“Divine is the task to relieve pain” – Hippocrates

Anti-Inflammatory & Antioxidant (AIAO) Supplements

The therapeutic supplements reviewed on this page are a family of formulations directed primarily for the treatment of chronic pain as well as anxiety and insomnia.

As with all treatment described on this website, including prescription and over-the-counter medications as well as nutriceutical and botanical supplements, are presented as information only and should be discussed and directed by a knowledgeable physician prior to engagement.


Carolina Cannabinoids offers a collection of 4 novel supplements primarily directed at treating the following conditions associated with chronic pain:

  1. Current Pain – Directed at reducing pain, as well as reducing anxiety and facilitating sleep, with these benefits expected to be appreciated within minutes to hours.
  2. Future Pain – Directed at reducing pain in the weeks, months and years to come, by reducing neuroinflammation, the driving force that transitions and maintains acute pain to chronic pain and is responsible for the central sensitization that magnifies the experience of pain over time.
  3. Systemic Inflammation (SI) – Directed at reducing systemic inflammation, one of the driving forces for developing the diseases associated with aging, including diabetes, fatty liver, heart attacks, strokes, Alzheimer’s and some forms of cancer.
  4. Oxidative Stress – Directed at reducing oxidative stress, a condition that causes damage to biomolecules, (i.e. proteins and DNA), cells and tissue, and is another one of the driving forces of  chronic pain and the development the diseases associated with aging, including diabetes, fatty liver, heart attacks, strokes, Alzheimer’s and some forms of cancer.


The following links are provided for those individuals interested in further exploration:


The Anti-Inflammatory & Anti-Oxidants supplements are now offered in 4 formulations (CarolinaCannabinoids.US):

    1. Anti-Inflammatory & Anti-Oxidants only (product label)
    2. Anti-Inflammatory & Anti-Oxidants, an Enhanced Broad Spectrum CBD (2000 mg)  – No THC (product label)
    3. Anti-Inflammatory & Anti-Oxidants, an Enhanced Full Spectrum THC/CBD (300/3000 mg) (product label)
    4. Anti-Inflammatory & Anti-Oxidants, an Enhanced Full Spectrum THC/CBD (450/3000 mg) (product label)

List of Ingredients and their Respective Benefits



Please be aware that the two products that contain THC may cause one to get “high,” impair judgement and/or cause sedation. Use of these products should not be started without first consulting with your physician regarding the safety concerns regarding the use of THC, including the potential for drug to drug interactions with other prescribed medications.

For more info on THC: THC (delta-9 THC)


When the products become available, each product above will have a link to the Carolina Cannabinoids website for purchase. Also, Rodriguez Pharmacy downstairs from Accurate Clinic will carry them.

(Dr. Ehlenberger serves as an unpaid medical consultant for Carolina Cannabinoids, but also please note that he receives no financial remuneration for sales of these products).


Key to Links:

  • Grey text – handout
  • Red text – another page on this website
  • Blue text – Journal publication or outside website

Definitions and Terms Related to Pain


The following information reproduced below is from a preclinical research document prepared by Eric Ehlenberger MD for Carolina Cannabinoids that reviews the concepts and results of an open label reseach study performed at Accurate Clinic in 2022:


Objective: This preliminary open label study investigates the efficacy of a novel botanical-based supplement with anti-inflammatory and antioxidant properties as adjuvant therapy for chronic pain management. Recent research strongly identifies the roles of neuroinflammation, sensitization of the peripheral and central nervous system and oxidative stress as driving forces in the chronification of pain.

Current evidence identifies the role of PPAR (peroxisome proliferator–activated receptors) in pain pathways. Additionally, the endocannabinoid system (ECS) has gained recent attention for its role in the management of pain through various mechanisms. As such, evidence suggests the potential synergistic benefit of combining PPAR agonists, cannabinoids and antioxidants as a novel approach for treating chronic pain.

This supplement is directed at suppressing these driving forces in chronic pain with the inclusion of pan-PPAR (peroxisome proliferator–activated receptor) agonists that modulates key metabolic and inflammatory pathways, cannabinoids that act through the ECS and other botanical antioxidants and terpenes.

