Palmitoylethanolamide (PEA): Clinical Applications by Neil McKinney, ND

Abstract

Natural narcotics – opiates and cannabis – are within the prescribing authority of naturopathic physicians in some jurisdictions.

Cannabidiol (CBD) has been serviceable for neuropathic pain, but with limitations, not the least of which is financial toxicity. A new cannabinoid-like natural remedy for pain, central and peripheral neuropathy is the phospholipid palmitoylethanolamide (PEA). PEA occurs naturally in peanuts, soybeans, egg yolks, and the human body. PEA is an endogenous fatty acid amide, a phospholipid which is analgesic via G-protein-coupled receptors. PEA is a nuclear factor agonist, neuroprotective, and neuroregenerative, reducing neuronal inflammation and edema. It has been found effective for sciatica, migraine, endometriosis, dysmenorrhea, chemical neuropathy, TMJ, and more, in human RCTs and meta-analyses. Adverse effects are unusual, with occasional mild gastrointestinal upset reported. The aim of this review is to discuss a novel approach on neuropathic pain management, which is based on the knowledge of processes that underlie the development of peripheral neuropathic pain; in particular focused on the role of glia and mast cells in pain and neuroinflammation.

The Pain Problem

Pain is what you feel. Unpleasant and uncomfortable, pain is a very subjective experience of noxious stimuli. A trauma, injury or noxious exposure sets off an alarm in local nerve endings. Signals include bradykinins, substance P, histamine and prostaglandins. Nerve endings pick up the signal and transfer it to spinal pathways. Afferent pain impulses enter the spinal dorsal horn ganglia and synapse with interneurons in the substantia gelatinosa. Signals then ascend the lateral spinothalamic tract to the reticular formation in the brain stem pons and medulla. It is switched through the thalamus to higher brain areas. Pain is constructed by the brain. Functional MRI studies demonstrate that pain is only partially created by a sensory stimulus. The prefrontal areas of the brain evaluate the potential for harm, and the expectation of relief.

Gate control theory explains how counter-irritation such as massage or hot pepper extracts can block pain signals. Peripheral nerve stimulation can create excessive traffic which “blows the fuse” so the cord “shuts the gate” to the central nervous system. Needling or laser acupuncture may also work in part by counter-irritation/gate control, but also increase CNS production of analgesic chemicals that modify or inhibit pain, called endorphins and enkephalins (Cheng 2014).

Naturopathic physicians have many modalities to ease suffering, but pharmaceuticals are often the default remedies for acute or severe pain situations. Natural analgesics such as wintergreen, Jamaican dogwood and white willow bark have limited utility. In British Columbia we are only permitted to prescribe one opiate, the synthetic drug Tramadol. Most wisely refrain from using it.

Mechanical damage such as traumatic brain injury, or nerve impingement, may each require completely different therapeutics. Compressed nerves and sciatica may be treated with manipulation, injection and physiotherapy. TBI and stroke require healing of reperfusion injury with vascular restoratives such as grapeseed extract, plus nutritional support-omega 3 oils, magnesium, and active B-complex.

Neuropathy from chemotherapy can be reduced with concurrent remedies such as thiamine, and L-glutamine. Natural medicines for neuropathy include alpha lipoic acid, acetyl-L-carnitine, methylcobalamin, n-acetyl-cysteine, agmantine sulphate, pyridoxal-5-phosphate, pyrroloquinolone quinone (PQQ), acupuncture, homeopathy, and hydrotherapy (McKinney 2020).

Cannabinoids are natural plant analogues of our innate endocannabinoid system, which regulates most biological functions and maintains homeostasis. Receptors for endocannabinoids anandamide (AEA) 2-arachidonolylglycerol (2-AG) are actually more abundant in humans than are opiate receptors. CB1 receptors for endocannabinoids are particularly abundant in the central nervous system, also in adipose tissue, liver, lungs, uterus, and placenta. Activation of CB1s in central and peripheral nerves can be analgesic. CB1 receptors on spinal GABA interneurons which can disinhibit pain projection neurons. Neurotransmitters modulated by cannabinoids include acetylcholine, norepinephrine, dopamine, 5-hydroxy-tryptamine, GABA and D-aspartate. Modulators of the endocannabinoid receptors impacts somatic, visceral, and neuropathic pain, and show clinical value for hyperalgesia, allodynia, pain of inflammation, and muscle spasticity (Piomelli 2003).

