Ultra-low dose THC

Just-A-Pinch-Of-Pot-—-A-Guide-To-Microdosing-Low-THC-Cannabis-.webp

~5 milligrams of THC can go a long way...

Timeline of Research

2022: In a mouse model of Alzheimer’s disease, low doses of THC decreased biomarkers of the disease

Low-Dose Delta-9-Tetrahydrocannabinol as Beneficial Treatment for Aged APP/PS1 Mice

https://www.mdpi.com/1422-0067/23/5/2757/htm

2022: In children with autism, the use of low doses of CBD & trace amounts of THC decreased behavioral problems, improved cognition & increased social interactions

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

https://pubmed.ncbi.nlm.nih.gov/34911567/

2021: In humans with Tourette’s, initial promise was seen with a combination of 10 mg of THC + 800 mg of PEA

A Phase-2 Pilot Study of a Therapeutic Combination of Δ 9-Tetrahydracannabinol and Palmitoylethanolamide for Adults With Tourette's Syndrome

https://pubmed.ncbi.nlm.nih.gov/34340527/

2021: In humans, a look at the pharmacology of taking Spectrum Red softgels (2.5 mg THC, ~.25 mg CBD)

Safety, Pharmacokinetics, and Pharmacodynamics of Spectrum Red Softgels in Healthy Participants

https://pubmed.ncbi.nlm.nih.gov/33848338/

2021: In humans with pain, a small amount of THC (2.5 to 10 mg) helps an opioid painkiller to work better

Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model

https://pubmed.ncbi.nlm.nih.gov/33879842/

2021: A remarkable case series showing the power of small amounts of synthetic THC (dronabinol) for neuropathic itch

Neuropathic itch treated with oral cannabinoids: A case series

https://pubmed.ncbi.nlm.nih.gov/34692966/

2021: In this case study, vaping a small amount of THC helped a patient with her headaches resulting from brain surgery

Significant reduction of symptomatic headache by medical marijuana – Case report

http://www.jpccr.eu/Significant-reduction-of-symptomatic-headache-by-medical-marijuana-Case-report,142773,0,2.html

2021: In a rat model of seizures, both THC & CBD have antiseizure properties but the most effective is a small amount of THC added to a larger dose of CBD

Antiseizure effects of the cannabinoids in the amygdala-kindling model 

https://pubmed.ncbi.nlm.nih.gov/34251027/ 

2020: In humans with MS, an average dose of 4 mg of THC relieved pain, spasticity & sleep disturbances

Safety and efficacy of low-dose medical cannabis oils in multiple sclerosis

https://pubmed.ncbi.nlm.nih.gov/33387864/

2020: In humans with fibromyalgia, low doses of THC helped with symptoms such as pain & fatigue

Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

https://pubmed.ncbi.nlm.nih.gov/33118602/

2019: A review of the brain benefits of ultra-low dose THC

Beneficial and deleterious effects of cannabinoids in the brain: the case of ultra-low dose THC

https://pubmed.ncbi.nlm.nih.gov/30864864/

2018: In humans with sleep apnea, 2.5 to 10 mg of THC helped improve scores

Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea

https://pubmed.ncbi.nlm.nih.gov/29121334/

2018: In older mice, low doses of THC made them perform better on a number of behavioral tests

Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol

https://pubmed.ncbi.nlm.nih.gov/29107185/

2017: In older mice, a chronic low dose of THC restores cognitive function

A chronic low dose of Δ 9-tetrahydrocannabinol (THC) restores cognitive function in old mice

https://pubmed.ncbi.nlm.nih.gov/28481360/

2015: In older humans with dementia, low doses of THC safe & well tolerated

Safety, pharmacodynamics, and pharmacokinetics of multiple oral doses of delta-9-tetrahydrocannabinol in older persons with dementia

https://pubmed.ncbi.nlm.nih.gov/25752889/

2015: In humans with Alzheimer’s, low doses of THC found safe & well tolerated

Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial

https://pubmed.ncbi.nlm.nih.gov/25972490/

2014: In a mouse model of neuroinflammation, very low doses of THC protected the brain

