Herbs and Nutrients That May Assist

Palmitoylethanolamide (PEA)
Palmidrol (Palmitoylethanolamide)(Levagen+™)
Saffron (Affron^®)
Crocus sativus
Vitamin B1
Thiamine hydrochloride

Actions

• Analgesic and antinociceptive
• Reduces nerve inflammation and ^sensitivity
• Preserves and protects nerve tissue

Clinical Applications

• Neuralgia and neuropathic pain
• Sciatica and compression neuropathy
• Neurodegenerative conditions
• Parkinson’s disease
• Multiple sclerosis
• Alzheimer’s disease and cognitive impairment

Bioavailable Palmitoylethanolamide (PEA), with Saffron and Thiamine for Nerve Pain

With the growing number of people experiencing chronic pain, approximately one in five suffer from neuropathic pain.^[1] Among these individuals, up to 75% report moderate to severe pain despite using analgesic medications.^[2] This highlights the urgent need for effective therapeutics.

Neuropathic pain is complex and multifaceted, with neuroinflammation playing a key role. After nerve injury, high levels of inflammatory cytokines lower nerve activation thresholds, increasing nerve sensitivity to tissue damage. This amplifies the nervous system’s response to pain (Figure 1).^[3] Additionally, unmanaged neuroinflammation is linked to neurodegenerative disorders like Alzheimer’s disease, underscoring its harmful effects on neuronal tissue. ^[4]

To support pain management, palmitoylethanolamide (PEA), saffron, and thiamine offer analgesic and neuroprotective benefits. PEA promotes the expression and activity of cannabinoid receptors 1 (CB1) and 2 (CB2), enhancing the endogenous cannabinoid system (ECS) to reduce pain and inflammation.^[5] PEA also minimizes pain amplification by mitigating glial cell activation and desensitizing pain receptors.^[5-7] Similarly, saffron reduces pain receptor sensitivity, while thiamine is essential for healthy nerve cell function. By targeting multiple mechanisms, PEA, saffron, and thiamine can effectively support the management of chronic pain.^[5-9]

Background Technical Information

The Physiology of Neuropathic Pain

Neuropathic pain is caused by disease or damage to sensory neurons and can be classified into two types^[10]:

• Peripheral neuropathic pain: This arises from injury to the peripheral nervous system (PNS) due to mechanical damage (e.g., nerve injury), medication-related side effects (e.g., chemotherapeutic drugs), metabolic diseases (e.g., diabetic neuropathy), or infections (e.g., shingles).
• Central neuropathic pain: This is triggered by damage to the central nervous system (CNS) such as spinal cord injury, brain damage, and neurodegenerative disorders.

When neurons are damaged, the immune system activates inflammatory processes at the injury site by releasing neuropeptides like substance P and calcitonin gene-related peptide (CGRP). ^[10] This triggers the release of inflammatory mediators such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), prostaglandins, histamine, nerve growth factor (NGF), and nitric oxide by local mast cells to facilitate tissue healing. ^[11] However, persistent neuron damage can prolong neuroinflammation and amplify pain signaling due to:

• Increased nociceptor sensitivity: Sensory receptors like transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) generate nerve impulses that produce pain signals. Chronic inflammation heightens TRPV1 and TRPA1 sensitivity, increasing pain perception. ^[12-14]
• Glial cell-mediated inflammation: Neuroinflammation increases the activation of glial cells (astrocytes and microglia) within the CNS, perpetuating proinflammatory mechanisms that amplify pain signaling. ^[3,10,13,15]
• Increased pain neurotransmission: Elevated nociceptor sensitivity^[16] and glial activation promote excessive glutamate activity in the CNS, increasing excitatory neuronal activity and pain transmission.^[13,15,17]
• Downregulation of opioid receptors: Chronic inflammation reduces opioid receptor activity, leading to a diminished analgesic response and increased pain signaling. ^[18,19]

These mechanisms collectively increase nerve excitability and decrease pain tolerance, leading to pain hypersensitivity. ^[10] This results in abnormal pain responses such as allodynia (pain in response to non-painful stimuli) and hyperalgesia (exaggerated pain perception due to damaged sensory fibers). ^[10] Therefore, strategies that effectively downregulate neuroinflammation can help manage chronic pain.^[2]

