Abstract
All nations which have undergone a nutrition transition have experienced increased frequency and falling latency of chronic degenerative diseases, which are largely driven by chronic inflammatory stress. Dietary supplementation is a valid strategy to reduce the risk and severity of such disorders. Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator with extensively documented anti-inflammatory, analgesic, antimicrobial, immunomodulatory and neuroprotective effects. It is well tolerated and devoid of side effects in animals and humans. PEA’s actions on multiple molecular targets while modulating multiple inflammatory mediators provide therapeutic benefits in many applications, including immunity, brain health, allergy, pain modulation, joint health, sleep and recovery. PEA’s poor oral bioavailability, a major obstacle in early research, has been overcome by advanced delivery systems now licensed as food supplements. This review summarizes the functionality of PEA, supporting its use as an important dietary supplement for lifestyle management.
1. Introduction
The nutrition transition has created multiple pandemics of chronic degenerative disease, which are overwhelming health care systems everywhere [1,2,3,4,5]. Deleterious lifestyle changes include exposure to environmental and industrial pollutants, the erosion of photoperiodism, decreased physical activity, high intakes of ultra-processed foods and a resulting increased dependence on pharmaceuticals [1,2,3,4]. These create dysnutrition, chronic inflammation, dysbiosis and immunosenescence, which in turn increase susceptibility to metabolic disease, cardiovascular disease, cancers, chronic pain, joint disease, asthma, gastrointestinal disorders, affective disorders and neurodegenerative disease [1,2,4,5,6,7].
Many pharmaceutical products have been developed to treat the symptoms of these disorders, but they do not address their fundamental causes and are too toxic to be used preventatively [5,8]. Foods and food derivatives are eminently suitable for public health interventions.
Due to their generally wide therapeutic indices, there is a clear and growing rationale to use supplementation to recreate pre-transitional dietary profiles, restore nutritional and metabolic normality [9,10,11,12,13] and salvage our public health. Such supplements should ideally protect against inflammatory and oxidative stress, and in the current public health environment, they should also target pathways involved in pain sensation, immune regulation, recovery and brain health.
Palmitoylethanolamide (PEA) is an endocannabinoid (eCB)-like bioactive lipid mediator [14,15] belonging to the N-acyl-ethanolamine (NAE) fatty acid amide family [16]. Synthesized on demand within the lipid bilayer [17], it acts locally [18] and is found in all tissues including the brain [18,19]. PEA is thought to be produced as a pro-homeostatic protective response to cellular injury [18] and is usually up-regulated in disease states [18,20]. Its pleiotropic effects include anti-inflammatory, analgesic, anticonvulsant, antimicrobial, antipyretic, antiepileptic, immunomodulatory and neuroprotective activities [14,17,21,22,23]. PEA’s multi-faceted effects are due to its unique mechanisms of action that affect multiple pathways at different sites [18]; primarily targeting the nuclear receptor peroxisome proliferator-activated alpha (PPAR-α), PEA also acts on novel cannabinoid receptor, G protein-coupled receptor 55 (GPR55) and G protein-coupled receptor 119 (GPR119) [9,14]. Moreover, it indirectly activates cannabinoid receptors 1 and 2 (CB1 and CB2) through inhibiting the degradation of the endocannabinoid, anandamide (AEA), a phenomenon known as the ‘entourage effect’ [9,16].
Additionally, PEA activates and desensitizes the transient receptor potential vanilloid receptor 1 (TRPV1) channels, contributing to a significant anti-nociceptive effect. It does so via several mechanisms, including the entourage effect, through PPAR-α activation and by potentially acting as an allosteric modulator [9,16]. PEA’s inhibition of mast cell (MC) activation also plays a role here, a mechanism discovered by Professor Rita Levi Montalcini and colleagues, who characterized this as Autacoid Local Inflammation Antagonism (ALIA) [23,24,25]. Detailed information into PEA’s mechanisms of action can be found elsewhere [9,23,24].
