In recent years, CBD or Cannabidiol has become a very popular dietary supplement. Not only is it being reported on in the media but among our clients at Murray Avenue Apothecary it has become an indispensable part of their health.
Many of our clients are using CBD as a supplement to manage their mental and emotional health. One our clients wrote,
“The (LabNaturals) CBD products sold at MAA calms me down before stressful days at work and other anxious moments. It helps me take a step back and breathe. Thank you to Susan and the wonderful staff at MAA for your compassion and expertise! I highly recommend this and other products from MAA for a better and healthier future.”
Another client suffering from anxiety wrote,
“I started taking CBD roughly 2 months ago..I’ve noticed no side effects, my daily nervousness/anxiety is gone, and I have more confidence. I also haven’t had an anxiety attack or panic attack since I’ve started. I was admittedly skeptical, but it’s been everything I’ve wanted. For once, I feel like the version of normal I’ve always wanted.”
What is the mechanism of action of CBD in the brain?
Cannabidiol exerts its effects through numerous chemical pathways. Unlike tetrahydrocannabinol, CBD is not believed to actually bind with the CB1 and CB2 cannabinoid receptors in the brain (although it does affect them), but acts through different receptors. CBD modulates the binding of protein-coupled neurons and affects numerous neuropathways in the brain. Some of the major effects of CBD include:
These are just a few of the potential therapeutic effects that CBD may have through its actions in the body. There are numerous other potential benefits to the use of CBD that affect numerous other neural pathways and specific receptor sites.”
Notes about Drug Interactions with CBD:
More than half of U.S. adults regularly take prescription medications and at least 75% take at least one Over-the-Counter supplement. 60-80% of all pharmaceuticals are broken down in the body by the Cytochrome P450-non-specific enzyme family. Both THC and CBD can inhibit OR amplify the CYP450 enzyme reactions. Interactions are more common when both (CBD and prescription drugs) are taken orally and processed through the liver.
At Murray Avenue Apothecary, we look at potential interactions and have the expertise to advise. In our 5 years of CBD experience we have not seen a serious interaction. Furthermore, we use the interaction of CBD and opiates to decreaste the opiate dose while increasing the CBD dose.
Unlike oil filled capsules, LabNaturals CBD capsules contain water soluble CBD (Cannabidiol) and may be taken on an empty stomach to enhance absorption. Ingested cannabinoids will have higher peak liver concentration than inhaled cannabinoids. By taking CBD and THC together, as many medical marijuana products suggest, people may find that the effects of the THC are tempered by the CBD but may be prolonged slightly because of the CYP450 interaction.
The research into Cannabidiol and other cannabinoids is still in its infancy. As more research is done, we will gain more insights into exactly how these natural substances affect the body and improve our natural balance.
Susan Merenstein, RPh/Owner
Murray Avenue Apothecary/LabNaturals
The use of cannabis as medicine for animals has been getting a lot of attention in the medical, scientific, and pet owning communities. One of the potential uses showing the most promise is in the treatment of seizures.
The use of cannabis to treat seizures is nothing new. Cannabis has been described as a therapy for people with seizures for hundreds, if not thousands, of years.
In recent years, cannabis, and cannabidiol (CBD) in particular, are once again being considered for the treatment of seizures in both humans and animals.
In ancient times, cannabis was used for seizures based purely on observational data, but today in-depth scientific research is being conducted to determine how and why cannabis is beneficial in the effort to determine how best to limit, and hopefully eliminate, seizures.
THE SCIENCE OF CANNABIS AND EPILEPSY
Despite the renewed interest and availability for research funding, the mechanisms by which cannabis effects seizures are still unclear. One consideration is a specific receptor on neurons, known as “GPR55,” which is thought to mediate seizure activity through regulating the excitability of neurons. CBD appears to limit GPR55’s ability to cause neuronal excitation which is speculated to reduce seizures.