Ultralow doses of cannabinoid drugs protect the mouse brain from inflammation-induced cognitive damage

https://pubmed.ncbi.nlm.nih.gov/25042014/

2013: In mice, low dose of THC protected the heart from insults

An ultra-low dose of tetrahydrocannabinol provides cardioprotection

https://pubmed.ncbi.nlm.nih.gov/23537701/

2012: In humans with cancer, low (1-4 sprays) & medium doses of Sativex were more effective than placebo for pain

Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial

https://pubmed.ncbi.nlm.nih.gov/22483680/

2012: In mice, the mechanisms of how THC protects the brain from neuronal insults

Long-term behavioral and biochemical effects of an ultra-low dose of Δ9-tetrahydrocannabinol (THC): neuroprotection and ERK signaling

https://pubmed.ncbi.nlm.nih.gov/22821081/

2011: In mice exposed to the neurotoxic drug pentylenetetrazole, a low dose of THC before or after the exposure protected the brain

Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage

https://pubmed.ncbi.nlm.nih.gov/21315768/

 

2011: In humans with dementia, 2.5 mg of THC helped with agitation

Randomized, controlled crossover trial of dronabinol, 2.5 mg, for agitation in 2 patients with dementia

https://pubmed.ncbi.nlm.nih.gov/21364345/

2010: In mice, a very low dose of THC altered the memory for 5 months

Long-term consequences of a single treatment of mice with an ultra-low dose of Delta9-tetrahydrocannabinol (THC)

https://pubmed.ncbi.nlm.nih.gov/19766676/

2008: In mice, a low dose of THC lowered performance in a maze test

Long-term cognitive deficits induced by a single, extremely low dose of tetrahydrocannabinol (THC): behavioral, pharmacological and biochemical studies in mice

https://pubmed.ncbi.nlm.nih.gov/17888506/

2007: In young adults, 5 mg of THC altered their reactions to risky decision making in gambling scenarios

The effects of low doses of delta-9 tetrahydrocannabinol on reinforcement processing in the risky decision-making of young healthy adults

https://pubmed.ncbi.nlm.nih.gov/17006433/

2007: In mice, a low dose of THC altered performance in a water maze

A single low dose of tetrahydrocannabinol induces long-term cognitive deficits

https://pubmed.ncbi.nlm.nih.gov/17092651/

2006: In humans with severe nighttime agitation, 2.5 mg of THC helps reduce nocturnal motor activity & agitation

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia

https://pubmed.ncbi.nlm.nih.gov/16521031/

2006: In humans, low doses of THC had differential gender effects on spatial memory

Low doses of delta-9 tetrahydrocannabinol (THC) have divergent effects on short-term spatial memory in young, healthy adults

https://pubmed.ncbi.nlm.nih.gov/16177808/

2005: In mice, low dose of THC protected from atherosclerosis

Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice

https://pubmed.ncbi.nlm.nih.gov/15815632/

2004: In humans with MS, THC reduced pain at 5 to 10 mg

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

https://pubmed.ncbi.nlm.nih.gov/15258006/

2015: in humans, this review of studies finds PEA safe & effective for glaucoma & other retinopathies (nice chart of mechanisms of action)

Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy

https://pubmed.ncbi.nlm.nih.gov/26664738/

2015: In two patients with autism, PEA caused “rapid improvements in cognitive, behaviors, and sociability”

Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases

https://pubmed.ncbi.nlm.nih.gov/26491593/

2015: In 160 dogs with red itchy skin, ultramicronized PEA was “effective and safe in reducing pruritus and skin lesions” & improving quality of life

Efficacy of Ultra-Micronized Palmitoylethanolamide in Canine Atopic Dermatitis: An Open-Label Multi-Centre Study

https://pubmed.ncbi.nlm.nih.gov/26283633/

2015: In rats with pain, PEA delays the tolerance effects of morphine

Delay of Morphine Tolerance by Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/25874232/