Effectively Managing Neuropathic Pain with Natural Medicine

To manage neuropathic pain, a combination of palmitoylethanolamide (PEA), saffron, and thiamine (vitamin B1) offers effective pain relief and can be safely prescribed alongside analgesic medications. ^[20-24] Supported by clinical data, these ingredients help downregulate both nociceptor sensitivity and glial activation, which contribute to chronic pain. ^{[3,6-8,25,26]} Additionally, PEA promotes ECS activity, exerting analgesic and anti-inflammatory effects by enhancing the expression and activity of CB1 and CB2 receptors (Figure 2). ^[10,27,28] Specifically, the activation of these receptors mitigates neuroinflammation and limits neuropathic pain. For example, PEA has been suggested to:

• Augment endogenous cannabinoid (eCB) activity of anandamide (AEA) and 2-arachidonylglycerol (2-AG) upon CB1 and CB2 pathways.
• Modulate eCB-degrading enzyme, fatty-acid-amide hydrolase (FAAH), which potentiates AEA activation of CB1 and CB2 pathways.

In addition, PEA promotes ECS activity, shown to exert analgesic and anti-inflammatory effects by enhancing the expression and activity of CB₁ and CB₂ Specifically, the activation of these receptors has been shown to mitigate neuroinflammation and limit neuropathic pain. ^[10,48-50] For example, PEA has been suggested to:

• Augment endogenous cannabinoid (eCB) activity of anandamide (AEA) and 2-arachidonylgylcerol (2-AG) upon CB₁ and CB₂ pathways ^[5,30-33]; and,
• Modulate eCB-degrading enzyme, fatty-acid-amide hydrolase (FAAH),^{[29,34, 35]} which potentiates AEA activation of CB₁and CB₂ pathways ^[32,36]

Analgesic and antinociceptive

Analgesics that target pain sensory receptors (e.g. TRPV1 and TRPA1) have been identified as effective therapeutics for neuropathic pain.^{[13,14,42,43]} PEA has been shown to desensitise TRPV1 within neurons by stabilising intracellular calcium levels, therefore preventing synaptic depolarisation and nociception.^[7] In addition, PEA has been shown to increase 2-AG^[5] and AEA^[44] levels to enhance CB₁ and CB₂ activation and reduce TRVP1 sensitivity.

Actions

Analgesic and antinociceptive

Likewise, saffron constituent, safranal, has been observed to desensitise TRPA1, thereby blocking the release of inflammatory neuropeptides in human cells and animal models.^[8] Further to this, saffron constituent, crocin, was observed to improve motor function following nerve injury.^[45] As such, both PEA and saffron can promote analgesia by diminishing TRPV1 and TRPA1 activation.

In addition, thiamine has been shown to prolong the effects of nerve blocking agents when administered concurrently.^[46] Research indicates that thiamine supports pain control^[82] and promotes synthesis of neurotransmitters, acetylcholine^[47,48] and gamma-amino butyric acid (GABA), to increase pain tolerance.^[48] Illustrating this, thiamine supplementation following nerve injury minimised dorsal root ganglion excitability, thereby reducing pain transmission.^[49] Moreover, thiamine promotes myelin synthesis surrounding axonal tissue to preserve nerve structure^[50] by enhancing transketolase enzyme activity.^[51] Therefore, preventing

Reduces Nerve Inflammation and Sensitivity

In response to neuroinflammation, palmitoylethanolamide (PEA) works to down-regulate the activation of mast cells, microglia, and astrocytes. ^[3,4] PEA shifts mast cell phenotypes from activated to resting^[6,20,52] and deactivates glial cells, reducing their pro-inflammatory effects that contribute to neuropathic pain. ^[3,53] These outcomes are associated with PEA’s ability to stimulate peroxisome proliferator-activated receptor alpha (PPAR-α), a transcription factor that regulates the expression of proteins like nuclear factor kappa B (Nf-κB) within cells, which signal the release of inflammatory cytokines such as IL-6, IL-1β, and TNF-α. ^{[3,6,29,36,54,55]}

Moreover, through its effects on microglia, PEA has been shown to attenuate the release of proinflammatory cytokines (e.g., TNF-α and IL-1β) that promote neuronal excitability, thereby moderating nerve sensitivity,^[28] Additionally, saffron and its isolated constituent, safranal, have been shown to decrease neuroinflammation by inhibiting microglial and astrocyte activation in models of nerve trauma and oxidative damage. Specifically, by reducing glial activation, safranal was shown to improve neuropathic allodynia in vivo, highlighting saffron’s ability to modulate pain sensitivity. Therefore, the combination of PEA and saffron mitigates several proinflammatory pathways to help moderate neuropathic pain.