Because patients suffering from chronic pain frequently have co-morbid anxiety and insomnia, this study also investigates the potential benefits for reducing these two conditions. Finally, as many chronic pain patients are treated with opioids and/or medical marijuana products, the study also seeks to determine if the use of this supplement allows for a reduction in patient reliance on these two classes of medications.

The results of this open study determined that the majority (>90%) of the subjects reported significant benefits for pain, anxiety and/or sleep with minimal adverse effects. Additionally, many subjects also identified a reduced reliance on both their use of opioids and medical marijuana. This study strongly suggests significant benefits for the management of chronic pain and associated co-morbidities. Additional studies are warranted.

Abbreviations : 2-AG, 2-arachidonoyl-glycerol; AJA, ajulemic acid; CBD, cannabidiol; FAAH, fatty acid amide hydrolase; FABP, fatty acid binding protein; PEA, Opioid Analgesic Tolerance (OAT), Palmitoylethanolamide; THC, Δ9 -tetrahydrocannabinol; VCAM, vascular cell adhesion molecule.


The management of chronic pain continues to be a challenge not well met by current practices. The mainstay of managing chronic pain continues to rely on the use of opioids due to a lack of more effective medications for millions of patients. While offering significant benefits for managing pain, opioids are accompanied by many well-known adverse effects that well not be focused on here.

Efforts to reduce patient reliance on opioids as well as improving the safety of opioid use are the most important challenges facing chronic pain management. Clearly the use of supplements that may act synergistically with opioids for analgesia to allow for a reduction in opioid use offers one important avenue to address these challenges.

In order to treat chronic pain effectively it is important to direct treatment towards the primary driving forces that initiate the transition of acute to chronic pain as well as those that serve to maintain chronic pain. These forces include inflammation and neuroinflammation, peripheral and central sensitization and oxidative stress.

Inflammation, Neuroinflammation and Pain

Cytokines and chemokines are agents released by immune cells in response to tissue injury or inflammation. Inflammation is important in the natural healing process but when it fails to resolve and becomes chronic, it leads to and maintains chronic pain. The term “neuroinflammation” distinguishes the inflammatory reaction in the central nervous system (CNS) from inflammation in other tissues.

Neuroinflammation is promoted by pro-inflammatory cytokines and neurotrophic factors that are the driving forces for neuropathic pain. Neuroinflammation can be triggered by noxious stimuli such as trauma, infection, autoimmunity and toxins, but also by psychological stress. Neuropathic pain (NP), defined as pain initiated or caused by a lesion, dysregulation or dysfunction in the nervous system, is the foundation of chronic pain and is associated with increased production of pro-inflammatory proteins.

Analgesic therapies focused on the reduction of these pro-inflammatory agents have demonstrated a reduction in NP in both animal models and clinical studies and have led to the exploration of potential novel therapies for NP conditions.

Anti-inflammatory Medications

The management of chronic inflammation remains inadequately understood and generally ineffective. The use of steroid medications provides powerful anti-inflammatory benefits but they are accompanied by serious adverse effects most often precluding their use, especially in chronic pain. Non-steroid anti-inflammatories (NSAIDs) such as ibuprofen provide limited benefits in chronic pain but are also frequently accompanied by significant adverse effects, also precluding their use by many chronic pain patients. Additionally, recent research suggests that NSAIDs may in fact contribute to the chronification of pain by suppressing the activity of resolvins which promote the natural resolution of inflammation.

Identifying safe and effective alternative agents that provide anti-inflammatory benefits is an extremely important goal for managing pain. This is especially critical for the management of chronic pain relative to the role of neuroinflammation in the maintenance of pain.


Peroxisome Proliferator-Activated Receptors (PPARs)

Research in the last few decades has identified peroxisome proliferator-activated receptors (PPARs) that play significant roles in pain and inflammation. PPARs are ligand-activated transcription factors with three isoforms (alpha, beta/delta, and gamma). It is believed that acting on the PPARs (agonists) exert anti-neuroinflammatory activity via multiple mechanisms including preventing upregulation of inflammatory mediators. Another mechanism is to suppress activity of ion channels to provide rapid reduction of inflammatory and neuropathic pain. A third mechanism is to repress the expression of genes that produce inflammatory mediators thus providing prolonged analgesic benefit.


