Legal cannabis hemp oil reduce mechanical pain sensitivity 10-fold for several hours – effectively treats chronic neuropathic pain

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Researchers examine the effectiveness of consuming hemp oil extracted from the whole Cannabis plant using a chronic neuropathic pain animal model.

Researchers at The University of New Mexico (UNM) showed that legal Cannabis hemp oil reduced mechanical pain sensitivity 10-fold for several hours in mice with chronic post-operative neuropathic pain.

Distinguished from its still largely criminally prohibited cousin, “hemp” refers to Cannabis plants with less than 0.3 percent tetrahydrocannabinol (THC) per mass. Hemp is now federally legal to produce and consume in most regions throughout the United States (U.S) as a result of the Hemp Farming Act, proposed by the U.S. Congress and signed into law by President Donald Trump in 2018.

This major breakthrough in cannabis prohibition now enables millions of Americans the ability to access a natural, effective, and relatively safe alternative option for treating chronic pain.

Conventional pharmacological drugs, namely opioids, are driving the leading form of preventable deaths and conventional medical errors are the third leading cause of death in the U.S.

The University of New Mexico has conducted a series of recent studies testing the effectiveness and safety of consuming the Cannabis plant, but this is the first study measuring the therapeutic potential of legal hemp oil with low THC levels.

“Cannabis plants with low THC are still psychoactive, but tend to result in less psychedelic experiences, while still offering profound and often immediate relief from symptoms such as pain, anxiety, and depression,” says co-researcher, Dr. Jacob Miguel Vigil, associate professor in the UNM Psychology Department.

Using a chronic neuropathic pain model that exposes mice to post-operative neuropathic pain equivalent to several years of chronic pain in human clinical patients, the researchers were able to examine how hemp oil influences momentary pain sensitivity to the affected region.

For several hours after Cannabis consumption the mice demonstrated effective pain relief, approaching the mechanical pain sensitivity of naïve control mice that did not undergo the surgical operation.

“Our lab utilizes a unique nerve injury model mimicking human neuropathic pain that has allowed demonstration of hemp’s reversal of the pain related behavior” said one of the lead investigators, Dr. Karin N. Westlund, Department of Anesthesiology, their article titled “The Therapeutic Effectiveness of Full Spectrum Hemp Oil Using a Chronic Neuropathic Pain Model,” published in the journal Life.

Studies in animals can be superior to clinical trials because they circumvent human biases and expectancy effects, or perceptual and cognitive reactions to enrollment in cannabis-themed experiments.

Several studies measuring the effects of cannabis in humans observe patients reporting psychedelic experiences, whether or not they received the active cannabis agent, otherwise referred to as the ‘placebo effect.’

The study examined the effectiveness of “LyFeBaak” hemp oil, produced by Organic-Energetic Solutions, which has been available for legal purchase in New Mexico since 2019.

“We grow hemp that is optimized to potentiate the plants utmost health and vitality through hypermineralization techniques, rather than merely plants that are grown in a state of fight-or-flight, which unfortunately is common in the cannabis industry.

These techniques have enabled us to produce hemp products that patients swear are effective for treating dozens of mental and physical health conditions.

The new changes in hemp laws are now allowing us to test these claims,” adds co-author and hemp grower, Anthony L. Ortiz.

“Hemp plants contain numerous therapeutic constituents that likely contribute to analgesic responses, including terpenes and flavonoids, which in theory, work together like members of a symphony, often described as the entourage effect,” says fellow researcher, Jegason P. Diviant.

Several clinical investigations have shown that medications based on synthetic cannabis analogues and isolated compounds tend to offer lower reported symptom relief and a greater number of negative side effects as compared to whole plant, or “full-spectrum” Cannabis flower and plant-based extracts.

The authors do caution that few studies exist on the long-term use of hemp oil, due mostly to historical federal prohibition laws in the U.S.

“However, this is an extremely exciting time in modern medical discovery, because the average citizen now has legal access to a completely natural and effective medication that can be easily and cheaply produced, simply by sticking a seed in the ground and caring for it as you would any other important part of your life,” says Vigil.

Funding: This investigation was supported in part by private donations from individuals to The University of New Mexico Medical Cannabis Research.