In addition, saffron^[25,26] and its isolated constituent, safranal,^[56] have been shown to decrease neuroinflammation by inhibiting microglial and astrocyte activation in models of nerve trauma and oxidative damage,^[25,26] Specifically, by reducing glial activation, safranal was shown to improve neuropathic allodynia in vivo,^[56] highlighting the ability of saffron to modulate pain sensitivity. As such, the combination of PEA and saffron mitigates several proinflammatory pathways to help moderate neuropathic pain.^[3,57,58]

Preserves and Protects Nerve Tissue

In healthy tissue, microglial activation protects the CNS by phagocytosing damaged cells and releasing inflammatory cytokines to initiate tissue healing. ^[59] However, in chronic neuroinflammation, prolonged inflammatory activity leads to oxidative conditions that impair neuronal repair, resulting in neuron damage and cell death. ^[4,59] Persistent neuroinflammation is implicated in neurodegenerative conditions such as Alzheimer’s disease.^[4]

Palmitoylethanolamide (PEA) has been shown to down-regulate mast cell and glial cell activation and enhance neuronal survival in neurodegenerative conditions. ^[3,6,49] By stimulating PPAR-α, PEA mitigates Nf-κB activity to limit chronic immune activation.^[6] For example, PEA treatment has been shown to improve cognitive function and motor deficits in models of Alzheimer’s and Parkinson’s diseases, supporting its neuroprotective effects. ^[57,61]

Furthermore, saffron constituents (crocin-1, crocin-2, crocin-3, crocin-4, and crocin-5) have also been shown to down-regulate microglial activation. ^[62,63] In several in vitro and in vivo studies, saffron increased intracellular antioxidant activity (e.g., glutathione and superoxide dismutase) and protected against neuron damage.^[64] Additionally, preventing thiamine deficiency has been shown to protect against synaptic dysfunction in neurodegenerative states. ^[65] Therefore, the combination of PEA, saffron, and thiamine works synergistically to preserve nerve tissue.

Clinical Applications

Neuralgia and Neuropathic Pain

In patients who experience chronic neuropathic pain, research has shown PEA provides effective symptom relief.^[66,67] For example, in an open-label study conducted in 30 patients, 1,200 mg/d of PEA over 50 days was shown to significantly improve chronic nerve pain.^[66] These outcomes were observed in individuals experiencing persistent pain despite pregabalin, gabapentin and/or tramadol use. Following PEA treatment, pain scores were reduced after 40 days from 82% to 58% (p<0.02). Furthermore, PEA also significantly decreased neuropathic symptoms including burning pain and paresthesia (5.20 ± 1.5 reduced to 3.8 ± 2.1; p<0.025).^[66]

Positive outcomes were also observed in a prospective-controlled study evaluating the effects of PEA for nerve pain due to chemotherapeutic use, trigeminal neuralgia and cervical spondylosis.^[67] Specifically, in 75 patients using conventional pain relief, 1,062 mg/d of PEA administered for 10 days, followed by an additional dose of 708 mg/d of PEA for 50 days was found to reduce pain frequency and intensity by over 50% (p<0.001). Moreover, significant improvements in neuropathic symptoms (e.g. burning, numbness and paresthesia) were also observed, which persisted for 30 days after PEA discontinuation (p<0.0001).^[67] As such, the pain-moderating effects of PEA are supported by clinical data for the management of neuralgia and neuropathic symptoms.