Cannabinoids and the Endocannabinoid System (ECS)

The ECS is actively involved in inflammation. Activation of all PPAR isoforms, primarily PPARα and γ, mediates some of the analgesic, neuroprotective, and anti-inflammatory effects of cannabinoids in the ECS along with activation of the cannabinoid CB1 and CB2 receptors and TRPV1 ion channels. Medications that impact the ECS, including PEA and the cannabinoids CBD and THC, offer significant benefit for pain driven by neuroinflammation.

Research to date, however, provides only weak evidence for the analgesic benefits of oral CBD isolate and broad spectrum products. The evidence for THC products is stronger for neuropathic pain but is still limited. Evidence suggests that combining other agents that offer additional analgesic benefits may provide a synergistic effect to enhance the analgesia provided by cannabis-based products.


Peripheral and Central Sensitization

Peripheral sensitization (PS) and central sensitization (CS) are very important processes that drive chronic pain. Sensitization is a process where nerves become more responsive to stimulation, both painful and non-painful. It may be due to a number of changes individually or in combination, including a decrease in threshold necessary for a response, an increase in magnitude of response, expansion of a receptive field and/or the emergence of spontaneous activity. The sensitization process that occurs in primary afferent nerves, those nerves carrying sensory information from the peripheral nervous system to the central nervous system, the spinal cord and brain is termed peripheral sensitization. This sensory information may be related to physical stimulation (mechanical damage or trauma, distention, contraction etc.), chemical stimulation or thermal (hot or cold) stimulation.

Central sensitization (CS) refers to increased nerve connections (synapses) and associated hyper-responsiveness established in the spinal cord following intense and prolonged peripheral noxious stimuli, tissue injury or nerve damage. This heightened synaptic nerve transmission leads to a reduction in pain threshold which leads to greater pain with less stimulation, an amplification of pain responses and a spread of pain sensitivity to non-injured areas.

The manifestations of CS include the perseverance of pain in which acute pain persists and becomes chronic, despite apparent resolution of the original condition initially provoking the pain. CS also manifests as an enhanced or magnified experience of pain in which a stimulus that is ordinarily mildly painful becomes moderately or severely painful.

Central sensitization (CS) can be an important contributing process to the chronic pain experience. It is associated with many chronic pain syndromes, especially fibromyalgia, chronic headaches, interstitial cystitis, irritable bowel syndrome and also chronic neck and back pain.

Sensitization of peripheral pain receptors in the skin and other tissues is caused by numerous factors that result in lower neuronal thresholds of activation and pain receptor (nociceptor) hyperexcitability. Factors that promote this peripheral sensitization (PS) include the exposure to biochemical mediators and inflammatory agents that are released from nociceptor nerve terminals. These biochemical mediators include cytokines, prostaglandins, neuropeptides, chemokines, interleukins and growth factors.

Central sensitization involves many mechanisms involving multiple nerve pathways, immune cells and various biochemical agents. Some of the primary players in central sensitization are the glial cell which are immune cells in the nervous system that contribute to neuroinflammation when activated by specific conditions including persistent pain. As with peripheral sensitization, activated glial cells release reactive oxidative species (ROS), inflammatory cytokines, neurotrophic factors, and prostaglandins that excite nociceptive neurons and contribute to the persistence of chronic pain and central sensitization.

It has been proposed that preventing glial cell activation through the use of glial cell inhibitors may suppress the development of CS and reduce the severity of symptoms. Unfortunately there are no established definitive treatments for these conditions as of yet. However, these mechanisms and pro-inflammatory agents may potentially be suppressed through the use of glia cell inhibitors. There is modest evidence that palmitoylethanolamide (PEA) may offer benefit in neuropathic pain and CS via its inhibition of glial cells. A synergistic effect achieved by combining CoQ10 with glial cell inhibitors has also been proposed for the treatment of neuroinflammation and sensitization.