Additionally, some studies have shown epileptic patients to have reduced anandamide (AEA) concentrations in their cerebrospinal fluid and/or alterations in their CB1 receptors. AEA is one of the naturally occurring neurotransmitters in the body that regulates the endocannabinoid system (ECS). CB1 receptors, also part of the ECS, are binding sites for AEA and changes in AEA and/or CB1 receptors are presumed to lead to changes in levels of other neurotransmitters that may ultimately lead to seizure activity. Tetrahydrocannabinol (THC) binds CB1 receptors and, in this way, may reduce seizure activity.
The FDA-approved pharmaceutical Epidiolex is a single-molecule CBD formulation used to treat two forms of pediatric epilepsy.
Pre-clinical research into other cannabinoids and terpenes suggest other compounds found in cannabis may also be effective for seizure treatment. For practical and legal reasons, however, much of the current research focuses on CBD.
Although the exact reasons why cannabis compounds have a positive effect on seizures are not crystal clear, great strides have been made with regards to their therapeutic use. In 2018, the FDA approved the first cannabis-derived pharmaceutical, Epidiolex. A single-molecule CBD formulation, Epidiolex is approved for the use of refractory seizures in two forms of pediatric epilepsy known as Lennox-Gastaut and Dravet Syndromes. Not only is Epidiolex of great benefit for the children it helps, the drug also represents a huge step forward in the federal government’s acknowledgement of the medicinal value of cannabis.
HOW DOES THE SCIENCE RELATE TO ANIMALS?
Veterinary specific research has also taken a big step forward this year with the publishing of the first clinical trial evaluating the effects of CBD on seizures in epileptic dogs. The study, conducted at Colorado State University, evaluated seizure frequency in dogs with and without the use of CBD. Results showed an 89% reduction in seizure frequency in dogs who received 2.5 mg/kg CBD twice daily compared to a 43% reduction in dogs not receiving CBD. Both groups of dogs were receiving other anti-seizure pharmaceuticals at the time of the study which is the reason the group not receiving CBD had a large reduction in seizures, as well. While these results are considered statistically significant, they are certainly not as dramatic as many hoped they would be. The authors noted this in their conclusions and stated further studies are warranted to see if higher doses of CBD may be more beneficial in the treatment of seizures in dogs.
Dogs who received 2.5 mg/kg CBD twice daily experienced an 89% reduction in seizure frequency.
One specific point to note about the study is the CBD formula used was not a CBD “isolate.” The hemp-based formula contained “trace amounts of other cannabinoids” which may or may not have contributed to its efficacy. Research suggests that multiple cannabinoids (CBD, THC, and others) as well as terpenes have anti-seizure properties and it may be that greater effects can be found with a “broader spectrum” formulation.
Speaking from the perspective of the benefits of “whole plant medicine,” broad spectrum formulations are usually more effective than single components. That said, from a research perspective, using pure CBD would clarify what effects are specific to the one compound.
Anecdotal reports from pet owners and veterinarians suggest that cannabis can not only reduce seizure frequency, it may be able to lessen seizure severity, shorten recovery time, and potentially even prevent an imminent seizure if the animal is medicated at the first signs of trouble.
With research ongoing, we certainly see promise in the use of CBD, and potentially other cannabinoids, for the treatment of seizures in animals. That said, cannabis as medicine should be used with caution. CBD given at moderate to high doses can potentially effect blood levels of other medications, including anti-seizure drugs. Because of this, it may be necessary to monitor levels at the beginning of cannabis therapy. For the safety of your furry family members, always consult with your veterinarian before starting any form of cannabis therapy for your pet.
By Gary Richter, MS, DVM, CVA, CVC, GDWVHM, a Project CBD contributing writer, is an Oakland-based veterinarian. His articles focus on practical information for using cannabis to treat medical conditions in pets.
Copyright, Project CBD. May not be reprinted without permission.
Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term ‘medical cannabis’ refers to physician-recommended use of the cannabis plant and its components, called cannabinoids, to treat disease or improve symptoms. Chronic pain is the most commonly cited reason for using medical cannabis. Cannabinoids act via cannabinoid receptors, but they also affect the activities of many other receptors, ion channels and enzymes. Preclinical studies in animals using both pharmacological and genetic approaches have increased our understanding of the mechanisms of cannabinoid-induced analgesia and provided therapeutical strategies for treating pain in humans. The mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neuron excitability, activation of descending inhibitory pain pathways, and reduction of neural inflammation. Recent meta-analyses of clinical trials that have examined the use of medical cannabis in chronic pain present a moderate amount of evidence that cannabis/cannabinoids exhibit analgesic activity, especially in neuropathic pain. The main limitations of these studies are short treatment duration, small numbers of patients, heterogeneous patient populations, examination of different cannabinoids, different doses, the use of different efficacy endpoints, as well as modest observable effects. Adverse effects in the short-term medical use of cannabis are generally mild to moderate, well tolerated and transient. However, there are scant data regarding the long-term safety of medical cannabis use. Larger well-designed studies of longer duration are mandatory to determine the long-term efficacy and long-term safety of cannabis/cannabinoids and to provide definitive answers to physicians and patients regarding the risk and benefits of its use in the treatment of pain. In conclusion, the evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults. Careful follow-up and monitoring of patients using cannabis/cannabinoids are mandatory.
Pain is one of the most common symptoms of disease. Acute pain is usually successfully managed with non-steroidal anti-inflammatory drugs (NSAIDs) and/or opioids (Vučković S. et al., 2006; Vučković S.M. et al., 2006; Vučković et al., 2009, Vučković et al., 2016), but chronic pain is often difficult to treat and can be very disabling (Gatchel et al., 2014). An adjuvant is a drug that is not primarily intended to be an analgesic but can be used to reduce pain either alone or in combination with other pain medications (Bair and Sanderson, 2011). Some of these drugs have been known for some time, but their acceptance has waxed and waned over time (Vučković et al., 2015; Srebro et al., 2016; Tomić et al., 2018). However, new approaches to targeting the pain pathway have been developed and adjuvant analgesics continue to attract both scientific and medical interest as constituents of a multimodal approach to pain management (Yaksh et al., 2015). The role of cannabis plant and its components, called cannabinoids, as adjuvant analgesics in the treatment of chronic pain, has been the subject of longstanding controversy (NASEM, 2017).
Flowering plants within the genus Cannabis (also known as marijuana) in the family Cannabaceae have been cultivated for thousands of years in many parts of the world for spiritual, recreational and medicinal purposes. Preparations of the cannabis plant, which are taken by smoking or oral ingestion, have been observed to produce analgesic, anti-anxiety, anti-spasmodic, muscle relaxant, anti-inflammatory and anticonvulsant effects (Andre et al., 2016). However, the prohibition of cannabis cultivation, supply and possession from the middle of the 20th century (due to its psychoactivity and potential for producing dependence), has impeded cannabis research (ElSohly et al., 2017). In recent years there is a growing debate about cannabis use for medical purposes. In many countries cannabis use for medical reasons is legal and some countries have also decriminalized or legalized the recreational use of cannabis.
The term medical cannabis is used to refer to the physician-recommended use of cannabis and its constituents, cannabinoids, to treat disease or improve symptoms (Rahn and Hohmann, 2009). The use of cannabis and cannabinoids may be limited by its psychotropic side effects (e.g., euphoria, anxiety, paranoia) or other central nervous system (CNS)-related undesired effects (cognitive impairment, depression of motor activity, addiction), which occur because of activation of cannabinoid CB1 receptors in the CNS (Volkow et al., 2014). As interest in the use of cannabinoids as adjunctive therapy for pain management has increased in the last decades (Hill et al., 2017), there has been a continuing need for an increase in cannabis research and bridging the knowledge gap about cannabis and its use in pain treatment. Therefore, research on cannabis and cannabinoids has increased dramatically in recent years. However, there are several obstacles that need to be overcome, such as the regulations and policies that restrict access to the cannabis products, funding limitations, and numerous methodological challenges (drug delivery, the placebo issue, etc.) (NASEM, 2017). This research is expected to explain and update the mechanisms of analgesic action of cannabis and its constituents, and to provide answers to questions about the safety of medicinal cannabis and its potential indications in the treatment of pain. Healthcare providers in all parts of the world must keep up to date with recent findings in order to provide valid information regarding the benefits, risks, and responsible medical use to patients in pain (Wilsey et al., 2016).