Sciatica and Compression Neuropathy

The efficacy of PEA in painful nerve compression has been observed in numerous clinical trials.^{[20,23,24,27,68]} For instance, in a large, randomised double-blinded placebo-controlled trial (n=636), 300 mg/d and 600 mg/d of PEA treatment prescribed for three weeks led to a clinically significant improvement in sciatic pain. At the end of the trial, pain scores were greatly reduced in the 600 mg/d group from 71% down to 21% (p<0.05).^[142],[143] These results are comparable to several other studies that evaluate the benefits of 600 mg/d of PEA over 30 days for sciatic pain,^[23,24] outlined in Table 1.

In the same vein, PEA has been shown to improve severe pain in patients with poor response to analgesic treatments. In two clinical trials, 1,200 mg/d of PEA prescribed for one month followed by 600 mg/d for a second month alongside pharmaceutical treatments (e.g. opioid medication, pregabalin and non-steroidal anti-inflammatory drugs [NSAIDs]) significantly reduced pain intensity.^[66,67] In one study,patients with severe lumbosciatic pain reported reduced pain scores from 80% to 58.5% after 30 days of PEA.^[68] Moreover, patient response to medication was enhanced by PEA treatment, lowering pain scores from 43% to 17% after two months (p<0.0001).^[69] Collectively, these studies indicate the benefits of PEA treatment to reduce the symptoms of compression neuropathy and sciatic pain.

Neurodegenerative conditions

Parkinson’s Disease

The neuroprotective effects of PEA have been shown to enhance patient outcomes in Parkinson’s disease.^[59] In one study, 600 mg/d of PEA administered over three months followed by 300 mg/d for a further 12 months led to significant patient improvement. Namely, PEA treatment reduced daily non-motor symptoms (i.e. depressed and anxious moods, sleep problems, pain and fatigue) as well as daily motor symptoms (e.g. impaired speech, dressing, tremor, walking and balance) after 12 months (p<0.001). PEA was also shown to increase motor assessment test scores (i.e. hand movement, resting tremor and gait control) and limit motor complications (i.e. functional impact of involuntary movement; p<0.0001).^[59] Therefore,these findings endorse the use of PEA to stabilise clinical symptoms related to neurodegeneration.

Multiple Sclerosis

In multiple sclerosis (MS), immune activation promotes nerve demyelination, leading to axonal injury and MS disability.^[70,71] Specifically, neuroinflammation following microglial activation is strongly associated with MS pathology.^[71] In relation to this, increased TNF-α levels observed in MS are linked to microglial activation,^[6.15] highlighting the relationship between cytokine levels and glial activation in MS. PEA has been shown to significantly reduce levels of TNF-α in MS.^[72] For instance, in a randomised, double-blind placebo-controlled trial, 600 mg/d of PEA administered for 12 months was shown to significantly lower TNF-α levels after six months, as well as interferon gamma (IFN-γ) and Il-17 after three months compared to placebo (p<0.05).^[55] These outcomes were also linked to reduced pain sensitivity in response to MS treatment (i.e. intramuscular IFN-β1 injection three times weekly), highlighting the positive effects of PEA in reducing treatment side effects.

Alzheimer’s Disease and Cognitive Impairment

Saffron has been shown to reduce cognitive decline in Alzheimer’s disease in two randomised double-blind clinical trials.^[73,74] In these studies, researchers examined the effects of 30 mg/d of saffron extract in relation to Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) outcomes over several months. For example, over 16 weeks, saffron was shown to increase cognitive scores by 3.69 points and prevented further cognitive decline that was observed in the placebo arm (which worsened by 4.08 points; p<0.0001).^[73] Similarly, over 22 weeks, saffron treatment was found to reduce cognitive dysfunction by 3.96 points, improving ADAS-cog scores as effectively as conventional treatment.^[74]

In summary, human data supports the combination of 600 mg/d of PEA and 45 mg/d of saffron for management of neuropathic pain and neurodegenerative conditions. Therefore, by providing analgesic, anti-inflammatory and neuroprotective benefits, PEA, saffron and thiamine can enhance clinical outcomes in these conditions.

Summary Table

Safety Information

Disclaimer: In the interest of supporting Healthcare Practitioners, all safety information provided at the time of publishing is in accordance with Natural Medicine Database (NATMED PRO), renowned for its professional monographs which include a thorough assessment of safety, warnings, and adverse effects.