2015: In rats with high blood pressure, PEA protected via several different pathways

Palmitoylethanolamide Treatment Reduces Blood Pressure in Spontaneously Hypertensive Rats: Involvement of Cytochrome p450-derived Eicosanoids and Renin Angiotensin System

https://pubmed.ncbi.nlm.nih.gov/25951330/

2015: In mice with damaged kidneys, PEA and silymarin combined to reduce “kidney dysfunction, histological damage, neutrophil infiltration and oxidative stress” & inhibited NF-κB and apoptosis pathways

Effects of Palmitoylethanolamide and Silymarin Combination Treatment in an Animal Model of Kidney Ischemia and Reperfusion

https://pubmed.ncbi.nlm.nih.gov/25981305/

2015: In rats with inflamed eyes, PEA “decreased the inflammatory cell infiltration and improved histological damage of eye tissues”, “reduced pro-inflammatory tumor necrosis factor (TNF-α) levels, protein extravasion and lipid peroxidation”, and “strongly inhibited iNOS expression and nuclear NF-κB translocation” – overall, reduced ocular inflammation

The Anti-Inflammatory Effects of Palmitoylethanolamide (PEA) on Endotoxin-Induced Uveitis in Rats

https://pubmed.ncbi.nlm.nih.gov/25934566/

2015: In mice with induced colitis, PEA helps via CB2, GPR55, PPAR-alpha & modulation of the TRPV1 channels

Palmitoylethanolamide, a Naturally Occurring Lipid, Is an Orally Effective Intestinal Anti-Inflammatory Agent

https://pubmed.ncbi.nlm.nih.gov/25205418/

2015: In a mouse model of MS, treatment with PEA or CBD reduced disease severity with diminished inflammation, demyelination, axonal damage & inflammatory cytokine expression – but they did not work as well together

Interaction between the protective effects of cannabidiol and palmitoylethanolamide in experimental model of multiple sclerosis in C57BL/6 mice

https://www.ncbi.nlm.nih.gov/pubmed/25637488

2015: In mice with painful nerve injuries, PEA restored their glutamate functioning & the changes in amino acid release (nice graphic)

Palmitoylethanolamide Reduces Pain-Related Behaviors and Restores Glutamatergic Synapses Homeostasis in the Medial Prefrontal Cortex of Neuropathic Mice

https://pubmed.ncbi.nlm.nih.gov/26260027/

2015: In cells challenged by the Aβ amyloids of Alzheimer’s, PEA “reduced expression of pro-inflammatory and pro-angiogenic markers” via PPARα

Palmitoylethanolamide Regulates Production of Pro-Angiogenic Mediators in a Model of β Amyloid-Induced Astrogliosis In Vitro

https://pubmed.ncbi.nlm.nih.gov/25801844/

2015: In neurons from mice challenged by the Aβ amyloids of Alzheimer’s, PEA rescued glutamate in non-transgenic mice but not the triple-transgenic murine model of AD

Differential Effects of Palmitoylethanolamide Against Amyloid-β Induced Toxicity in Cortical Neuronal and Astrocytic Primary Cultures From Wild-Type and 3xTg-AD Mice

https://pubmed.ncbi.nlm.nih.gov/25765918/

2014: In 30 diabetic patients, micronized PEA effectively reduced pain – blood work & urine analysis saw no significant alterations

Micronized Palmitoylethanolamide Reduces the Symptoms of Neuropathic Pain in Diabetic Patients

https://pubmed.ncbi.nlm.nih.gov/24804094/

2014: In 60 patients with eczema, a PEA/AEA topical improved “passive and active skin functions simultaneously”

N-palmitoylethanolamine and N-acetylethanolamine Are Effective in Asteatotic Eczema: Results of a Randomized, Double-Blind, Controlled Study in 60 Patients

https://pubmed.ncbi.nlm.nih.gov/25071367/

2014:Iin a patient with chronic vulvar & anal pain, a topical of PEA & baclofen decreased her pain by 50% and allowed for sex again