PEA’s multiple mechanisms of action generate therapeutic benefits in many disorders, including allergic reactions [17,21,25,26], influenza [24], common cold [24], chronic pain [27,28], joint pain [29], psychopathologies [27,30] and neurodegeneration [14,15,16,17,19]. They also contribute to enhanced muscle recovery [31] and improved cognition [26,32], mood [26,28,33] and sleep [34,35]. Endogenous PEA is generally insufficient to counter chronic allostatic load as seen in chronic inflammatory disorders [30,36,37], making exogenous administration a viable therapeutic strategy to top-up endogenous levels and restore bodily homeostasis [36,37].
A number of PEA-containing products are licensed for use as nutraceuticals, food supplements or foods for medical purposes in different countries, with a generally recommended dose of 1200 mg/day [16]. A novel form of PEA using LipiSperse® technology to achieve enhanced bioavailability will likely allow lower dosages (See Section 9). These products testify to PEA’s excellent clinical and pre-clinical safety record, which goes back to the 1950s [18,24,25].
Table 1 lists the applications of PEA in physical and mental health management.
Table 1.
Overview of PEA as a potential lifestyle management solution.
| Effects | Indications | References |
|---|---|---|
| Anti-inflammatory/prophylactic | Anti-ageing, immuno-enhancement |
[38,39,40,41,42,43,44] |
| Anti-inflammatory | Allergic reactions, Exercise recovery, Brain health | [24,25,31,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60] |
| Antinociceptive/Anti-inflammatory | Pain, Joint health, Sleep, Brain health | [15,16,17,19,26,27,29,34,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78] |
| Anti-inflammatory/anxiolytic | Brain health, Sleep | [27,29,34,35,79,80] |
| Nootropic | Brain health | [16,19,26,27,31,33,56,57,58,59,81,82] |
| Gut microbiome modulation | Immunity, Brain health, Various | [82,83,84,85] |
2. PEA and Immunity
Emergent viruses underline the importance of immune health. In the absence of vaccines, the body’s innate immune system is the primary defense against pathogens [86]. The immune system and especially the innate components are also key to self/non-self differentiation and recognition, and to proteostasis and tissue repair [87].
Innate cellular components include phagocytes (e.g., macrophages), neutrophils, MC and others [87]. These and innate humoral components, including cytokines, modulate the inflammatory response, maintaining immune-surveillance and the acute inflammatory reaction. Conversely, the modern diet and the ageing process create imbalances which drive chronic inflammation [88]. The synthetic anti-inflammatory drugs have applications in the short-term management of chronic inflammation but are too toxic for long-term and/or preventive use at the public health level. Endogenous and/or food-derived supplements offer a safer alternative [89].
In the 1960s, PEA was first marketed for prophylactic treatment of influenza and the common cold. Research interest increased in the 1970s, with six clinical trials confirming the effectiveness of PEA on influenza symptoms and incidence. Pre-clinical work had suggested that this prophylactic action was due to PEA’s ability to increase the body’s nonspecific (innate) resistance to bacteria and viruses [90]. The immunomodulatory effects of PEA are summarized in Table 2.
Table 2.
Summarization of PEA’s immunomodulatory effects.
| Effects | Mechanisms of Action | References |
|---|---|---|
| Anti-inflammatory/prophylactic | Regulation of macrophages and cytokines via PPAR-α | [38,39] |
| Anti-inflammatory | Control of MC degranulation | [40,41] |
| Prophylactic | Nonspecific bacterial resistance | [42,43,44] |
| Entourage | Modulation of migration and phagocytic activities of macrophages and microglial cells | [91,92,93] |
| Anti-inflammatory/Gut-derived immunity modulation | Maintenance of gut barrier and microbiome integrity via PPAR-α | [83,84] |
2.1. PEA’s Antiviral Activities
PEA binds to the PPAR-α receptor and initiates mechanisms which activate macrophages and, thus, enhance resistance to infection. Influenza infection is characterized by increased production of inflammatory cytokines such as tumor necrosis factor α (TNF)-α, interleukin- (IL-) 1, IL-6, and IL-10, which may lead to a hyper-inflammatory state known as a ‘cytokine storm’ [94]. This contributes to the increased morbidity and mortality associated with virulent infections [95]. PEA’s binding to PPAR-α receptors of immune cells such as macrophages and MCs leads to reduced production of inflammatory signals and reduced pain signals [38], as documented in over 60 PubMed indexed papers. PEA also modulates interleukin chemistry. Di Paola et al. demonstrated that 10 mg/kg body weight PEA significantly reduced intestinal damage and inflammation in a reperfusion injury murine model, inhibiting proinflammatory cytokine production (TNF-α, IL-1β), adhesion molecule (ICAM-1, P-selectin) expression and NF-κB expression [39]. PEA’s anti-inflammatory and cytokine modulating actions explain its documented ability to provide symptomatic relief at the onset of influenza and common cold.