Oxidative Stress

“Oxidative stress” is an imbalance in the body of excessive “oxidants” (oxidizing or chemically active, agents, including free radicals obtained from the diet or produced by the body) and insufficient “antioxidants” (chemically active agents that are also obtained from the diet or produced by the body) that neutralize oxidants. This overabundance of oxidants causes damage to biomolecules, (lipids, proteins, DNA), cells and tissue, eventually contributing to aging and chronic diseases including
neuroinflammation, arthritis and pain, atherosclerosis, cancer, diabetes, heart diseases and stroke.

Antioxidants are produced in the mitochondria within cells throughout the body and serve to detoxify free radicals and protect tissues from such damage. Another important source of antioxidants is the diet. Diets rich in antioxidants are protective against the disease processes noted above. Fruits and vegetables are especially rich in antioxidants including vitamin E (tocotrienols), vitamin C, vitamin A and curcumin. Diets rich in fruits and vegetables result in high blood antioxidant capacity and reduced oxidative stress.


Oxidative Stress and Opioid Analgesic Tolerance

One of the factors contributing to increased use of opioids is the development of opioid analgesic tolerance (OAT). Recent research has identified a role of oxidative stress in the development of OAT, suggesting a potential role for the use of antioxidants to suppress OAT.


In the development of a novel approach to the management of chronic pain, it was determined that the new formulations be directed to achieve multiple goals:

  1. Provide an acute response benefit of analgesia for chronic pain, a response that would be perceived relatively quickly after dosing. It is believed that to gain a patient’s confidence of analgesic benefit, that benefit must be perceived in a manner of minutes to hours.
  1. Provide a long term response benefit of analgesia for chronic pain. In other words, a benefit that would be perceived only after a period of weeks to months, manifest by a reduction in the baseline severity of the patients chronic pain. This benefit would be achieved by suppressing the driving forces of chronic pain: neuroinflammation, peripheral and central sensitization and oxidative stress.
  2. Provide benefit directed at the comorbid conditions that often accompany chronic pain, including anxiety and insomnia. Recognizing the overlap of therapeutic benefits related to pain and these comorbidities offered by the constituents of the formulations, the treatment of these comorbidities would not only serve to reduce chronic pain indirectly by improving these comorbidities but also reduce the suffering imposed by these comorbidities themselves.
  3. As adjuvant supplements for chronic pain relative to the concurrent therapeutic use of opioids and medical cannabis, an optimal goal is to reduce patient reliance on these agents, both of which have the potential for overuse and misuse, significant adverse events related to their use and the development of therapeutic tolerance leading to a reduction of their clinical benefits.
  4. While not specifically measured in this stage of the study, it is also recognized that the constituents in these formulations that may suppress the processes of neuroinflammation and oxidative stress may also have secondary clinical benefits of reducing patient risk for the development of the chronic diseases associated with aging that are also driven by these processes. Such diseases include insulin resistance, hepatic steatosis, cardiovascular diseases and Alzhiemer’s disease and others.

We assessed formulations developed by Carolina Cannabinoids as monotherapy and adjuvant therapy in combination with opioids. These formulations by Carolina Cannabinoids are novel as they are the only botanical pan-PPAR agonists that are commercially available. Due to synergistic action with cannabinoids, these formulations also activate CB1, CB2, 5HT, TRPV1 and GPR receptors (7,10,11). Antioxidant activity is provided by beta carotene, CoQ10 and tocotrienols. Anti-inflammatory effects are provided primarily by PEA and cannabinoids.

In the absence of other clinically approved anti-inflammatory and antioxidant pan-PPAR agonists, these novel botanical formulations developed by Carolina Cannabinoids are promising as therapeutic interventions for chronic pain management by not only reducing current and future pain but also by reducing opioid-related adverse effects.


Patient Selection

The study subjects, patients in a chronic pain management program, were offered for purchase a supplement presented as possibly offering benefits for chronic pain, anxiety and sleep. The subjects electing to participate in the study included those who suffer from inflammatory diseases including osteoarthritis, rheumatoid arthritis and interstitial cystitis as well as those with chronic headaches, neck and low back pain, sciatica, peripheral neuropathy and fibromyalgia. Forty-one patients elected to participate in the trial.

