Cannabis is very effective at reducing pain with relatively minimal negative side effects


Using the largest database of real-time recordings of the effects of common and commercially available cannabis products in the United States (U.S.), researchers at The University of New Mexico (UNM) found strong evidence that cannabis can significantly alleviate pain, with the average user experiencing a three-point drop in pain suffering on a 0-10 point scale immediately following cannabis consumption.

With a mounting opioid epidemic at full force and relatively few alternative pain medications available to the general public, scientists found conclusive support that cannabis is very effective at reducing pain caused by different types of health conditions, with relatively minimal negative side effects.

Chronic pain afflicts more than 20 percent of adults and is the most financially burdensome health condition that the U.S faces; exceeding, for example, the combined costs of treating heart disease and cancer.

“Our country has been flooded with an over-prescription of opioids medications, which then often leads to non-prescription opioid and heroin use for many people.

This man-made disaster is killing our families and friends, regardless of socio-economic status, skin tone, and other superficial human differences” said Jacob Miguel Vigil, one of the lead investigators of the study, titled “The Effectiveness of Self-Directed Medical Cannabis Treatment for Pain,” published in the journal Complementary Therapies in Medicine.

Vigil explains, “Cannabis offers the average patient an effective alternative to using opioids for general use in the treatment of pain with very minimal negative side effects for most people.”

The researchers relied on information collected with Releaf App, a mobile software program developed by co-authors Franco Brockelman, Keenan Keeling and Branden Hall. The app. enables cannabis users to monitor the real-time effects of the breadth of available cannabis-based products, which are always variable, of course, given the complexity of the Cannabis plant from which these products are obtained.

Since its release in 2016, the commercially developed Releaf App has been the only publicly available, incentive-free app for educating patients on how different types of products (e.g., flower or concentrate), combustion methods, cannabis subspecies (Indica, Sativa, and hybrid), and major cannabinoid contents (THC and CBD) affect their symptom severity levels, providing the user invaluable feedback on their health status, medication choices, and the clinical outcomes of those choices as measured by symptom relief and side effects.

Scientifically, software like the Releaf App enables researchers to overcome the inherent limitations of government-funded clinical trials on the real-time effects of Cannabis, which are rare in general, but also often limited by onerous federal regulations, including its Schedule I status (no accepted medical use and a high abuse potential) and the mandate that investigators use the notoriously poor quality and low potency cannabis products supplied by the National Institute of Drug Abuse.

“Even just rescheduling cannabis just from Schedule I to Schedule II, i.e., classifying it with fentanyl, oxycodone, and cocaine rather than heroin and ecstasy, could dramatically improve our ability to conduct research and only would require that the DEA recognizes that accepted medical uses for cannabis exist, as clearly evidenced by our results and the flourishing medical cannabis programs in the majority of U.S. states,” pointed out co-author Sarah Stith.

Among the study’s findings the greatest analgesic responses were reported by people that used whole dried cannabis flower, or “buds,” and particularly cannabis with relatively high levels of tetrahydrocannabinol, otherwise known as THC.

The more recently popularized cannabinoid, cannabidiol or CBD, in contrast, showed little association with the momentary changes in pain intensity, based on the massive database explored in the study.

Cannabis likely has numerous constituents that possess analgesic properties beyond THC, including terpenes and flavonoids, which likely act synergistically for people that use whole dried cannabis flower,” said Vigil, “Our results confirm that cannabis use is a relatively safe and effective medication for alleviating pain, and that is the most important message to learn from our results.

It can only benefit the public for people to be able to responsibly weigh the true risks and benefits of their pain medication choices, and when given this opportunity, I’ve seen numerous chronic pain patients substitute away from opioid use, among many other classes of medications, in favor of medical cannabis.”

“Perhaps the most surprising result is just how widespread relief was with symptom relief reported in about 95 percent of cannabis administration sessions and across a wide variety of different types of pain,” added lead author of the study, Xiaoxue Li.

The authors do caution that cannabis use does carry the risks of addiction and short-term impairments in cognitive and behavioral functioning, and may not be effective for everyone.

However, there are multiple mechanisms by which cannabis alleviates pain suffering.

In addition to its anti-inflammatory properties, cannabis activates receptors that are colocalized with opioid receptors in the brain.

Cannabis with high THC also causes mood elevation and adjusts attentional demands, likely distracting patients from the aversive sensations that people refer to [as] ‘pain,'” explains Vigil.

“When compared to the negative health risks associated with opioid use, which currently takes the lives of over 115 Americans a day, cannabis may be an obvious value to patients.

Chronic opioid use is associated with poorer quality of life, social isolation, lower immune functioning and early morbidity.

In contrast, my own ongoing research increasingly suggests that cannabis use is associated with a reversal of each of these potential outcomes,” said Vigil.