Cannabidiol (CBD) from hemp or marijuana has been serviceable for neuropathic pain, but with limitations, not the least of which is financial toxicity. CBD interacts strongly with CB1 receptors and may also decrease inflammation via the A2A adenosine receptor, which also down-regulates dopamine and glutamate in CNS (Argueta et al 2020).

CBD also interacts with the vanillinoid receptor system aka TRPV1 receptor, which is also activated by eugenol from cloves, and capsaicin from chili peppers (Kleckner et al 2019, Sledzinski et al 2018).

The narcotic and psychotropic cannabinoid from cannabis is tetrahydrocannabinol (THC). Severe pain requires both THC and CBD (Abrams et al 2011, Martin-Sanchez et al 2009). While 20mg THC has the analgesic effects of about 120mg of codeine, THC gives significantly more psychiatric effects. Large doses also incur considerable financial toxicity.

Other plants with cannabinoid-like activity:

• Theobroma cacao (chocolate) – anandamine.
• Piper nigrum (black pepper) – guineensis.
• Echinacea purpurea (coneflower) – N-alkyl amides.
• Helichrysum italicum (curry aster) – cannabigerol.
• Piper methysticum (kava) – yangonin kavalactone.
• Tuber melanosporum (black truffle) – anandamine.
• Rhododendron anthopogonoides –CBC, CBL, CBT.
• Acmella oleracea (electric daisy) – N-isobutylamides

Pain Relief from Food Sources – PEA – Palmitoylethanolamide

Palmitoylethanolamide (PEA) is a nutraceutical endocannabinoid that was retrospectively discovered in egg yolks. Feeding poor children with known streptococcal infections prevented rheumatic fever. Subsequently, it was found to alter the course of influenza (Ganley et al 1958). This natural phospholipid was later also found in peanuts, soybeans, and the human body (Paladini et al 2016, Petrosino and Di Marzo 2017).

PEA (C16:0 N-acylethanolamine), a lipid mediator biologically synthesized in many plants as well as in cells and mammal tissues belongs to the class of non-endocannabinoid (NAE) compounds that are much more abundant than the endocannabinoid anandamide in several animal tissues and endowed with important biological actions (Beggatio et al 2019).

PEA targets nonclassical cannabinoid receptors rather than CB1 and CB2 receptors. PEA indirectly activates classical cannabinoid receptors by an entourage effect with vanillinoid receptors (Mattace et al 2014). PEA may indirectly activate CB1 and CB2 receptors by acting as a false substrate for fatty acid amide hydrolase (FAAH), the enzyme involved in the degradation of the endocannabinoid AEA (Petrosino et al 2019, Petrosino et al 2017). This action leads to increased levels of AEA and, in turn, an increased activation of cannabinoid receptor-mediated signaling.

There are no reported drug-drug interactions and very few reported adverse effects from PEA, having demonstrated high safety and tolerability (Davis et al 2019, Gabrielsson et al 2016, Nestmann 2016, Petrosino and Di Marzo 2017). PEA is virtually non-toxic at doses of 600 mg twice daily as commonly used in case reports and studies (Germini et al 2017). Relevant PEA-induced side effects were not seen in humans at oral doses of up to 1,800mg/day. PEA has proven efficacious in humans in a number of clinical settings, including a significant number of prospective and randomized trials demonstrating the pain-relieving effects of PEA. There is lesser evidence of benefit in patients with non-pain symptoms related to depression, Parkinson disease, strokes, and autism. None of the clinical trials with PEA to date have reported significant adverse effects, only occasional mild gastrointestinal upset (Beggatio et al 2019, Nestmann 2016).