All patients in the study group were currently taking prescription opioids at dosages ranging from 30 to 285 morphine equivalents (ME) per day. The opioids were either taken as stand-alone medications or taken with adjuvant medications including gabapentinoids, antidepressants, NSAIDs and/or medical marijuana products including CBD and THC-based formulations. During the study period one patient obtained a lumbar epidural steroid injection for low back pain associated with severe sciatica.


Primary Outcome Measures

The subjects were queried on their follow-up pain management visit one month after initiating use of their pan-PPAR supplement as to any benefits identified with use of the supplement. Patients self-reported perceived clinical benefits including reduction of pain and/or anxiety and improvement of insomnia. Additionally, when applicable, patients reported whether use of the formulation allowed for sparing of the use of therapeutic opioids or medical cannabis. Additionally, subjects were asked how use of their experimental formulation compared to previous experience of benefits associated with the use of other CBD-based OTC products.

The Trial Formulations

The trial formulations contain multiple botanical constituents which provide anti- inflammatory and antioxidant effects via different mechanisms of action. While many of the included constituents have complex, multi-mechanistic therapeutic activities, a common denominator of many of the constituents which contributes to the novelty of these formulations is PPAR activation. The synergy of their activation of different PPAR isoforms is proposed to contribute significantly to the markedly beneficial therapeutic responses to these formulations. PPAR γ isoforms are activated by a blend of proprietary botanical terpenes and hemp-derived cannabinoids including CBD and THC while PPAR α isoforms are activated by palmitoylethanolamide (PEA). Additional activation of PPAR β/δ isoforms is provided by cinnamaldehyde.

Antioxidant activity is provided by beta carotene, CoQ10 and the tocotrienols. Anti- inflammatory activity is provided by omega-3, PEA and cannabinoids. Bio-availability enhancement is achieved with water dispersible Self Micro Emulsifying Delivery System (SMEDS). Having a family of formulations with multiple constituents to achieve synergistic agonism of multiple receptors including PPARS, CB1, CB2, 5HT, TRPV1 and GPR offers improved efficacy as all these receptors impact both pain and inflammation.

Based on their pan-PPAR agonism mechanisms of action, formulations that are inclusive of CBD, THC, PEA and other botanical terpenes offer potentially significant synergistic benefits for analgesia, anxiety and insomnia. Additional benefits appear to include the potential to reduce reliance on opioids and cannabis use. When combined with botanical antioxidants such as omega-3, beta carotene, tocotrienols and CoQ10, there may be additional long term benefits for reducing chronic pain related to neuroinflammation and central sensitization as well as a reduction or limited progression of opioid analgesic tolerance.

  1. Patients were offered the option to purchase a 32-day therapeutic supply (one 240ml bottle) of one of four formulations from Carolina Cannabinoids as an adjuvant therapy to their current pain management regimens.
  2. Patients who were cannabinoid-naive were encouraged to first trial Product 1, containing Anti-Inflammatory & Antioxidant Complex with broad spectrum CBD.
  3. Patients currently incorporating medical THC-based cannabis products as part of their pain management regimen were encouraged to first trial either the Anti-Inflammatory & Antioxidant Complex with full spectrum, low dose THC (Product 2) or high dose THC (Product 3), depending on their current level of THC tolerance and dosing.
  4. Patients with a history of adverse events associated with previous use of CBD were encouraged to first trial the Anti-Inflammatory & Antioxidant Complex with no CBD or THC (Product 4).


The four formulations from Carolina Cannabinoids:

  1. Anti-Inflammatory&AntioxidantComplexwithBroadSpectrum2000mgCBD (THC free) per 240ml bottle
  2. Anti-Inflammatory&AntioxidantComplexwithFullSpectrum(3000mgCBD: 300 mg THC) per 240ml bottle
  3. Anti-Inflammatory&AntioxidantComplexwithFullSpectrum(3000mgCBD: 450 mg THC) per 240ml bottle
  4. Anti-Inflammatory&AntioxidantComplex(noCBDorTHC)per240mlbottle

Patients were advised to slowly titrate up the dosing of their formulations, initially starting with a 1/2 tsp (2.5ml) oral dose at night then to slowly increase this dose to twice a day then three times a day as tolerated to achieve a target dose of 7.5 mL per day.