The enactment of the Hemp Farming Act, effectively beginning in 2019, was a monumental milestone in the history of Cannabis prohibition in the United States (U.S.), because it enabled the legal consumption, commercial production, and market trade of any type of product made from certain variants of the Cannabis plant.

Only differing from their federally illegal counterparts, arbitrarily defined as Cannabis plants containing over 0.3% tetrahydrocannabinol (THC) potency levels, the legal variety of the Cannabis plant – conventionally referred to as ‘hemp’ – still contains hundreds of additional phytochemicals, including cannabinoids (e.g., cannabidiols, CBDs), terpenes, terpenoids, and flavonoids that may offer potent therapeutics, both individually and synergistically [1–4].

Despite widespread Cannabis usage in the U.S., with estimated annual revenues now in the tens of billions of dollars, current patients and providers still have little scientific evidence on the likely effectiveness of common and commercially available cannabis-based products for pharmaceutical application.

This is because the federal government has largely limited clinical investigations to plant-inspired isolates, concocted formulants, or synthetic analogues not representative of the whole, natural Cannabis plant-based products most widely used by millions of people in the U.S. [5,6].

Another frequent and unavoidable limitation of extant human trials measuring Cannabis’ pharmacodynamics is that they cannot control for placebo and expectancy effects, or visceral, perceptual, and/or cognitive reactions to enrollment in a cannabis-themed experiment, with several studies observing Cannabis-related experiences reported by both active agent and placebo group participants [7,8].

While animal models can control for expectancy effects, few paradigms have created a persistent state of chronic pain, with the majority of conventional pain models resulting in a recoverable, and hence qualitatively different forms of pain than one that is ‘chronic’ in nature, and hence often and uniquely tethered with comorbid affective disturbances (e.g., depression) [9,10].

One well-established and reliable chronic pain model, the Foramen Rotundum Inflammatory Constriction Trigeminal Infraorbital Nerve injury (FRICT-ION) model involves an insertion of 3 mm of chromic gut suture (4-0) along the maxillary branch as it passes into the foramen rotundum through a tiny scalpel incision in the buccal/cheek crease [11].

Mechanical hypersensitivity reliably develops on the snout persisting through 100 days, likely due to consistent inflammatory response caused in part by movement of the nerve during chewing.

The extended 3–10 week timeframe for study allowed by the FRICT-ION model is reportedly equivalent to 5–8 years of chronic pain in clinical patients [12,13].

Studies examining the neuropharmacology of neuropathic pain have implicated opioid (e.g., MOP/DOP) [14–16], serotonin (e.g., 5-HT7) [17,18], dopamine (e.g., D2) [19,20] and glutamate (e.g., GluN2B) [21–23] receptor systems as potential therapeutic targets; however, no studies to date have examined the effects of whole plant-extracted hemp oil on chronic pain.

Therefore, in the present study, we investigated the analgesic effects of “full-spectrum” whole plant oil extracted from the hemp plant, using ethanol and evaporation-based procedures commonly used in the Cannabis industry, on mechanical neuropathic chronic pain sensitivity in mice.

By creating a continuous state of irritation in the infraorbital nerve, the FRICT-ION mouse model of chronic orofacial neuropathic pain can initiate mechanical allodynia in the mouse whisker pad for pharmaceutical investigation.

We use a standard von Frey test for mechanical hypersensitivity at 7 weeks post-surgery to measure the effects of orally administered hemp oil over a 6 h observation window, in comparison to vehicle only and naïve control mice, to estimate the general efficacy of commonly used hemp-based products for therapeutic application.

Hemp Oil Dosing

Prior to testing the effects of hemp oil on the behavioral changes, mechanical allodynia was confirmed in the mice in weeks 1–6 after induction of the nerve trauma and re-tested in week 7, prior to the experiment (Figure 2A).

The mechanical pain threshold was measured hourly (0–6 h) following dosing among animals exposed to 5 µL of hemp oil dissolved in peanut butter as the vehicle (0.138 mg/kg; n = 6), the peanut butter vehicle alone (n = 3), or a naïve control condition (n = 3) (Figure 2B).

The naïve mice underwent all procedures and tests except the surgery. The animals immediately ate the peanut butter with or without the hemp oil.

The mechanical threshold on the whisker pad on the side of the inflamed nerve and on the contralateral side was assessed hourly after consumption for 6 h.