Vulvodynia and Proctodynia Treated With Topical Baclofen 5 % and Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/24691823/

2014: In dogs with red itchy skin, PEA probably helps via the downregulation of mast cells – levels of PEA increase as the disease progresses

Increased Levels of Palmitoylethanolamide and Other Bioactive Lipid Mediators and Enhanced Local Mast Cell Proliferation in Canine Atopic Dermatitis

https://pubmed.ncbi.nlm.nih.gov/24423192/

2014: In a rat model of Alzheimer’s, PEA was able to restore the alterations via PPARα & reverse the cognitive impairments

Palmitoylethanolamide Controls Reactive Gliosis and Exerts Neuroprotective Functions in a Rat Model of Alzheimer's Disease

https://pubmed.ncbi.nlm.nih.gov/25210802/

2014: In mice with an inflamed colon, PEA improved transit time of GI tract & increased AEA levels, mediated by CB1 receptors (possibly via the AEA) & modulated the TRPV1 channels

Palmitoylethanolamide Normalizes Intestinal Motility in a Model of Post-Inflammatory Accelerated Transit: Involvement of CB₁ Receptors and TRPV1 Channels

https://pubmed.ncbi.nlm.nih.gov/24818658/

2014: In the intestines of rats undergoing chemotherapy (and using mast cell knockout rats), PEA works via the mast cells for protection

Palmitoylethanolamide Regulates Development of Intestinal Radiation Injury in a Mast Cell-Dependent Manner

https://pubmed.ncbi.nlm.nih.gov/24848354/

2014: In a rat model of inflammatory pain, micronized/ultramicronized PEA worked better orally than PEA

Micronized/ultramicronized Palmitoylethanolamide Displays Superior Oral Efficacy Compared to Nonmicronized Palmitoylethanolamide in a Rat Model of Inflammatory Pain

https://pubmed.ncbi.nlm.nih.gov/25164769/

2014: In mice, PEA treatment increased the ability of macrophages to phagocytose (engulf & digest) E. coli

Palmitoylethanolamide Stimulates Phagocytosis of Escherichia Coli K1 by Macrophages and Increases the Resistance of Mice Against Infections

https://pubmed.ncbi.nlm.nih.gov/24927796/

2014: In colon cells, PEA improved all macroscopic signs of ulcerative colitis & decreased all proinflammatory markers tested via PPARα

Palmitoylethanolamide Improves Colon Inflammation Through an Enteric Glia/Toll Like Receptor 4-dependent PPAR-α Activation

https://pubmed.ncbi.nlm.nih.gov/24082036/

2013: In 24 women with endometriosis & chronic pelvic pain, micronized PEA & polydatin reduced pelvic pain, dysmenorrhea (cramps) & dyspareunia (pain during sex) but not dysuria (painful urination) & dischezia (strained stools) – overall increased quality of life

[Administration of Micronized Palmitoylethanolamide (PEA)-transpolydatin in the Treatment of Chronic Pelvic Pain in Women Affected by Endometriosis: Preliminary Results]

https://pubmed.ncbi.nlm.nih.gov/24051945/

2013: In 7 patients with chronic idiopathic axonal polyneuropathy (intense pain), PEA reduced pain significantly with no side effects

Chronic Idiopathic Axonal Neuropathy and Pain, Treated With the Endogenous Lipid Mediator Palmitoylethanolamide: A Case Collection

https://pubmed.ncbi.nlm.nih.gov/24049461/

2013: In rats with a form of epilepsy, PEA reduces seizures via the PPAR-α receptors & indirectly by the CB1 receptors

Antiepileptic Action of N-palmitoylethanolamine Through CB1 and PPAR-α Receptor Activation in a Genetic Model of Absence Epilepsy

https://pubmed.ncbi.nlm.nih.gov/23206503/

2013: In mice with spinal cord trauma, they found that PPAR-δ & PPAR-γ also contribute to PEA’s anti-inflammatory effects

