF
• in PD improved results in the MoCA test
• 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, Nrf2
  • enhanced sirtuin-based telomere maintenance with the help of telomere binding proteins
  • increased stress resistance through regulation of the tumour-suppressor protein p53
  • reduction of forkhead box O gene 3a (FOXO3a)-mediated apoptosis
• improved odds of increased lifespan associated with complete blood count and telomere investigations, and with the improved situational awareness improved acuity brings

Psychiatry / Mental Health / Mood / Anxiety / Addiction

• improved scores on longitudinal improvements in anxiety and depression on GAD-7, and PHQ-9, PTSD Checklist for DSM-5 (PCL-5), and reduced neuroticism
• increased forgiveness, gratitude, humility, sense of connection, self-transcendence, and intimacy
• 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
• 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 haemorrhage
  • 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 dyskinesia, insomnia, screaming, apathy
  • and in incident dementia faster cognitive decline, increased risk of severe dementia, and death
• via substitution for antidepressants in Tyr129Ser, rs1176744 HTR3 SNP subjects, reduction in cocaine addiction
• reduction in tobacco use, morbidity, mortality, and associated costs
• increased conscientiousness
• motivational neuroadaptations during alcohol dependence

Immunology / Inflammation / Anti-allergic / Antioxidant

• (Shared anti-inflammatory effects implied via BDNF elevation, laughter benefits reducing IL-6/TNF-alpha, etc., but no unique new mechanisms listed beyond overlaps)

Pain / Rheumatology / Anti-arthritic

• antinociceptive effects

Gerontology / Anti-aging / Longevity

• (Covered under Neurology above, with CR-mimesis, sirtuin pathways, telomere maintenance, etc.)

Cardioprotective / Vascular (additional)

• (Laughter benefits include nitric oxide-dependent cardioprotection, vasodilation, reduced vascular inflammation)

Reproductive / Sexual / Developmental

• prevention of preconception paternal alcohol effects in offspring such as
  • pre- and post-natal growth reduction
  • delayed parturition
  • degraded long-term metabolic programming in offspring
• 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

Other Medical (Antipyretic, etc.)

• enhanced smell and taste
• rescue of alcohol-mediated reductions in vitamins A, B, C, D, E, K, and calcium, magnesium, iron, and zinc deficiencies

Sociological / Psychosocial / Behavioral

• 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
• 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
• 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
• reduced absenteeism
• pro-economic effects on property damage, police and justice services, and the medical insurance system
• reduced flight-induced mortality, injury, and property damage
• elimination of accidental death or injury in CaPs-related vehicular fleeing
• 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