Hemp Cultivation and Oil Extraction

The hemp oil was cultivated by Organic-Energetic Solutions LLC (Albuquerque, NM, USA) and commercially available under the “LyFeBaak” label. The oil is derived from “Cherry Blossom” hemp plants that have been cultivated using proprietary methods that hypermineralize the plants throughout the vegetative and flowering phases of cultivation.

The cannabinoid and terpene analytics of the Cherry Blossom plants used to produce the hemp oil are shown in Tables 1 and 2, respectively. Mature Cannabis hemp buds were used in an alcohol bath extraction procedure using ethanol as a solvent.

The procedure stripped the cannabinoids, terpenes, chlorophyll, fats, lipids and wax compounds from plant material by suspending those compounds in an alcohol solution form.

The solution was then separated from the plant material using a strainer and the alcohol solution was further filtered until it was free of particulates. The alcohol was evaporated out of the solution, leaving a highly concentrated

form of the botanical components harvested from the Cannabis plants, which was then combined with medium-chain triglyceride (MCT) oil in its final (retail) form. In the current study, 5 µL of hemp oil were combined with peanut butter (0.138 mg/kg) for the active agent group.

Table 1. Cherry Blossom cannabinoid analytics.

Phytochemical% Total Weightmg/g
Cannabichromene (CBC)0.1201.200
Cannabigerolic Acid (CBGA)0.2812.810
Cannabigerol (CBG)0.0460.460
Tetrahydrocannabivarin (THCV)0.0220.220
Delta-8-Tetrahydrocannabinol (∆8THC)0.0000.000
Cannabidivarin (CBDV)0.0000.000
Cannabinol (CBN)0.0000.000
Cannabidiolic Acid (CBDA)14.464144.640
Cannabidiol (CBD)0.5065.060
Delta-9-Tetrahydrocannabinol (∆9THC)0.0570.570
Tetrahydrocannabinolic acid (THCA)0.6616.610
Total16.157161.570

Table 2. Cherry Blossom terpene analytics.

Phytochemical% Total Weightmg/g
Alpha-Humulene0.0360.360
Alpha-Pinene0.0480.480
Beta-Myrcene0.2562.560
Alpha-Bisabolol0.0400.400
Beta-Caryophyllene0.1211.210
Limonene0.0220.220
Guaiol0.0430.430
Farnesene0.0800.800
Total0.6466.460

Note. Only detectable terpenes at levels greater than 0.007% are shown above. Terpenes with non-detectable levels include: alpha-cedrene, alpha-terpinene, beta-pinene, borneol, camphene, camphor, caryophyllene oxide, cedrol, sabinene, sabinene hydrate, terpineol, terpinolene, trans-nerolidol, valencene, pulegone, alpha-phellandrene, ocimene, nerol, linalool, geranyl acetate, geraniol, gamma-terpinene, fenchone, eucalyptol, isoborneol, hexahydrothymol, fenchyl alcohol, 3-carene, cis-nerolidol, isopulegol.