Molecular Evidence for the Involvement of PPAR-δ and PPAR-γ in Anti-Inflammatory and Neuroprotective Activities of Palmitoylethanolamide After Spinal Cord Trauma

https://pubmed.ncbi.nlm.nih.gov/23374874/

2013: In rats with high blood pressure, PEA reduced blood pressure & reduced damage to the kidneys

N-Palmitoylethanolamide Protects the Kidney From Hypertensive Injury in Spontaneously Hypertensive Rats via Inhibition of Oxidative Stress

https://pubmed.ncbi.nlm.nih.gov/23917217/

2013: In mice with pain, PEA helped via recruitment and protection of mast cells, decrease of nerve growth factor, preservation of the nerves & the reduction of microglia activation in the spinal cord

Non-neuronal Cell Modulation Relieves Neuropathic Pain: Efficacy of the Endogenous Lipid Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/23394519/

2013: PEA targets both glial & mast cells for antiinflammation & neuroprotective effects

Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator

https://www.ncbi.nlm.nih.gov/pubmed/23813098

2013: In mice injured by formalin, PEA activated microglia & glia cells, significantly reduced mechanical allodynia & thermal hyperalgesia, and suggests use for spinal cord injuries

Palmitoylethanolamide Reduces Formalin-Induced Neuropathic-Like Behaviour Through Spinal Glial/Microglial Phenotypical Changes in Mice

https://pubmed.ncbi.nlm.nih.gov/23394524/

2013: In rat neuronal cells challenged with the Aβ amyloid plaques of Alzheimer’s, “PEA is able to blunt Aβ-induced astrocyte activation and to exert a marked protective effect on neurons”

Neuroglial Roots of Neurodegenerative Diseases: Therapeutic Potential of Palmitoylethanolamide in Models of Alzheimer's Disease

https://pubmed.ncbi.nlm.nih.gov/23394526/

 

2013: In cells, PEA activated TRPV1, perhaps via PPARα

Activation and Desensitization of TRPV1 Channels in Sensory Neurons by the PPARα Agonist Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/23083124/

2012: In humans, a case series on PEA for pain

Therapeutic Utility of Palmitoylethanolamide in the Treatment of Neuropathic Pain Associated With Various Pathological Conditions: A Case Series

https://pubmed.ncbi.nlm.nih.gov/23166447/

2012: In an observational study of 600+ patients, PEA helped all of them with their treatment-resistant chronic pain & caused no adverse effects

Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis

https://pubmed.ncbi.nlm.nih.gov/22845893/

2012: In a patient with ALS, PEA improved clinical picture – probably via the microglia and mast cells

Amyotrophic Lateral Sclerosis Treatment With Ultramicronized Palmitoylethanolamide: A Case Report

https://pubmed.ncbi.nlm.nih.gov/22998138/

2012: In mice, PEA helped to protect from a Parkinson’s like insult – probably via PPARα

Neuroprotective Activities of Palmitoylethanolamide in an Animal Model of Parkinson's Disease

https://pubmed.ncbi.nlm.nih.gov/22912680/

2012: In rats, PEA protected the brain after injury by many pathways

Reduction of Ischemic Brain Injury by Administration of Palmitoylethanolamide After Transient Middle Cerebral Artery Occlusion in Rats

https://pubmed.ncbi.nlm.nih.gov/23046519/

2012: In a mouse model of traumatic brain injury, PEA protected the brain via several pathways & improved neurobehavioral functions

Administration of Palmitoylethanolamide (PEA) Protects the Neurovascular Unit and Reduces Secondary Injury After Traumatic Brain Injury in Mice

https://pubmed.ncbi.nlm.nih.gov/22884901/

2012: In a mouse model of Alzheimer’s, injected PEA significantly helped with learning & memory disfunction – probably via the PPARα pathway