Food source ALIAmides (autacoid local injury antagonist amides) like PEA can also counteract the inflammatory cascade, in both acute and chronic inflammatory pathologies (Peritor et al 2019, Tsuboi et al 2018).

N-acylethanolamines such as palmitoylethanolamide exert anti-inflammatory, analgesic, and anorexic effects through nuclear receptors for peroxisome proliferator-activated receptor α (Tsuboi 2018). PEA is an endogenous PPAR-α ligand which modulates mitochondrial oxidative capacity and oxidative stress, influencing fatty acid and glucose metabolic flexibility (Annunziata et al 2020). PEA increases the levels of CB2 receptor mRNA and protein as a result of PPAR-α activation, and this effect is involved in PEA-induced microglia changes associated with increased migration and phagocytic activity (Guida et al 2017). PEA is an abundant acylethanolamide produced in the central nervous system (CNS) by neurons and glial cells. Anti-hyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. PEA modulation of PPAR-α has been implicated in its beneficial impacts on peripheral neuropathies such as diabetic neuropathy, drug-induced peripheral neuropathy, carpal tunnel syndrome, sciatic pain, osteoarthritis, low-back pain, failed back surgery syndrome, dental pains, neuropathic pain in stroke and multiple sclerosis, chronic pelvic pain, postherpetic neuralgia, and vaginal pains. (Hesselink and Hekker 2012). PEA appears to benefit neuropathic pain from chemotherapy drugs, and restores myelinated fibre function lost to these neurotoxins (Hesselink 2013, Truini et al 2011). Acute neuropathy from diabetes or trauma also improved with PEA (Cocito et al 2014, Gatti et al 2012).

ALIAmides represent a group of endogenous bioactive lipids, including PEA, which play a central role in numerous biological processes, including pain, inflammation, and lipid metabolism. These compounds are emerging thanks to their anti-inflammatory and anti-hyperalgesic effects, due to the down regulation of activation of mast cells. Collectively, preclinical and clinical studies support the idea that ALIAmides merit further consideration as a therapeutic approach for controlling inflammatory responses, pain, and related peripheral neuropathic pain. (D’Amico et al 2020).

PEA is an endogenous endocannabinoid acting both centrally and peripherally, via G-protein-coupled receptors GPR 55 and GPR 119, influencing potassium and other membrane channels. GPR55 forms receptor heteromer with either CB1 or CB2 receptors (Balenga et al 2014, Martínez-Pinilla et al 2014, Martínez-Pinilla et al 2019). The anti-neuroinflammatory effects of PEA might be mediated, at least in part, by GPR55 activation (Kallendrusch et al 2013).

PEA is a nuclear factor agonist, reducing neuronal inflammation in part by mast cell modulation (De Fillipis et al 2013). PEA controls mast cell degranulation and substance P (SP)-induced histamine release in rat basophilic leukemia (RBL-2H3) cells, a mast cell model. PEA stimulation of 2-AG biosynthesis leads to activation of CB2 and thus to the inhibitory effects on degranulation (Petrosino et al 2019). The down regulation of mast cell activation in glial cells explains a great deal of the ability of PEA to abolish neuroinflammation (Paladini et al 2016). PEA reduces neuronal edema, is neuroprotective, restorative, and potent for pain (Artukoglu et al 2107). PEA has been studied and found helpful for lumbosacral sciatica (Domínguez et al 2012), failed back surgery syndrome (Paladini et al 2017), carpal tunnel syndrome (Faig-Marti and Martínez-Catassús 2017), and inflammatory bowel syndromes (IBS) (Couch et al 2017, Cremon et al 2017). A randomized clinical trial compared the effect of PEA with ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) for pain relief in temporomandibular joint disorder (TMJ), osteoarthritis and arthralgia. PEA demonstrated effective antagonism to autacoid local inflammation, and modulated mast cell behavior, controlling both acute and chronic inflammation (Marini et al 2012). In a rat model of osteoarthritis PEA was compared to the NSAID drug meloxicam. PEA co-ultramicronized with the natural antioxidant quercetin (PEA-Q) showed superior effects compared to meloxicam, with none of the long-term adverse effects seen with NSAIDS (Britti et al 2017).