Cannabis (Cannabis sativa) is a dioic plant that belongs to the Cannabaceae family (Magnoliopsida, Urticales).

Knowledge of the medical and psychoactive properties of cannabis dates back to 4000 B.C.

All of the different varieties of cannabis, including the one known as Cannabis indica, belong to the same species. All C. sativa plants produce active compounds, but each variety produces these compounds in different concentrations and proportions, which do not only depend on genomic background, but also on growing conditions and climate, meaning that they can be referred to as chemical varieties or chemovars, rather than strains [1].

Each chemovar contains varying concentrations of cannabinoids, a class of mono- to tetracyclic C21 (or C22) meroterpenoids.

While more than 100 different cannabinoids can be isolated from C. sativa, the primary psychoactive compound is Δ9-tetrahydrocannabinol (THC), which was first isolated in its pure form by Gaoni and Mechoulam in 1964 [2].

Other pharmacologically important analogues are cannabidiol (CBD), cannabinol, cannabinoid acids, cannabigerol, and cannabivarins.

In addition to cannabinoids, other components, such as the monoterpenoids myrcene, limonene, and pinene and the sesquiterpenoid β-caryophyllene, can also mediate the pharmacological effects of C. sativa [3].

Although phytocannabinoids have similar chemical structures, they can elicit different pharmacological actions.

The identification of THC paved the way for the discovery, in 1988, of cannabinoid receptor type 1 (CB1) [4], and, later, of cannabinoid receptor type 2 (CB2) [5].

CB1 and CB2 belong to a family of seven transmembrane Guanosine Binding Protein-Coupled Receptors, are widely expressed and distinguished by their specific functions, localization and signalling mechanisms.

They are one of the important endogenous lipid signalling pathways, named the ‘endocannabinoid system’, which consists of cannabinoid receptors, the endogenous ligands of cannabinoid receptors (endocannabinoids) and the enzymes that regulate the biosynthesis and inactivation of endocannabinoids.

This lipid signalling system is involved in many important physiological functions in the central and peripheral nervous system and in the endocrine and immune systems [6,7].

The psychotropic effects of cannabis are principally mediated by CB1, which is widely distributed throughout the brain, but mainly in the frontal cortex, basal ganglia and cerebellum.

CB1 is also present in several tissues and organs, including adipose tissue, the gastrointestinal tract, the spinal cord, the adrenal and thyroid glands, liver, reproductive organs and immune cells.

The presence of CB1 receptors on chondrocytes and osteocytes, as well as evidence for their presence on fibroblast-like synoviocytes, makes CB1 particularly interesting in the study of rheumatic diseases [8].

CB1 activation inhibits adenylate cyclase and reduces cAMP levels and protein kinase A (PKA) activity, resulting in the activation of the A-type potassium channels and decreased cellular potassium levels [9].

CB2 is principally expressed in immune cells, but can also be found in various other cell types, including chondrocytes, osteocytes and fibroblasts, meaning that it can be considered the peripheral cannabinoid receptor.

It is also present in some nervous tissues, such as dorsal root ganglia and microglial cells.

CB2 shows 44% amino acid similarity with CB1, and similarly inhibits adenylate cyclase as well as activating mitogen-activated protein kinase.

Moreover, CB2 activation can increase intracellular calcium levels via phospholipase C. While both CB1 and CB2 are coupled to G-proteins, the transduction pathways that they activate can be different, for example, in their interactions with ion channels [10].

The association of a particular variant of CB2, known as Q63R, with coeliac disease, immune thrombocytopenic purpura and juvenile idiopathic arthritis is particularly interesting for the field of autoimmune and rheumatic diseases [11].

Overall, seven different endogenous ligands have been identified as acting within the endocannabinoid system to date.

The first two endocannabinoids are the derivatives of arachidonic acid N-arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol [12].

A third endocannabinoid, 2-arachidonoyl glyceryl ether (noladin ether) was discovered in 2001. N-arachidonoyl dopamine, O-arachidonoyl-ethanolamide (virodhamine), docosatetraenoylethanol-amide, lysophosphatidylinositol and oleoylethanolamide have since been described as ligands of endocannabinoid receptors [7].

The endocannabinoid system’s contribution to the regulation of such a variety of processes makes phytocannabinoid pharmacological modulation a promising therapeutic strategy for many medical fields, including the studies of analgesic, neuroprotective, anti-inflammatory and antibacterial activity [13,14].

THC is the primary psychoactive component of cannabis and works primarily as a partial agonist of CB1 (Ki = 53 nM) and CB2 (Ki = 40 nM) receptors [15] and has well-known effects on pain, appetite enhancement, digestion, emotions and processes that are mediated through the endocannabinoid system [7].