It was recommended patients take their formulations orally before meals, and swallow with warm water.

Warnings were provided regarding the potential for mild adverse effects including drowsiness, belching and nausea. Patients were informed of the risks of Cyp P450 enzyme inhibition with cannabinoids that could impact serum levels of other medications leading to possible adverse effects.

Person to person interviews by a physician and/or physician assistant were engaged to obtain feedback evaluations to asses patients responses to the formulations.



Patients reported potent analgesic benefits in those suffering from inflammatory diseases including osteoarthritis, rheumatoid arthritis and interstitial cystitis. Patients with fibromyalgia also reported benefits for their pain, fatigue and non-restful sleep. Many patients throughout the pain spectrum reported improvement with anxiety and insomnia.

Opioid sparing benefits were frequently reported, surprisingly including those patients trialing the formulation that included CBD without THC. These opioid sparing benefits were observed with the use of the pan-PPAR agonists in patients taking as little as 30 ME/day or as much as 270ME/day. There appeared to be a trend toward greater opioid- sparing benefits with the use of the pan-PPAR agonist formulations that included THC.

Of note, one patient with severe rheumatoid arthritis noted exceptional “10/10” pain relief with the PPAR formulation with CBD but no THC, describing herself as being “ecstatic” with her response to the supplement. Anxiolytic benefits were reported with use of both PPAR formulations with or without THC but there appeared to be a trend to a more frequent benefit with use of the non- THC formulation.


One surprise result was reported by a patient taking both opioids and medical marijuana who received a lumbar epidural steroid injection for severe sciatica while taking the pan- PPAR formulation with THC. This patient volunteered an “unexpectedly high degree of pain relief” that surprised both the patient and the interventional pain physician who performed the injection. Given that this patient was already using THC at substantial doses, the benefit he received was postulated as coming from the synergy from the pan-PPAR agonists and CBD.

Later in the study patients were queried as to the presence of cannabis product sparing with the use of the pan-PPAR formulations and a positive correlation was found predominantly in THC containing formulations. Because this question was not presented until later in the study, only 9 patients were queried but of these 9, eight patients noted a reduction in their use of THC-based medical cannabis products, including one patient using the CBD non-THC formulation.

The formulations were well tolerated with minimal adverse effects limited to mild drowsiness, nausea and belching that did not require discontinuation of use. Also noted were complaints of the formulation’s disagreeable taste which did lead to discontinuation of use in two subjects.

Overall, patients reported a superior response to the test formulations when compared to their previous experience with PEA supplements and medical cannabis products with similar CBD and terpenes content when used as an adjuvants to opioids. This superior response also applied to previous full spectrum, terpene-rich CBD products previously manufactured by Carolina Cannabinoids.



In fourteen years of a non-invasive clinical pain management practice, a host of complementary and alternative medications (CAM) have been recommended and trialed by hundreds of chronic pain patients. These CAM treatments have included palmitoylethanolamide (PEA), anti-inflammatories, antioxidants, CBD, terpenes and phyochemicals, often taken alone or in various combinations.

This also includes previous trials with custom formulations developed by Carolina Cannabinoids (CC) containing only broad spectrum CBD and botanical terpenes which also demonstrated significantly inferior responses compared with the formulations used in this study. Given the similarity of the previous CC formulations to the trial formulations, the enhanced benefits provided by the trial formulations is highly likely to be based on the presence of the pan-PPAR agonists in the trial formulations and the synergistic benefits they contributed.

The therapeutic benefits provided by these earlier agents have not been consistent and have rarely reduced patient reliance on opioids. The use of these treatments are frequently discontinued, having failed to be convincing for their usefulness by the patients. While arguably the clinical benefits of these treatments may nevertheless have been present but under the radar, the lack of recognition of benefit ultimately led to treatment failure through discontinuation.