PEA also modulates MC activity. MCs are strategically localized at sites that directly interface with the external environment and act as sensors/transponders, detecting different kinds of injuries and responding with varying degrees of activation. When activated, they regulate innate and adaptive immune responses by releasing pre-formed and newly synthesized mediators [96]. MC hyper-activation, which can be disabling and even lethal, is treated with anti-histamines and anti-leukotrienes. These drugs have serious side effects, including vomiting, heartburn and immune suppression [97,98].
Cannabinoid-based drugs have shown promise but are beset by ethical problems [96]. PEA prevents MC degradation in vitro and in vivo, and down-regulates MC-derived inflammation [40]. More recently, PEA was shown to inhibit release of histamine, prostaglandin D2 and TNF-α induced by allergens in isolated canine skin MC in a dose-dependent manner ranging from 10-8 to 10-6 M of PEA concentration [41]. In this way, PEA can be used as an immune checkpoint.
2.2. PEA’s Antibacterial Activities
PEA protects against bacterial infection via innate immune modulation involving MCs, macrophages and microglia. Prophylactic PEA at a dose of 0.1 mg/kg body weight prolonged survival rate and reduced neuro-inflammation in an aged murine bacterial meningitis model, in the absence of antibiotics [42]. In the early phase of infection, the PEA pre-treated mice showed lower bacterial titers in spleen, liver and blood than controls. PEA pre-treatment also increased the survival rate and bacterial clearance of immunocompetent young mice challenged with E. coli [42]. Other pre-clinical studies have similarly shown PEA’s ability to increase resistance to systemic bacterial infections [43,44].
Microglia cells, the resident macrophage population in the central nervous system (CNS), defend the CNS from infection [99], clear cellular debris [100] and provide various support functions to neurons. Exposure to PEA stimulates E. coli uptake in macrophages and microglia [91], likely via CB2-enhanced chemotaxis and PPAR-α-induced phagocytosis [92]. PEA’s ‘entourage effect’ enhances the physiological effects of endocannabinoids such as AEA by preventing their enzymatic-mediated hydrolysis by fatty acid amide hydrolase (FAAH), which results in TRPV1 and CB2 stimulation. This provides another route to the activation of macrophages, neutrophils and other immune cells [93], thus contributing to PEA’s anti-infective properties. AEA also has anti-inflammatory and pro-apoptotic activities through which it can inhibit TNF-α and NF-κB [101]. PEA is considered to constitute a “parallel” endocannabinoid signaling system without the adverse effects of synthetic endocannabinoids.
2.3. PEA’s Modulation of Gut-Derived Immunity
The majority of immune cells are localized within the gut-associated lymphoid tissue (GALT) [87]. When food is ingested, the body is exposed to abundant antigenic stimulation, requiring the immune system to discriminate between potential pathogens, and food proteins and symbionts. The gut microbiota plays an important role in nutrient metabolism and absorption. It is a critical factor in determining gut health, providing energy for epithelial cells, regulating local and systemic immune function and maintaining epithelial barrier integrity [102]. Acute and chronic gastrointestinal tract (GIT) inflammation caused by dysbiosis or vitamin D deficiency damages the epithelial barrier, known colloquially as ‘leaky gut’. This triggers efflux of immune cells from GALT, causing immune dysregulation and a range of pathologies [103].