Palmitoylethanolamide Protects Against the amyloid-β25-35-induced Learning and Memory Impairment in Mice, an Experimental Model of Alzheimer Disease

https://pubmed.ncbi.nlm.nih.gov/22414817/

2012: In mice with intestinal injuries, pretreatment with PEA reduced inflammation & cell death – probably via the PPARα pathway

Effects of Palmitoylethanolamide on Intestinal Injury and Inflammation Caused by Ischemia-Reperfusion in Mice

https://pubmed.ncbi.nlm.nih.gov/22469754/

2012: In mice with injured kidneys, PEA protected via several different pathways – probably via the PPARα pathway

Palmitoylethanolamide Reduces Early Renal Dysfunction and Injury Caused by Experimental Ischemia and Reperfusion in Mice

https://pubmed.ncbi.nlm.nih.gov/22772472/

2012: In mice experiencing pain, PEA increased allopregnanolone (ALLO) levels via PPARα & it “restored the expression of two proteins involved in neurosteroidogenensis"

Implication of Allopregnanolone in the Antinociceptive Effect of N-palmitoylethanolamide in Acute or Persistent Pain

https://pubmed.ncbi.nlm.nih.gov/21890273/

2012: In neurons challenged by the β-amyloids of Alzheimer’s (astrocytes), PEA blunted activation & improved neuronal survival

Palmitoylethanolamide Exerts Neuroprotective Effects in Mixed Neuroglial Cultures and Organotypic Hippocampal Slices via Peroxisome Proliferator-Activated Receptor-α

https://pubmed.ncbi.nlm.nih.gov/22405189/

2012: In microglial cells, PEA caused increased phagosytosis of E. coli & strep

Palmitoylethanolamide Stimulates Phagocytosis of Escherichia Coli K1 and Streptococcus Pneumoniae R6 by Microglial Cells

https://pubmed.ncbi.nlm.nih.gov/22244572/

2011: In 20 patients undergoing chemo, PEA helped with the pain & showed positive effects on the myelinated fiber groups

Palmitoylethanolamide Restores Myelinated-Fibre Function in Patients With Chemotherapy-Induced Painful Neuropathy

https://pubmed.ncbi.nlm.nih.gov/22229320/

2011: In tissue, PEA appears to regulate neurosteroidogenesis in astrocytes & increase allopregnanolone (ALLO) via PPARα

Palmitoylethanolamide Stimulation Induces Allopregnanolone Synthesis in C6 Cells and Primary Astrocytes: Involvement of Peroxisome-Proliferator Activated Receptor-α

https://pubmed.ncbi.nlm.nih.gov/21554431/

2011: In this specialized neuron, PEA reduced the number of microglial cells & protected the neurons via PPARα

Palmitoylethanolamide Protects Dentate Gyrus Granule Cells via Peroxisome Proliferator-Activated Receptor-α

https://pubmed.ncbi.nlm.nih.gov/20221904/

2011: In mice with spinal cord injuries, PEA “reduced the degree of the severity of spinal cord trauma through the reduction of mast cell infiltration and activation [and] reduced the activation of microglia and astrocytes expressing cannabinoid CB(2) receptor”

Effects of Palmitoylethanolamide on Release of Mast Cell Peptidases and Neurotrophic Factors After Spinal Cord Injury

https://pubmed.ncbi.nlm.nih.gov/21354467/

2011: In astrocytes, the β-amyloids of Alzheimer’s increased PEA levels – treatment with PEA blunted its proinflammatory effects, probably via PPARα, as well as increasing 2-AG levels

Palmitoylethanolamide Counteracts Reactive Astrogliosis Induced by β-Amyloid Peptide

https://pubmed.ncbi.nlm.nih.gov/21255263/

2010: In mice, PEA modulates the hypnotic effect of phenobarbital via PPARα’s increase of allopregnanolone (ALLO) & a positive modulation of GABA

Palmitoylethanolamide Modulates Pentobarbital-Evoked Hypnotic Effect in Mice: Involvement of Allopregnanolone Biosynthesis

https://pubmed.ncbi.nlm.nih.gov/19864116/

2010: In canine mast cells, PEA downregulated their activity via several factors (decrease of Histamine, PGD(2) and TNFalpha)