This article is a narrative review of the published preclinical and clinical research of the pharmacodynamics, pharmacokinetics, efficacy, safety and tolerability of cannabis/cannabinoids in the treatment of pain.
Materials and Methods
In March 2018 we searched the MEDLINE database via PubMed (United States National Library of Medicine) for articles published up to March 1st, 2018 for the key words: ‘cannabis’ or ‘cannabinoids’ and ‘pain’ (in title/abstract). This was followed by filter species (humans/other animals) and language (English) selection. The abstracts of the 1270 citations extracted were screened for relevance by two reviewers (SV and DS). Discrepancies were resolved by discussion. The literature relevant to pharmacodynamic, pharmacokinetics, efficacy and safety of cannabis/cannabinoids in pain treatment was included. Both preclinical in vitro and in vivo data and clinical studies were included. Data on cannabis use among children, adolescents and pregnant women were excluded. We also examined the reference lists of reviewed articles.
Pharmacodynamics: Cannabis and Cannabinoids Act on Multiple Pain Targets
For many years it was assumed that the chemical components of the cannabis plant, cannabinoids, produce analgesia by activating specific receptors throughout the body, in particular CB1, which are found predominantly in the CNS, and CB2, found predominantly in cells involved with immune function (Rahn and Hohmann, 2009). However, recently this picture has become much more complicated, as it has been recognized that cannabinoids, both plant-derived and endogenous, act simultaneously on multiple pain targets (Ross, 2003; Horvath et al., 2008; Pertwee et al., 2010; O’Sullivan, 2016; Morales et al., 2017) within the peripheral and CNS. Beside acting on cannabinoid CB1/CB2 receptors, they may reduce pain through interaction with the putative non-CB1/CB2 cannabinoid G protein-coupled receptor (GPCR) 55 (GPR55; Staton et al., 2008) or GPCR 18 (GPR18), also known as the N-arachidonoyl glycine (NAGly) receptor; Huang et al., 2001), and other well-known GPCRs, such as the opioid or serotonin (5-HT) receptors (Russo et al., 2005; Scavone et al., 2013). In addition, many studies have reported the ability of certain cannabinoids to modulate nuclear receptors (peroxisome proliferator-activated receptors (PPARs) (O’Sullivan, 2016), cys loop ligand-gated ion channels (Barann et al., 2002; Hejazi et al., 2006 Ahrens et al., 2009; Sigel et al., 2011; Xiong et al., 2011, 2012; Shi et al., 2012; Oz et al., 2014; Bakas et al., 2017) or transient receptor potential (TRP) channels (TRPV, TRPA, and TRPM subfamilies), (Pertwee et al., 2010; Lowin and Straub, 2015; Morales et al., 2017), among others. It has been shown that all these receptors represent potentially attractive targets for the therapeutic use of cannabinoids in the treatment of pain. Moreover, TRPV1 and CB1 or CB2 are colocalized at peripheral and/or central neurons (sensory neurons, dorsal root ganglia, spinal cord, brain neurons), which results in their intracellular crosstalk in situations where these receptors are involved simultaneously (Cristino et al., 2006; Anand et al., 2009). New data also demonstrate a variety of interactions between cannabinoid, opioid, and TRPV1 receptors in pain modulation (Zádor and Wollemann, 2015). All of these provide an opportunity for the development of new multiple target ligands and polypharmacological drugs with improved efficacy and devoid of side effects for the treatment of pain (Reddy and Zhang, 2013).
Several lines of evidence indicate that cannabinoids may contribute to pain relief through an anti-inflammatory action (Jesse Lo et al., 2005; Klein, 2005). In addition, non-cannabinoid constituents of the cannabis plant that belong to miscellaneous groups of natural products (terpenoids and flavonoids) may contribute to the analgesic, as well as the anti-inflammatory effects of cannabis (Andre et al., 2016; ElSohly et al., 2017).
Based on their origin, cannabinoids are classified into three categories: phytocannabinoids (plant-derived), endocannabinoids (present endogenously in human or animal tissues), and synthetic cannabinoids.