For further information on specific interactions with medications, please contact Clinical Support on 1800 777 648, or via email, anz_clinicalsupport@metagenics.com

Pregnancy and Lactation

• Possibly unsafe/insufficient reliable information available; avoid using.[75]

Contraindications

• Contraindication with Colchicine; avoid this combination.[75]

References

1. Henderson J, Pollack AJ, Pan Y, Miller GC. Neuropathic and non-neuropathic chronic pain at GP encounters: Prevalence, patient characteristics, suffering and pregabalin use. Aust Fam Physician. 2016;45(11):783-86.
2. O'Connor AB. Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics. 2009;27(2):95-112. doi:10.2165/00019053-200927020-00002
3. Skaper SD, Facci L, Giusti P. Mast cells, glia and neuroinflammation: partners in crime? Immunology. 2014;141(3):314-27. doi:10.1111/imm.12170
4. Kempuraj D, Thangavel R, Natteru PA, et al. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine. 2016;1(1):1003. PMID: 28127589.
5. Petrosino S, Schiano Moriello A, Cerrato S, et al. The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. Br J Pharmacol. 2016;173(7):1154-62. doi:10.1111/bph.13084
6. Grabacka M, Pierzchalska M, Płonka PM, Pierzchalski P. The role of PPAR alpha in the modulation of innate immunity. Int J Mol Sci. 2021;22(19):10545. doi:10.3390/ijms221910545.
7. Ambrosino P, Soldovieri MV, Russo C, Taglialatela M. Activation and desensitization of TRPV1 channels in sensory neurons by the PPARα agonist palmitoylethanolamide. Br J Pharmacol. 2013;168(6):1430-44.
8. Li Puma S, Landini L, Macedo SJ Jr, et al. TRPA1 mediates the antinociceptive properties of the constituent of Crocus sativus L., safranal. J Cell Mol Med. 2019;23(3):1976-1986.
9. Song X-J. Analgesic and neuroprotective effects of B vitamins. In: Nutritional modulators of pain in the aging population. London: Academic Press Elsevier; 2017.
10. D'Amico R, Impellizzeri D, Cuzzocrea S, Di Paola R. ALIAmides update: palmitoylethanolamide and its formulations on management of peripheral neuropathic pain. Int J Mol Sci. 2020 27;21(15):5330. doi:10.3390/ijms21155330
11. Héron A, Dubayle D. A focus on mast cells and pain. J Neuroimmunol. 2013;264(1-2):1-7. doi:10.1016/j.jneuroim.2013.09.018.
12. Gouin O, L'Herondelle K, Lebonvallet N, et al. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell. 2017;8(9):644-661. doi:10.1007/s13238-017-0395-5.
13. Souza Monteiro de Araujo D, Nassini R, Geppetti P, De Logu F. TRPA1 as a therapeutic target for nociceptive pain. Expert Opin Ther Targets. 2020;24(10):997-1008. doi:10.1080/14728222.2020.1815191.
14. Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: on the road to pain relief. Curr Mol Pharmacol. 2008;1(3):255-69. doi:10.2174/1874467210801030255.
15. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154 Suppl 1(1):S10-S28. doi:10.1016/j.pain.2013.06.022.
16. Malek N, Pajak A, Kolosowska N, Kucharczyk M, Starowicz K. The importance of TRPV1-sensitisation factors for the development of neuropathic pain. Mol Cell Neurosci. 2015;65:1-10. doi:10.1016/j.mcn.2015.02.001.
17. Ralston SH, Penman ID, Strachan M, Hobson R. Davidson’s principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018.
18. Zheng BX, Malik A, Xiong M, Bekker A, Tao YX. Nerve trauma-caused downregulation of opioid receptors in primary afferent neurons: Molecular mechanisms and potential managements. Exp Neurol. 2021;337:113572. doi:10.1016/j.expneurol.2020.113572.
19. Thompson SJ, Pitcher MH, Stone LS, et al. Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat. Pain. 2018;159(9):1856-1866.doi:10.1097/j.pain.0000000000001282.
20. Keppel Hesselink JM, Hekker TA. Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series. J Pain Res. 2012;5:437–442. doi:10.2147/JPR.S32143.
21. Del Giorno R, Skaper S, Paladini A, Varrassi G, Coaccioli S. Palmitoylethanolamide in fibromyalgia: results from prospective and retrospective observational studies. Pain Ther. 2015 Dec;4(2):169-78. doi:10.1007/s40122-015-0038-6.