Adverse psychoactive events can be caused by THC, depending on dose and previous patient tolerance. By contrast CBD, which is the major non-psychoactive phytocannabinoid component of C. sativa, has little affinity for these receptors, (Ki for human CB1 and CB2 of 1.5 and 0.37 µM, respectively), and acts as a partial antagonist CB1 and as a weak inverse CB2 agonist (Ki as antagonist of CP55940 from 4.2 ± 2.4 to 0.75 ± 0.3 µM in different human cell lines) [16].

In a recent paper, experiments based on the functional effects of CBD on PLCβ3, ERK, arrestin2 recruitment and CB1 internalization, show a negative allosteric modulation of CB1 at concentration below 1 µM [17].

Additionally, other non-CB1 receptor mechanisms of CBD have been proposed, among them its agonism at serotonin 1A receptor (or 5-TH1A), vanilloid receptor 1 (TRPV1) and adenosine A2A receptors [18,19].

The complex physiological and pharmacological mechanisms and interaction of CBD with the endocannabinoid system and other molecular targets are extensively reviewed by McPartland et al. [20].

These data may help explain some of the observed CBD effects including analgesic, anti-inflammatory, anti-anxiety and anti-psychotic activity [21].

The combination of THC and CBD with other phytocannabinoids and other components, such as terpenoids and flavonoids, in cannabis may have a synergistic effect on pain treatment [22,23].Go to:

Role of Cannabinoids in Inflammation and Pain

Pain and inflammation are the body’s physiological responses to tissue injury, infection and genetic changes [24].

These responses can be divided into two phases: acute and chronic.

The acute phase is the early, non-specific phase and is characterized by local vasodilatation, increased capillary permeability, the accumulation of fluid and blood proteins in the interstitial spaces, the migration of neutrophils out of the capillaries, and the release of inflammatory mediators (e.g., cytokines, lymphokines and histamine).

Pain is produced by all these pro-inflammatory agents, that also lead to hyperalgesia through the activation of the corresponding receptors, which are expressed by nociceptive terminals (Figure 1).

If the condition that causes the damage is not resolved, the inflammatory process progresses towards subacute/chronic inflammation, which is characterized by immunopathological changes, such as the infiltration of inflammatory cells, the overexpression of pro-inflammatory genes, the dysregulation of cellular signalling and the loss of barrier function.

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Figure 1
Simplified scheme representing the pathogenesis of pain following inflammatory disease or nociceptive stimulus, the cytokines involved in the process, the descending supraspinal modulation and the relive neurotransmitters and endocannabinoid retrograde signalling mediated synaptic transmission. Endocannabinoids are produced from postsynaptic terminals upon neuronal activation. Natural and synthetic cannabinoids act like the two major endocannabinoids shown in the scheme: 2-arachidonolglycerol (2-AG) and anandamide (AEA). Endocannabinoids readily cross the membrane and travel in a retrograde fashion to activate CB1 located in the presynaptic terminals. Activated CB1 will then inhibit neurotransmitter (NT) release through the suppression of calcium influx. NT can bind to ionotropic (iR) or metabotropic (mR) receptors. 2-AG is also able to activate CB1 located in astrocytes. Although endocannabinoid retrograde signalling is mainly mediated by 2-AG, AEA can activate presynaptic CB1 as well. Fatty acid amide hydrolase (FAAH) found in postsynaptic terminals is responsible for degrading AEA to AA and ethanolamine (Et). Inflammation lead to release of biochemical mediators (bradykinin (BK), serotonin (5-HT), prostaglandins (PG) etc.) and the up-regulation of pain mediator nerve growth factor (NGF). The substance P (SP) and calcitonin gene-related peptide (CGRP) vasoactive neuropeptides, released from sensory nerve, have also role in inflammation. The interaction with opioids, THC and nonsteroidal anti-inflammatory drugs are also represented.

Chronic state of inflammation plays an important role in the onset of classic inflammatory diseases (e.g., arthritis) but also of various diseases, including cardiovascular and neurodegenerative diseases, diabetes, cancer, asthma.

The suppression or inhibition of inflammatory/pro-inflammatory mediators using synthetic anti-inflammatory compounds (both steroidal and non-steroidal) is one of the major routes for the treatment of inflammatory disorders.

However, several common side effects, including gastric irritation and ulceration, renal and hepatic failure, haemolytic anaemia, asthma exacerbation, skin rashes, are often associated with the use of synthetic anti-inflammatory drugs [25].

Increasing amounts of evidence demonstrate that the endocannabinoid system actively participates in the pathophysiology of osteoarthritis-associated joint pain.

Production and release of endocannabinoids are mediated, during inflammatory-joint disease, by the generation of pro inflammatory cytokines (interferon [IFN]-c, interleukin (IL-12, IL-15, IL-17, IL-18), chemokines, chemical mediators, such as nitric oxide synthetase (NOS)-2, cyclooxygenase-2 (COX-2), matrix metalloproteinases (MMPs) and various other arachidonic acid metabolic by-products [7].