PEA may contribute to correcting the effects of dysbiosis. In an induced inflammation state, such as vitamin D deficiency in mice, intraperitoneal administration of PEA increases the level of commensal bacteria such as Akkermansia muciniphila (protective effects against obesity and diabetes), Eubacterium (microbiome regulatory properties) and Enterobacteriaceae [83]. Moreover, exogenous administration of PEA relieves chronic and acute GIT inflammation via its action on PPAR-α in the colon [84]. For these reasons, PEA is becoming an increasingly popular topic in microbiome research.
2.4. Future Directions of PEA’s Role as An Immunomodulator
The beneficial effects of PEA on immune function are documented in over 350 peer-reviewed papers, including animal and human studies [38]. These show that PEA’s multifaceted immunomodulation reflects its ability to target multiple pathways which work synergistically and physiologically to produce therapeutic effects [104].
PEA’s safety/efficacy profile also makes it suitable for prophylactic use. Unlike other endocannabinoids, catabolism of PEA in the body gives rise to relatively inactive products (palmitic acid and ethanolamine), which do not produce adverse effects [105]. Regular administration of PEA can, therefore, be used to maintain immune health in programs designed to support health in general and healthy ageing.
3. PEA and Inflammatory Reactions
PEA’s Antiallergic Effects
Allergic reactions such as allergic rhinitis, allergic dermatitis and allergic asthma are characterized by inflammation and inflammatory cell infiltration [106,107,108]. Upon recognition of an allergenic factor, MCs are activated and degranulate, releasing mediators such as histamine, cytokines and chemokines, which trigger an inflammatory response. The antiallergic effects of PEA can be traced back to the 1950s, when Coburn and colleagues reported that a phospholipid fraction isolated from egg yolk demonstrated antiallergic activity in guinea pigs [45].
More recent animal studies have confirmed PEA’s antiallergic actions, which include down-regulation of MC recruitment and degranulation. PEA’s protective effects are mediated by its cellular targets, including the direct activation of PPAR-α and GPR55 receptors and the indirect activation of cannabinoid receptors (CB1 and CB2) and TRPV1 channels [46]. In one study conducted on canine skin mast cells, PEA (in doses ranging from 10-8 M to 10-5 M) induced a significant and dose-dependent inhibition of PGD2, TNF-α and histamine release [41]. In Ascaris hypersensitive beagle dogs, a single oral dose of um-PEA (at doses of 3, 10 and 30 mg/kg) significantly reduced allergic wheal reactions in skin [47]. Treatment with PEA also showed improvement of clinical signs in cats with eosinophilic granuloma [48]. Another study showed that treatment with PEA was effective in the improvement of skin lesions and pruritus in dogs with atopic dermatitis and moderate pruritus [49]. In mice sensitized with aerosolized ovalbumin, bronchial levels of PEA were reduced, while CB2 and GPR55 were up-regulated [46]. Leukocyte infiltration and pulmonary inflammation were significantly inhibited by 10 mg/kg PEA supplementation prior to sensitization. Furthermore, pulmonary mast cell recruitment and degranulation, and leukotriene C4 production were also significantly inhibited, demonstrating a depletion/repletion scenario.
Mice with 2,4-dinitrofluorobenzene (DNFB)-induced contact allergic dermatitis (CAD) showed increased ear skin PEA levels, and increased TRPV1, PPAR-α and NAPE-PLD in ear keratinocytes in the early stage of the condition [50]. In this model, PEA given intraperitoneally exerted anti-inflammatory effects, likely through TRPV1 receptors. The authors also report findings from in vitro experiments that exogenous PEA treatment inhibited the expression and release of the inflammatory cytokine MCP-2 in poly-(I:C)-treated HaCaT cells, again likely through a TRPV1 mediated mechanism [50]. In late-stage CAD, 5 mg/kg PEA administration reduced numbers of MCs in the ear while inhibiting VEGF and its receptor Flk-1, components in angiogenesis, which is a major characteristic of contact hypersensitivity reactions [51]. Vaia and colleagues also reported that PEA administration led to the restoration of levels of 2-AG. This, together with findings of the reduction in MC activation and neo-angiogenesis being blocked by a CB2 receptor antagonist, points to a CB2 receptor mediated mechanism of anti-inflammatory action [51]. Abramo et al. reported increased expression of CB1 and CB2 receptors in the lesional skin of dogs with atopic dermatitis compared to normal dogs [52]. These findings highlight the importance of PEA as an anti-inflammatory and protective modulator.