22. Passavanti MB, Fiore M, Sansone P, et al. The beneficial use of ultramicronized palmitoylethanolamide as add-on therapy to tapentadol in the treatment of low back pain: a pilot study comparing prospective and retrospective observational arms. BMC Anesthesiol. 2017;17(1):171. doi:10.1186/s12871-017-0461-9.

23. Domínguez CM, Martín AD, Ferrer FG, et al. N-palmitoylethanolamide in the treatment of neuropathic pain associated with lumbosciatica. Pain Manag. 2012;2(2):119-24. doi:10.2217/pmt.12.5

24. Morera C, Sabates S, Jaen A. Sex differences in N-palmitoylethanolamide effectiveness in neuropathic pain associated with lumbosciatalgia. Pain Manag. 2015;5(2):81-7. doi: 10.2217/pmt.15.5.

25. Shaheen MJ, Bekdash AM, Itani HA, Borjac JM. Saffron extract attenuates neuroinflammation in rmTBI mouse model by suppressing NLRP3 inflammasome activation via SIRT1. PLoS One. 2021;16(9):e0257211. doi: 10.1371/journal.pone.0257211.
26. Zhang Q, Ye YL. Neuroprotective effects of saffron on the late cerebral ischemia injury through inhibiting astrogliosis and glial scar formation in rats. Biomed Pharmacother. 2020;126:110041. doi: 10.1016/j.biopha.2020.110041.

27. Guida F, Luongo L, Boccella S, et al. Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. Sci Rep. 2017;7(1):375. doi:10.1038/s41598-017-00342-1.

28. D’Aloia A, Molteni L, Gullo F, et al. Palmitoylethanolamide modulation of microglia activation: characterization of mechanisms of action and implication for its neuroprotective effects. Int J Mol Sci. 2021;22(6):3054. doi:10.3390/ijms22063054

29. Donvito G, Nass SR, Wilkerson JL, et al. The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain. Neuropsychopharmaco. 2018;43(1):52-79. doi: 10.1038/npp.2017.204.

30. Grotenhermen F. Cannabinoids and the endocannabinoid system. Cannabinoids. 2006;1(1):10-4.

31. Wang J. Glial endocannabinoid system in pain modulation. Int J Neurosci. 2019;129(1):94-100.

32. Peritore AF, Siracusa R, Crupi R, Cuzzocrea S. Therapeutic efficacy of palmitoylethanolamide and its new formulations in synergy with different antioxidant molecules present in diets. Nutrients. 2019;11(9). e2175. doi:10.3390/nu11092175.

33. Muccioli GG, Stella N. Microglia produce and hydrolyze palmitoylethanolamide. Neuropharmacology. 2008;54(1):16–22. doi:10.1016/j.neuropharm.2007.05.015
34. Guasti L, Richardson D, Jhaveri M, et al. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain. Mol Pain. 2009;5(1):35–35. doi: 10.1186/1744-8069-5-35.
35. Ho WS, Barrett DA, Randall MD. 'Entourage' effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharmacol. 2008;155(6):837-46. doi:10.1038/bjp.2008.324.
36. Davis MP, Behm B, Mehta Z, Fernandez C. The potential benefits of palmitoylethanolamide in palliation: a qualitative systematic review. Am J Hosp Palliat Care. 2019;36(12):1134-154.
37. Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016 ;79(7):516-25. doi:10.1016/j.biopsych.2015.07.028.

38. Alhouayek M, Muccioli GG. Harnessing the anti-inflammatory potential of palmitoylethanolamide. Drug Discov Today. 2014;19(10):1632-9.

39. Beggiato S, Tomasini MC, Ferraro L. Palmitoylethanolamide (PEA) as a potential therapeutic agent in Alzheimer's disease. Front Pharmacol. 2019; 10:821.
40. Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol. 2016;82(4):932-42.