The clinical response noted in this preliminary, open label investigation of these novel formulations has been surprisingly impactful, with greater than 90% of patients achieving a relatively rapid and favorable clinical response, beneficial enough to warrant their continued purchase for use. While these results alone are remarkable relative to pain relief, the additional benefits for anxiety and insomnia are significant as well.

It is important to remember that in addition to the recognizable beneficial acute therapeutic responses, it is quite possible that there will be long term beneficial therapeutic responses that would otherwise be forsaken if the acute responses did not drive the continued use of the formulations. This one month study did not allow for recognition or measurement of the long term impact of these formulations on neuroinflammation, peripheral and central sensitization and oxidative stress, but this can be the focus of additional investigations.

Based on this study it appears evident that there is a synergistic benefit achieved by the combination of pan-PPAR agonists along with other botanical anti-inflammatories and antioxidants that has produced the unexpected high percentage of beneficial responses in this study group.

Based on these preliminary findings, further studies are warranted to evaluate both acute and long term benefits for pain and other comorbid conditions as well as to also explore reduction of patient reliance on opioids and cannabis.

These formulations represent an important novel, paradigm shift in chronic pain management by focusing not just on the acute response to chronic pain but also on the driving forces that maintain chronic pain. To my knowledge there has never been a formulation developed that has been directed in this way.


Supplementation with this unique formulation of botanical pan-PPAR agonists, cannabinoids, anti-inflammatories and antioxidants in chronic pain patients treated with opioids alone or with adjuvant medications including cannabis-based products appears to provide significant analgesic, anxiolytic and sleep benefits in numerous pain conditions including inflammatory conditions and fibromyalgia. Additional benefits also suggested by this study include a reduction in dosing of opioids and medical cannabis products. The unexpectedly profound analgesic enhancement of an epidural steroid injection for severe sciatica also suggests a possible synergistic effect when combined with steroids.

Future Investigation

Based on this preliminary clinical evaluation, appropriate clinical trials with larger sample sizes are warranted for further evaluations of botanical pan-PPAR agonist formulations regarding their benefits for their acute response for pain, anxiety and insomnia. Additionally, based on current theories of the role of neuroinflammation in the chronification of pain and central sensitization, studies are also warranted to evaluate the long term impact of botanical pan-PPAR agonist formulations on these debilitating conditions.

Dual PPAR agonists, which bind to both the α and γ PPAR isoforms, are currently under active investigation for treatment of a larger subset of symptoms of metabolic syndrome including diabetes mellitus and insulin resistance hyperlipidemia
and atherosclerosis. However many of these experimental compounds have been associated with significant adverse effects. As such, future evaluation of botanical pan- PPAR agonist formulations as shown in this study to be well tolerated is warranted for patients suffering from metabolic disorders as well as chronic pain.



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PEA (Palmitoylethanolamide)