There are a few studies demonstrating the efficacy of PEA formulations in allergic conditions in humans. Findings from a multinational, multicenter study on atopic eczema showed that topical application of a cream with a unique lamellar matrix containing PEA significantly reduced intensities of erythema, pruritus, excoriation, scaling, lichenification and dryness [53]. There is also an intriguing case report of a 13-year-old child with autism, presenting with significant atopic illness including chronic eczema, allergic rhinitis and asthma. The physicians reported that daily oral administration of PEA for one month (first at 600mg/day and later increased to 1200mg/day) resulted in a marked reduction in allergy stigmata, skin eczema and urticaria [26]. There is a need for further clinical studies to confirm these findings.
4. PEA and Brain Health
Neuroinflammation is now regarded as a key aspect in the pathogenesis of many if not all neurodegenerative disorders [15,18] including Alzheimer’s (AD) [14,16,17,18,19,54,55], Parkinson’s disease (PD) [32,109], stroke [56], traumatic brain injury (TBI) [20,57,58,81], autism spectrum disorder (ASD) [26,59], epilepsy [21] and cognitive [32], behavioral [26,59] and mood disorders [28].
Key inflammatory cells in these conditions include MCs, microglia and astrocytes [55]. While the detailed biochemistry of neuroinflammation is beyond the scope of this review, the neuroinflammatory cascade degrades neuronal structures, impairing neuronal function and viability [18,54]. Dampening neuroinflammation may, therefore, be an effective way to preserve brain structure and function [55,109]. There is evidence that NAEs such as PEA exert neuroprotective actions by promoting the resolution of neuroinflammation [33]. The increased PEA levels in several CNS pathologies may, therefore, be an endogenous cytoprotective response to injury [18,21,28]. PEA and its receptors are present in different cell types in the CNS [17,18], and as PEA crosses the blood brain barrier [110], additional exogenous PEA may find uses in the prevention and long-term management of various neuroinflammatory conditions.
4.1. PEA’s Neuroprotective Effects
PEA’s neuroprotective effects are due to its ability to modify MC, microglia and astrocyte activation [18,57]. It enhances microglial migration without promoting activation [18], thereby increasing resistance to infection without measurable pro-inflammatory effects [14]. This highlights PEA’s role as an immunomodulator rather than an immunosuppressant [14].
Other neuroprotective actions include inhibiting apoptosis and autophagy [16,18] by modulating the (bcl-2-associated X protein) bax/bcl-2 [56,58] and Akt/mTOR/p70S6K pathways [27,57]; limiting necrotic processes [18]; targeting NMDA receptors, thereby protecting cells against glutamate toxicity [28]; modulating synaptic homeostasis [28]; promoting neurogenesis [28]; and down-regulating the development of cerebral edema [18,20] and local inflammatory cascades [18]. PEA’s inhibition of pro-inflammatory cytokines likely contributes to its ability to prevent cortical spreading depression in pre-clinical models [111] and its therapeutic effects in migraine [60].
The above mechanisms correlate with PEA’s protective effects in ex vivo and murine models of Alzheimer’s Disease [14,15,16,17,19,54,55], Parkinson’s Disease [33,109], ASD [26,59], stroke [56] and traumatic brain injury [57,58,81]. In these models, chronic PEA administration (10–100 mg/kg) attenuated gliosis and neuroinflammation [15,16,17,19,33,54,55,56,57,58], protected against neuronal degeneration and apoptosis [15,16,17,19,33,54,55,56,57,58,81,109], rescued glutamate toxicity [16], inhibited oxidative stress processes [16,56,57] and improved behavioral [19,33,56,58,81], motor [33,57,109] and cognitive deficits [16,19,33,57].