Effects of Palmitoylethanolamide on Immunologically Induced Histamine, PGD2 and TNFalpha Release From Canine Skin Mast Cells

https://pubmed.ncbi.nlm.nih.gov/19625089/

2009: In mice, pretreatment with PEA lowered pain via PPARα’s inhibition of NF-kappaβ nuclear signaling in dorsal root ganglia – reduced COX-2 & iNOS

Central Administration of Palmitoylethanolamide Reduces Hyperalgesia in Mice via Inhibition of NF-kappaB Nuclear Signalling in Dorsal Root Ganglia

https://pubmed.ncbi.nlm.nih.gov/19386271/

2008: In this study of 2456 patients with eczema, PEA topical treatment caused less itching, more sleeping & half of them stopped using their corticosteroids

Adjuvant Treatment of Atopic Eczema: Assessment of an Emollient Containing N-palmitoylethanolamine (ATOPA Study)

https://pubmed.ncbi.nlm.nih.gov/18181976/

2008: In mice with a model of MS, CB2 was upregulated as was 2-AG & PEA – but not AEA – PEA applied exogenously reduced disability and lowered inflammation

Study of the Regulation of the Endocannabinoid System in a Virus Model of Multiple Sclerosis Reveals a Therapeutic Effect of Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/18657182/

2008: In mice with spinal cord injury, PEA reduced “1) the degree of spinal cord inflammation and tissue injury, 2) neutrophil infiltration, 3) nitrotyrosine formation, 4) proinflammatory cytokine expression, 5) nuclear transcription factor activation-kappaB activation, 6) inducible nitric-oxide synthase expression, and 6) apoptosis” & it helped with recovery of motor function

Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury

https://pubmed.ncbi.nlm.nih.gov/18367664/

2008: In mice, PEA helped with pain via CB1, TRPV1 & PPARγ

The Endogenous Fatty Acid Amide, Palmitoylethanolamide, Has Anti-Allodynic and Anti-Hyperalgesic Effects in a Murine Model of Neuropathic Pain: Involvement of CB(1), TRPV1 and PPARgamma Receptors and Neurotrophic Factors

https://pubmed.ncbi.nlm.nih.gov/18602217/

2008: In rat arteries, the ability of AEA to induce relaxation was potentiated by both PEA & OEA – possibly via TRPV1

'Entourage' Effects of N-palmitoylethanolamide and N-oleoylethanolamide on Vasorelaxation to Anandamide Occur Through TRPV1 Receptors

https://pubmed.ncbi.nlm.nih.gov/18695637/

2007: In mice with pain, preadministration of PEA reduced swelling & inflammation via PPARα

Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-Alpha Agonist, Modulates Carrageenan-Induced Paw Edema in Mice

https://pubmed.ncbi.nlm.nih.gov/17565008/

2005: Piomelli identifies PPARα as PEA’s mechanism – in this mouse model, it reduced inflammation

The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-Alpha Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/15465922/

2003: In mice, PEA potentiates the ability of AEA to induce microglia migration – not mediated by CB1 or CB2

Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility

https://www.ncbi.nlm.nih.gov/pubmed/12944505

2002: In a patient after stroke, levels of AEA, PEA & OEA all rise

Release of fatty acid amides in a patient with hemispheric stroke: a microdialysis study

https://www.ncbi.nlm.nih.gov/pubmed/12154273

2002: In cancer cells, PEA seems to potentiate the antiproliferative effects of AEA via the vanilloid system

Effect on Cancer Cell Proliferation of Palmitoylethanolamide, a Fatty Acid Amide Interacting With Both the Cannabinoid and Vanilloid Signalling Systems

https://pubmed.ncbi.nlm.nih.gov/12570018/

2001: In breast cancer cells, PEA inhibits expression of FAAH & enhances anti-proliferative effects of AEA