Sublingual ultra-micronized PEA was found to significantly reduce migraine headache days per month, duration and intensity of pain crisis, and number of analgesics taken per month. Thermographic testing of migraine sufferers showed a reduction of hypothermia as well as the response to trigger factors. No serious adverse events were observed (Volta et al 2016).

PEA appears to be highly effective for pelvic pain in young women, for example from dysmenorrhea (Tartaglia et al 2015). Endometriosis pain can be completely debilitating, with the pain being driven by inflammation linked to degranulating mast cells. Women with endometriosis treated for three months with oral PEA 400mg and polydatin 40mg, twice daily for 90 days showed reduced deep dyspareunia, dyschezia, dysuria, dysmenorrhoea, and analgesic drug use in all subjects. Additionally, some improvements in endometriotic lesions were demonstrated by imaging (Indraccolo and Barbieri 2010). The efficacy of the palmitoylethanolamide-polydatin combination for controlling chronic pelvic pain was later confirmed in a meta-analysis (Indraccolo et al 2017). Micronized palmitoylethanolamide-polydatin also reduced pain and urinary frequency in interstitial cystitis and other bladder pain syndromes (Cervigni et al 2019).

Growing evidence suggests that PEA may be neuroprotective during CNS neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, by switching off inflammation caused by mast cell activation (Skaper et al 2015). Mechanisms of action include modulation of peroxisome proliferator-activated receptor (PPAR) (Ye et al 2020) which controls calcium ion (Ca⁺²)-activated intermediate-and/or big-conductance potassium ion (K⁺) channel opening, a driver of neuronal hyperpolarization. This is reinforced by the increase of the inward chloride ion (Cl⁻) currents due to the modulation of the GABA receptors and by the desensitization of the TRPV1 receptors. PEA blunted Aβ-induced neuroinflammation in an in vitro rodent model of Alzheimer’s (Scuderi et al 2011) by significantly diminishing either the altered expression of pro-inflammatory molecules, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), or the enhanced release of prostaglandin PGE2, nitric oxide, IL-1β, and TNF-α. A PPAR-α antagonist was able to partly blunt the PEA-induced effects against Aβ-induced astrogliosis and neuroinflammation, thus suggesting a significant, but not exclusive, involvement of the PPAR-α in mediating these PEA effects (Paterniti et al 2013). PEA critically diminished the activation of p38 and Jun N-terminal kinase (JNK), as well as the subsequent activation of nuclear transcription factors, such as nuclear factor kappaB (NF-kB) and activator protein 1 (AP-1) (Beggatio et al 2019). This gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neuro-steroid synthesis. Overall, the integration of these different modes of action allows PEA to exert robust control over neuron excitability and neuronal inflammation, maintaining cellular homeostasis (Raso 2014). 

PEA used for one year at 600mg daily slowed down Parkinson’s disease progression and disability (Brotini et al 2017).

Some lesser evidence suggests other uses for PEA besides pain syndromes. PEA apparently reduces atherosclerotic plaque by promoting an anti-inflammatory and pro-resolving phenotype of lesional macrophages (Rinne et al 2018). PEA moderated eczema, and allergic dermatitis in a canine model (Cerrato et al 2012). Inflammation as well as glutamate excitotoxicity have been proposed to participate in the propagation of autism. PEA prevents glutamatergic toxicity and may augment therapeutic effects of risperidone on autism-related irritability and hyperactivity in children (Khalaj et al 2018).

In major depressive disorder there was a rapid onset of improvement with PEA given as an adjunct to Citalopram standard of care, with no additional adverse effects (Ghazizadeh et al 2018).

Summary

PEA is a natural food-source pain reliever with an unusual safety to efficacy profile. It is useful in a wide range of acute and chronic neurological injuries and diseases, and combines well with other therapies. Research suggests doses of 600 to 800mg twice daily for pain and acute conditions, yet as little as 600 to 800mg once daily for chronic conditions.

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