As the endocannabinoid system regulates axonal growth, guidance, neurogenesis and behavior [59], these neurotrophic actions likely contribute to PEA’s benefits in maintaining cognitive, behavioral and mental health in individuals.
4.2. PEA’s Effects on Mood, Cognition and Behavior
ECs and NAEs are involved in the regulation of behavior, mood and cognition [32], and their levels are generally dysregulated in anxiety [30,32], depression [28,112,113], post-traumatic stress disorder (PTSD) [30] and ASD [26]. PEA levels are increased by acute psychosocial stress [30,112], presumably as a protective response to aversive and/or hazardous situations [30] and a modifier of the induced Cell Danger Response (CDR) [114]; but are unaffected [112] or reduced [28] in depression.
The therapeutic use of endocannabinoids in these disorders has produced promising results [26,28,30]. Analogously, many patients with PTSD self-medicate with cannabis [30] and antidepressants have been reported to increase brain PEA levels [28].
In one study, PEA levels were found to be higher in individuals suffering from PTSD compared to trauma-exposed individuals without PTSD and correlated with a greater symptom severity [30]. This suggests that endogenous NAE levels are insufficient to restore homeostasis in chronic aversive states, which would explain why PTSD patients self-medicate with cannabis [30] and why, in animal models of AD [33] and TBI [57,58,81], PEA administration improves memory function and reduces anxiety, aggressiveness and depression [57,58,59,81].
Interestingly PEA was shown to increase hippocampal neurogenesis and neuroplasticity in an established murine model of autism [33], and prevented the decrease in brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in a murine model of cerebral ischemia [56]. It also promotes the maturation of oligodendrocyte precursor cells [115]. Such nootropic effects may play a part in PEA’s cognitive-enhancing capacities. This further strengthens the potential use of PEA as a brain health-enhancing compound.
Much of the preclinical work has been replicated in human studies of variable quality. When used as an add-on therapy to levodopa in PD patients, PEA was found to improve motor and non-motor symptoms, including mood deficits, fatigue, sleep and mental tasks, after continuous administration for one year [32]. Caltagirone et al. investigated the effect of a co-ultramicronized composite containing 700 mg PEA and 70 mg luteolin in stroke patients, in combination with standard rehabilitation therapy, and found that PEA therapy for 60 days significantly improved neurological status, cognitive abilities and degree of spasticity, pain and independence [56]. De Palma et al. studied the effects of PEA treatment as an add-on to neuro-rehabilitation in a 12-year-old boy with traumatic brain injury in an intensive care unit [20]. At the end of the treatment period, the patient showed considerable improvements in motor and cognitive functions while being in a minimally conscious state. The authors deemed this improvement greater than had been seen in patients with similar conditions [20]. A double-blind, randomized, placebo-controlled study found that patients with major depressive disorder (MDD) receiving 600 mg PEA in addition to citalopram for 6 weeks twice daily demonstrated significantly greater improvements in depressive scores and symptoms compared to citalopram plus placebo group [28]. Three case studies on autistic children reported PEA administration (600–700 mg per day for several months to a year) improved behavior, sociability and cognition [26,59].
PEA’s ability to enhance neurogenesis [56] and facilitate synaptic plasticity [28,56] likely plays a role in improving behavior and cognition, but as depression and chronic pain can interfere with cognition, memory and decision making, PEA’s antidepressant, anxiolytic and analgesic actions are potentially also involved here [28,29,81].
PEA’s ability to target neuro-inflammation, pain, depression, anxiety and at the same time support neurogenesis and synaptic pruning makes it a viable therapeutic aid for brain disorders. The clinical data look promising, but further clinical trials are needed to confirm these findings. As all human studies to date report PEA to be well tolerated and without adverse effects [20,26,28,33,56], the potential role of PEA in enhancing brain health in clinically healthy populations becomes another key area of interest.