Overall, preclinical and clinical data support the potentially effective anti-inflammatory properties of endocannabinoid agonists that target CB2 receptors.

The chronic pathological pain state, including neuropathic pain, is a leading health problem worldwide as it endures beyond the resolution of the pain source and can deeply impact quality of life [26].

Unlike physiological pain, in which tissue injury and/or inflammation can induce reversible adaptive changes in the sensory nervous system leading to protective sensitization, changes in sensitivity become persistent or chronic in neuropathic pain.

Furthermore, the nervous system, peripheral or central, is injured in neuropathic pain. It is characterised by pain in the absence of a noxious stimulus and may be spontaneous in its temporal characteristics or be evoked by sensory stimuli (hyperalgesia and dynamic mechanical allodynia). For example, neuropathy is still among the most common diabetes complications, affecting up to 50% of patients, despite recent advances in treatment.

There is no effective treatment with which to prevent or reverse neuropathic pain [27], thus current treatment is only directed at reducing symptoms.

The treatment of chronic pain is still an unmet clinical need, where adequate pain relief is obtained using drugs with adverse effects on central nervous system side [28].

The quality of life of neuropathic pain patients is often aggravated by comorbidities such as sleep disorders, depression and anxiety compromise.

The finding of the endocannabinoid-mediated retrograde synaptic signalling pathway has opened up a new era, for cannabinoid research, including evaluations of their therapeutic use [29].

Selective CB2 agonists have shown considerable efficiency in a variety of neuropathic pain preclinical models, while increasing amounts of evidence, derived from clinical studies, have confirmed the potential of the cannabinoid system in affording benefits for patients with chronic pain and chronic inflammatory diseases (arthritis).

Currently, patients with chronic arthritic and musculoskeletal pain are the most prevalent users of therapeutic cannabis products [30].

Preclinical studies have shown that cannabinoid receptor agonists block pain in various acute and chronic pain models and that inflammation is attenuated [31,32,33].

Both CB1 and CB2 receptor agonists demonstrate anti-nociceptive activity, whether used singly or in combination, with CB2 activity believed to affect microglial cells and thereby reduce neuro-inflammatory mechanisms [34,35].

The CB2 receptor is thought to be particularly important in central neuronal pain circuits, as agonist activity induces dopamine release in mid-brain areas, contributing to descending pain control and the placebo effect [36].

Inflammatory effects can either be modulated via the upregulation of cannabinoid receptor activity or increased production of endocannabinoids, providing an attenuation in joint destruction in preclinical models of inflammatory arthritis that mimic human rheumatoid arthritis [30,32].

Similarly, CB1 and CB2 receptor proteins and endocannabinoids are found in the human synovial tissue of patients with both rheumatoid arthritis and osteoarthritis [37].

Data from clinical trials on synthetic and plant-derived cannabis-based medicines have suggested that they are a promising approach for the management of chronic neuropathic pain of different origins [38,39,40].

It is also hypothesised that cannabis reduces the alterations in cognitive and autonomic processing that are present in chronic pain states [41].

The frontal-limbic distribution of CB receptors in the brain suggests that cannabis may preferentially target the affective qualities of pain [42].

Furthermore, cannabis may improve neuropathic pain reducing the low-grade inflammation consistent in the pathology [43].

Considering as a whole the problems of chronic neuropathic pain syndromes, which has a poorly understood pathogenesis, a complexity of symptoms and the lack of an optimal treatment, the potential of a therapeutic strategy centered on cannabinoid system appears really quite attractive.

However, a range of adverse events (particularly somnolence or sedation, confusion, psychosis) may limit the clinical applications of therapeutics based on cannabis.

Some current clinical guidelines and systematic reviews consider cannabis-based medicines as third- or fourth-line therapies for chronic neuropathic pain syndromes, for use when established therapies (e.g., anticonvulsants, antidepressants) have failed [44,45].

Beyond its effects on the inflammatory pathway, the endocannabinoid system also plays a fundamental role in neuronal development affecting axon and dendrite growth [46] and preclinical models have demonstrated that cannabinoid administration alters brain maturation in young animals and leads to neuropsychiatric consequences in adults [47].

Moreover, endocannabinoid system has also been accepted to play a significant role in the maintenance of gut homeostasis, and this is therefore, of particular interest in the management of inflammatory bowel diseases (i.e., Crohn’s disease and ulcerative colitis) that show increasing prevalence in Westernised countries [48].

More information: Xiaoxue Li et al. The effectiveness of self-directed medical cannabis treatment for pain, Complementary Therapies in Medicine (2019). DOI: 10.1016/j.ctim.2019.07.022

Provided by University of New Mexico


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