  1. Editorial- The Role of Neuroinflammation in Chronic Pain Development and Maintenance – 2021
  2. The Neuroimmunology of Chronic Pain- From Rodents to Humans – 2021
  3. Advanced nanomedicines for the treatment of inflammatory diseases – 2020
  4. Chronic Pain in Dogs and Cats- Is There Place for Dietary Intervention with Micro-Palmitoylethanolamide – 2021
  5. Neuroinflammation after surgery- from mechanisms to therapeutic targets – 2021
  6. Food supplements based on palmitoylethanolamide plus hydroxytyrosol from olive tree or Bacopa monnieri extracts for neurological diseases – 2020
  7. Therapeutic Strategies for Treatment of Inflammation-related Depression – 2017
  8. Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia – 2021
  9. Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia – 2020
  10. Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC FC) in the treatment of neuropathies secondary to rheumatic diseases – 2021
  11. Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders – 2022
  12. Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder- A Systematic Review of Human and Animal Evidence – 2021
  13. Palmitoylethanolamide- A Natural Compound for Health Management – 2021
  14. Therapeutic Efficacy of Palmitoylethanolamide and Its New Formulations in Synergy with Different Antioxidant Molecules Present in Diets – 2019
  15. Palmitoylethanolamide- A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries—A Systematic Review – 2020
  16. ALIAmides Update- Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic Pain -2022
  17. Effect of Ultra-Micronized-Palmitoylethanolamide and Acetyl-l-Carnitine on Experimental Model of Inflammatory Pain – 2021
  18. The Protective Effects of Pre- and Post-Administration of Micronized Palmitoylethanolamide Formulation on Postoperative Pain in Rat – 2020
  19. N-Palmitoylethanolamine and Neuroinflammation a Novel Therapeutic Strategy of Resolution – PubMed – 2015
  20. Molecular evidence for the involvement of PPAR-δ and PPAR-γ in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma – 2013
  21. Palmitoylethanolamide in CNS health and disease – PubMed – 2014
  22. Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels -f Alzheimer’s Disease – 2020
  23. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent – 2015
  24. Palmitoylethanolamide- A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold 2013 – REFERENCES
  25. Palmitoylethanolamide for the treatment of pain – pharmacokinetics, safety and efficacy – 2016
  26. Micronized Palmitoylethanolamide-Polydatin Reduces the Painful Symptomatology in Patients with Interstitial Cystitis:Bladder Pain Syndrome – 2019 Efficacy of Palmitoylethanolamide for Pain ? A Meta-Analysis – 2017
  27. Effects of a massage-like essential oil application procedure using Copaiba T and Deep Blue oils in individuals with hand arthritis – 2018
  28. An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events – 2020
  29. Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels -f Alzheimer’s Disease – 2020
  30. Micronized ultramicronized palmitoylethanolamide (PEA) as natural neuroprotector against COVID-19 inflammation – 2021
  31. PPARα Agonist WY-14643 Relieves Neuropathic Pain through SIRT1-Mediated Deacetylation of NF-κB – 2020
  32. The inflammatory profile of cerebrospinal fluid, plasma, and saliva from patients with severe neuropathic pain and healthy controls-a pilot study – 2021
  33. Ultramicronized Palmitoylethanolamide and Paracetamol, a New Association to Relieve Hyperalgesia and Pain in a Sciatic Nerve Injury Model in Rat – 2020


Post-COVID “Long-Haul” Symptoms

  1. Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19 – A Systematic Review – 2021
  2. COVID-19 ‘Long-Haul’ Symptoms Overlap With ME:CFS – 2021
  3. COVID%u201019-pulmonary-mast-cells-cytokine-storms-and-beneficial-actions-of-luteolin-2020
  4. Covid-19-hyperinflammation-and-post-Covid-19-illness-may-be-rooted-in-mast-cell-activation-syndrome-2020
  5. The Functional Medicine Approach to COVID-19- Additional Research on Nutraceuticals and Botanicals 5-2020
  6. COVID-19_Nutraceutical-and-Botanical-Recommendations-for-Patients_v4
  7. The Functional Medicine Approach to COVID-19 – Primer on SARS-CoV-2 Testing
  8. Palmitoylethanolamide counteracts autistic-like behaviours – Contribution of central and peripheral mechanisms – 2018
  9. Micronized ultramicronized palmitoylethanolamide (PEA) as natural neuroprotector against COVID-19 inflammation – 2021


Peroxisome Proliferator-Activated Receptor (PPAR) AgonistS

  1. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH – 2021
  2. Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain- PPARγ Agonists as a Promising Tool – 2019
  3. An update on PPAR activation by cannabinoids – 2016
  4. Therapeutic Potential of Polyphenols in the Management of Diabetic Neuropathy – 2021 PPAR and Pain – PubMed – 2009
  5. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH – 2021
  6. Peroxisome proliferator-activated receptor agonists modulate neuropathic pain- a link to chemokines
  7. PPAR γ Prevents Neuropathic Pain by Down-Regulating CX3CR1 and Attenuating M1 Activation of Microglia in the Spinal Cord of Rats Using a Sciatic Chronic Constriction Injury Model – 2021
  8. Beta-caryophyllene protects against diet-induced dyslipidemia and vascular inflammation in rats Involvement of CB2 and PPAR-γ receptors – PubMed – 2019
  9. Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System – 2021