41. Briskey D, Mallard AR, Rao A. Increased absorption of palmitoylethanolamide using a novel dispersion technology system (LipiSperse^®). J Nut Food Sci. 2020 May;5(2):1-6.

42. Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med. 2013;11(6):377-83.
43. Moran MM. TRP channels as potential drug targets. Annu Rev Pharmacol Toxicol. 2018;58:309-30. doi:10.1146/annurev-pharmtox-010617-052832.
44. De Petrocellis L, Davis JB, Di Marzo V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett. 2001;506(3):253-6. doi:10.1016/s0014-5793(01)02934-9.
45. Karami M, Bathaie SZ, Tiraihi T, Habibi-Rezaei M, Arabkheradmand J, Faghihzadeh S. Crocin improved locomotor function and mechanical behavior in the rat model of contused spinal cord injury through decreasing calcitonin gene related peptide (CGRP). Phytomedicine. 2013;21(1):62-7. doi: 10.1016/j.phymed.2013.07.013.
46. Alemanno F, Ghisi D, Westermann B, et al. The use of vitamin B1 as a perineural adjuvant to middle interscalene block for postoperative analgesia after shoulder surgery. Acta Biomed. 2016 May 6;87(1):22-7. PMID: 27163892.

47. Naser PV, Kuner R. Molecular, cellular and circuit basis of cholinergic modulation of pain. Neuroscience. 2018;387:135-48. doi:10.1016/j.neuroscience.2017.08.049.