Source:
University of New Mexico

References

  1. Russo, E.B. Taming  THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage  effects.Br. J. Pharmacol. 2011, 163, 1344–1364. [CrossRef]
  2. Lewis, M.A.; Russo, E.B.; Smith, K.M. Pharmacological Foundations of Cannabis Chemovars. Planta Med.2018, 84, 225–233. [CrossRef]
  3. Andre, C.M.; Hausman, J.-F.; Guerriero, G. Cannabis sativa: The Plant of the Thousand and One Molecules.Front. Plant Sci. 2016, 7, 19. [CrossRef]
  4. Fischedick, J.E.S. Cannabinoids and Terpenes as Chemotaxonomic Markers in Cannabis. Nat. Prod. Chem. Res.2015, 3. [CrossRef]
  5. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research; National Academies Press: Washington, DC, USA, 2017. [CrossRef]
  6. Stith, S.S.; Vigil, J.M. Federal barriers to Cannabis research ALTHOUGH THE MAJORITY of the general Digital identifi ers for fungal species No surprise that comb jellies poop. Science 2016, 352, 1182.
  7. Kirk, J.M.; Doty, P.; De Wit, H. Effects of expectancies on subjective responses to oral ∆-tetrahydrocannabinol.Pharmacol. Biochem. Behav. 1998. [CrossRef]
  8. Metrik, J.; Rohsenow, D.J.; Monti, P.M.; McGeary, J.; Cook, T.A.; de Wit, H.; Kahler, C.W.  Effectiveness of  a Marijuana Expectancy Manipulation: Piloting the Balanced-Placebo Design for Marijuana. Exp. Clin. Psychopharmacol. 2009. [CrossRef]
  9. Bair, M.J.; Robinson, R.L.; Katon, W.; Kroenke, K. Depression and Pain Comorbidity: A Literature Review. Arch. Intern. Med. 2003. [CrossRef]
  10. Torta, R.; Ieraci, V.; Zizzi, F. A Review of the Emotional Aspects of Neuropathic Pain: From Comorbidity to Co-Pathogenesis. Pain Ther. 2017. [CrossRef]
  11. Montera, M.; Westlund, K. Minimally Invasive Oral Surgery Induction of the FRICT-ION Chronic Neuropathic Pain Model. Bio-Protocol 2020. [CrossRef]
  12. Hannaman, M.R.; Fitts, D.A.; Doss, R.M.; Weinstein, D.E.; Bryant, J.L. The refined biomimetic NeuroDigm GELTM model of neuropathic pain in a mature rat. F1000Research 2017. [CrossRef]
  13. Dutta, S.; Sengupta, P. Men and mice: Relating their ages. Life Sci. 2016. [CrossRef]
  14. Vicario, N.; Parenti, R.; Aricò, G.; Turnaturi, R.; Scoto, G.M.; Chiechio, S.; Parenti, C. Repeated activation of delta opioid receptors counteracts nerve injury-induced TNF-α up-regulation in the sciatic nerve of rats with neuropathic pain: A possible correlation with delta opioid receptors-mediated antiallodinic effect. Mol. Pain 2016. [CrossRef]
  15. Vicario, N.; Pasquinucci, L.; Spitale, F.M.; Chiechio, S.; Turnaturi, R.; Caraci, F.; Parenti, C. Simultaneous Activation of Mu and Delta Opioid Receptors Reduces Allodynia and Astrocytic Connexin 43 in an Animal Model of Neuropathic Pain. Mol. Neurobiol. 2019. [CrossRef]
  16. Lowery, J.J.; Raymond, T.J.; Giuvelis, D.; Bidlack, J.M.; Polt, R.; Bilsky, E.J. In vivo characterization of MMP-2200, a mixed δ/µ opioid agonist, in mice. J. Pharmacol. Exp. Ther. 2011. [CrossRef]
  17. Santello, M.; Nevian, T. Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation. Neuron 2015. [CrossRef]
  18. Santello, M.; Bisco, A.; Nevian, N.E.; Lacivita, E.; Leopoldo, M.; Nevian, T. The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain. Neurobiol. Dis. 2017. [CrossRef]
  19. Sogabe, S.; Yagasaki, Y.; Onozawa, K.; Kawakami, Y. Mesocortical dopamine system modulates mechanical nociceptive responses recorded in the rat prefrontal cortex. BMC Neurosci. 2013. [CrossRef]
  20. Santana, N.; Mengod, G.; Artigas, F. Quantitative analysis of the expression of dopamine D1 and D2 receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex 2009. [CrossRef]
  21. Kindred, J.H.; Li, K.; Ketelhut, N.B.; Proessl, F.; Fling, B.W.; Honce, J.M.; Shaffer, W.R.; Rudroff, T. Cannabis use in people with Parkinson’s disease and Multiple Sclerosis: A web-based investigation. Complement. Ther. Med. 2017, 33, 99–104. [CrossRef]
  22. Sun, T.; Wang, J.; Lia, X.; Lia, Y.; Feng, D.; Shi, W.; Zhao, M.; Wang, J.; Wua, Y. Gastrodin relieved complete Freund’s adjuvant-induced spontaneous pain by inhibiting inflammatory response. Int. Immunopharmacol. 2016. [CrossRef] [PubMed]
  23. Fan, Y.F.; Guan, S.Y.; Luo, L.; Li, Y.J.; Yang, L.; Zhou, X.X.; Liu, G. Tetrahydroxystilbene glucoside relieves the chronic inflammatory pain by inhibiting neuronal apoptosis, microglia activation, and GluN2B overexpression in anterior cingulate cortex. Mol. Pain. 2018. [CrossRef] [PubMed]

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