Palmitoylethanolamide Inhibits the Expression of Fatty Acid Amide Hydrolase and Enhances the Anti-Proliferative Effect of Anandamide in Human Breast Cancer Cells

https://pubmed.ncbi.nlm.nih.gov/11485574/

2001: In kidney cells, PEA enhances AEA’s stimulation of VR1

Palmitoylethanolamide Enhances Anandamide Stimulation of Human Vanilloid VR1 Receptors

https://pubmed.ncbi.nlm.nih.gov/11602256/

1996: In neurons, PEA – but not AEA – protected against glutamate toxicity & prevented neuron loss

The ALIAmide Palmitoylethanolamide and Cannabinoids, but Not Anandamide, Are Protective in a Delayed Postglutamate Paradigm of Excitotoxic Death in Cerebellar Granule Neurons

https://pubmed.ncbi.nlm.nih.gov/8633002/

1995: In mast cells, they found that while CB2 is present – only activation by PEA - and not AEA  - downmodulates mast cell activation – in fact, AEA antagonized the effect (“ALIAmides”)

Mast Cells Express a Peripheral Cannabinoid Receptor With Differential Sensitivity to Anandamide and Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/7724569/

1993: Levi-Montalcini’s big paper where she said PEA worked via mast cells & where she coined the acronym ALIA

A Proposed Autacoid Mechanism Controlling Mastocyte Behaviour

https://pubmed.ncbi.nlm.nih.gov/7505999/

1980: Epps finds PEA accumulating in infarcted myocardium – first to suggest that fatty molecules may play a protective role during ischemia & that its presence:” may signify a response of myocardial tissue to injury directed at minimizing damage and promoting survival”

Accumulation of N-acylethanolamine Glycerophospholipids in Infarcted Myocardium

https://pubmed.ncbi.nlm.nih.gov/7397206/

1979: 3 large trials shows PEA’s help for acute respiratory infections with no negative effects on antibody production

Studies on prophylactic efficacy of N-2-hydroxyethyl palmitamide (Impulsin) in acute respiratory infections. Serologically controlled field trials

https://pubmed.ncbi.nlm.nih.gov/392005/

1975: First supportive effects of PEA in cancer as a modulator of toxicity in chemotherapy found in an animal model (confirmed by Gruccu’s group in 2011)

The Effect of Long-Term Administration of N-(2-hydroxyethyl)palmitamide on the Chemotherapy of RBA Rat Leukemia

https://pubmed.ncbi.nlm.nih.gov/1214924/

1975: First small pilot for rheumatic pain supported analgesic properties

Letter: Slow Encephalopathies, Inflammatory Responses, and Arachis Oil

https://pubmed.ncbi.nlm.nih.gov/51386/

1974: Two large scale double-blind trials show PEA helping symptoms of respiratory tract infections – but not their timecourse

Prophylactic efficacy of N-2-hydroxyethyl palmitamide (impulsin) in acute respiratory tract infections

https://pubmed.ncbi.nlm.nih.gov/4439865/

1972: In mice, PEA caused decreased mortality from a variety of immunological insults

Non-specific Resistance Induced by Palmitoylethanolamide

https://pubmed.ncbi.nlm.nih.gov/4561079/

1965: Bachur’s work finds PEA consistently present in brain, liver & muscle of rats and guinea pigs

FATTY ACID AMIDES OF ETHANOLAMINE IN MAMMALIAN TISSUES

https://pubmed.ncbi.nlm.nih.gov/14284696/

1957: Initial discovery paper

The identification of N-(2-hydroxyethyl)-palmitamide as a naturally occurring anti-inflammatory agent

https://www.researchgate.net/publication/231508405_Kuehl_Jr_FA_Jacob_TA_Ganley_OH_Ormond_RE_Meisinger_MAP_The_identification_of_N-2-hydroxyethyl-palmitamide_as_a_naturally_occurring_anti-inflammatory_agent_J_Am_Chem_Soc_79_5577-5578