48. Sharma A, Bist R. Alteration in cholinesterases, γ-aminobutyric acid and serotonin level with respect to thiamine deficiency in Swiss mice. Turkish J Biochem. 2019 Apr 1;44(2):218-23.
49. Song XS, Huang ZJ, Song XJ. Thiamine suppresses thermal hyperalgesia, inhibits hyperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats. Anesthesiology. 2009;110(2):387-400. doi:10.1097/ALN.0b013e3181942f1e.
50. Dhir S, Tarasenko M, Napoli E, Giulivi C. Neurological, psychiatric, and biochemical aspects of thiamine deficiency in children and adults. Front Psychiatry. 2019;10:207. doi:10.3389/fpsyt.2019.00207.
51. Hazell AS, Faim S, Wertheimer G, Silva VR, Marques CS. The impact of oxidative stress in thiamine deficiency: a multifactorial targeting issue. Neurochem Int. 2013;62(5):796-02. doi: 10.1016/j.neuint.2013.01.009.
52. Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo-controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology. 2019;27(3):475-85.
53. Artukoglu BB, Beyer C, Zuloff-Shani A, Brener E, Bloch MH. Efficacy of palmitoylethanolamide for pain: a meta-analysis. Pain Physician. 2017;20(5):353-62.
54. Schifilliti C, Cucinotta L, Fedele V, Ingegnosi C, Luca S, Leotta C. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain Res Treat. 2014; 2014:849623.
55. Orefice NS, Alhouayek M, Carotenuto A, Montella S, Barbato F, Comelli A, et al. Oral palmitoylethanolamide treatment is associated with reduced cutaneous adverse effects of interferon-β1a and circulating proinflammatory cytokines in relapsing-remitting multiple sclerosis. Neurotherapeutics. 2016;13(2):428-38.
56. Zhu KJ, Yang JS. Anti-allodynia effect of safranal on neuropathic pain induced by spinal nerve transection in rat. Int J Clin Exp Med. 2014;7(12):4990-6. PMID: 25663997.
57. Esposito E, Cuzzocrea S. Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma. Mini Rev Med Chem. 2013;13(2):237-55. PMID: 22697514.
58. Bartolucci ML, Marini I, Bortolotti F, et al. Micronized palmitoylethanolamide reduces joint pain and glial cell activation. Inflamm Res. 2018;67(10):891-901. doi:10.1007/s00011-018-1179-y.
59. Brotini S, Schievano C, Guidi L. Ultra-micronized palmitoylethanolamide: an efficacious adjuvant therapy for Parkinson's disease. CNS Neurol Disord Drug Targets. 2017;16(6):705-13. doi:10.2174/1871527316666170321124949.
60. Scuderi C, Stecca C, Valenza M, et al. Palmitoylethanolamide controls reactive gliosis and exerts neuroprotective functions in a rat model of Alzheimer's disease. Cell Death Dis. 2014;1;5:e1419. doi: 10.1038/cddis.2014.376.
61. Holubiec MI, Romero JI, Suárez J, Portavella M, Fernández-Espejo E, Blanco E. Palmitoylethanolamide prevents neuroinflammation, reduces astrogliosis and preserves recognition and spatial memory following induction of neonatal anoxia-ischemia. Psychopharmacology (Berl). 2018;235(10):2929-45. doi:10.1007/s00213-018-4982-9.
62. Poma A, Fontecchio G, Carlucci G, Chichiriccò G. Anti-inflammatory properties of drugs from saffron crocus. Antiinflamm Antiallergy Agents Med Chem. 2012;11(1):37-51. PMID: 22934747.
63. Hatziagapiou K, Kakouri E, Lambrou GI, Bethanis K, Tarantilis PA. Antioxidant properties of crocus sativus l. and its constituents and relevance to neurodegenerative diseases; focus on Alzheimer's and Parkinson's disease. Curr Neuropharmacol. 2019;17(4):377-402. doi: 10.2174/1570159X16666180321095705.
64. Boskabady MH, Farkhondeh T. Antiinflammatory, antioxidant, and immunomodulatory effects of crocus sativus l. and its main constituents. Phytother Res. 2016 Jul;30(7):1072-94. doi: 10.1002/ptr.5622.
65. Yu Q, Liu H, Sang S, et al. Thiamine deficiency contributes to synapse and neural circuit defects. Biol Res. 2018;51(1):35. doi: 10.1186/s40659-018-0184-5.
66. Cocito D, Peci E, Ciaramitaro P, Merola A, Lopiano L. Short-term efficacy of ultramicronized palmitoylethanolamide in peripheral neuropathic pain. Pain Res Treat. 2014;854560. doi:10.1155/2014/854560.
67. Chaurasia ID, Vinayak K, Tiwari S, Malpani P, Behram S, Koshariya M. Therapeutic potential of palmitoylethanolamide in the management of neuropathic pain. Rom Neurosurg. 2018;32(4):654-61. doi:10.2478/romneu-2018-0085.
68. Chirchiglia D, Paventi S, Seminara P, Cione E, Gallelli L. N-palmitoyl ethanol amide pharmacological treatment in patients with nonsurgical lumbar radiculopathy. J Clin Pharmacol. 2018;58(6):733-39. doi: 10.1002/jcph.1070.
69. Paladini A, Varrassi G, Bentivegna G, Carletti S, Piroli A, Coaccioli S. Palmitoylethanolamide in the treatment of failed back surgery syndrome. Pain Res Treat. 2017;1486010. doi:10.1155/2017/1486010.
70. Zahid M, Busmail A, Penumetcha SS, et al. Tumor necrosis factor alpha blockade and multiple sclerosis: exploring new avenues. Cureus. 2021 Oct;13(10):e18847. doi: 10.7759/cureus.18847.
71. Moreno B, Jukes JP, Vergara-Irigaray N, et al. Systemic inflammation induces axon injury during brain inflammation. Ann Neurol. 2011;70(6):932-42. doi: 10.1002/ana.22550.
72. Ghiasian M, Khamisabadi F, Kheiripour N, et al. Effects of crocin in reducing DNA damage, inflammation, and oxidative stress in multiple sclerosis patients: A double-blind, randomized, and placebo-controlled trial. J Biochem Mol Toxicol. 2019;33(12):e22410. doi: 10.1002/jbt.22410.
73. Akhondzadeh S, Sabet MS, Harirchian MH, et al. Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial. J Clin Pharm Ther. 2010;35(5):581-8. doi:10.1111/j.1365-2710.2009.01133.x.
74. Akhondzadeh S, Shafiee Sabet M, Harirchian MH, et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer's disease. Psychopharmacology (Berl). 2010;207(4):637-43. doi:10.1007/s00213-009-1706-1.
75. Natural Medicines Database. AusDi; 2024. Accessed September 20, 2024. https://ausdi.hcn.com.au/