There are about 100 different cannabinoids isolated from the cannabis plant (Andre et al., 2016). The main psychoactive compound is (-)-trans-Δ9-tetrahydrocannabinol (THC), which is produced mainly in the flowers and leaves of the plant. The THC content varies from 5% in marijuana to 80% in hashish oil. THC is an analog to the endogenous cannabinoid, anandamide (ananda is the Sanskrit word for bliss; arachidonoylethanolamide, AEA). It is responsible for most of the pharmacological actions of cannabis, including the psychoactive, analgesic, anti-inflammatory, anti-oxidant, antipruritic, bronchodilatory, anti-spasmodic, and muscle-relaxant activities (Rahn and Hohmann, 2009; Russo, 2011). THC acts as a partial agonist at cannabinoid receptors (CB1 and CB2) (Pertwee, 2008). A very high binding affinity of THC with the CB1 receptor appears to mediate its psychoactive properties (changes in mood or consciousness), memory processing, motor control, etc. It has been reported that a number of side effects of THC, including anxiety, impaired memory and immunosuppression, can be reversed by other constituents of the cannabis plant (cannabinoids, terpenoids, and flavonoids) (Russo and Guy, 2006; Russo, 2011; Andre et al., 2016).
The non-psychoactive analog of THC, cannabidiol (CBD), is another important cannabinoid found in the cannabis plant. It is thought to have significant analgesic, anti-inflammatory, anti-convulsant and anxiolytic activities without the psychoactive effect of THC (Costa et al., 2007). CBD has little binding affinity for either CB1 or CB2 receptors, but it is capable of antagonizing them in the presence of THC (Thomas et al., 2007). In fact, CBD behaves as a non-competitive negative allosteric modulator of CB1 receptor, and it reduces the efficacy and potency of THC and AEA (Laprairie et al., 2015). CBD also regulates the perception of pain by affecting the activity of a significant number of other targets, including non-cannabinoid GPCRs (e.g., 5-HT1A), ion channels (TRPV1, TRPA1 and TPRM8, GlyR), PPARs, while also inhibiting uptake of AEA and weakly inhibiting its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) (Russo et al., 2005; Staton et al., 2008; Ahrens et al., 2009; De Petrocellis et al., 2011; Burstein, 2015; Morales et al., 2017). It has been demonstrated that cannabidiol can act synergistically with THC and contribute to the analgesic effect of medicinal-based cannabis extract (Russo, 2011). At the same time, CBD displays an entourage effect (the mechanism by which non-psychoactive compounds present in cannabis modulate the overall effects of the plant), and is capable of improving tolerability and perhaps also the safety of THC by reducing the likelihood of psychoactive effects and antagonizing several other adverse effects of THC (sedation, tachycardia, and anxiety) (Russo and Guy, 2006; Abrams and Guzman, 2015). The differences in concentration of THC and CBD in the plant reflect the differences in the effects of different cannabis strains. Although CBD as a monotherapy in the treatment of pain has not been evaluated clinically, its anti-inflammatory (Ko et al., 2016) and anti-spasmodic benefits and good safety profile suggest that it could be an effective and safe analgesic (Wade et al., 2003).
Other phytocannabinoids that can contribute to the overall analgesic effects of medical cannabis are cannabichromene (CBC), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and many others (Morales et al., 2017). Similarly to CBD, these compounds do not display significant affinities for cannabinoid receptors, but they have other modes of action. This is a new area of research that needs to be addressed (Piomelli et al., 2017).
This system seems to regulate many functions in the body, including learning and memory, mood and anxiety, drug addiction, feeding behavior, perception, modulation of pain and cardiovascular functions. The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), transport proteins and enzymes that synthesize or degrade the endocannabinoids.
Cannabinoid CB1 and CB2 receptors are 7-transmembrane G-protein coupled receptors (GPCRs). They play an important role in peripheral, spinal, and supraspinal nociception, including ascendant and descendent pain pathways (Hill et al., 2017). The signal transduction pathway of CB1 and CB2 involves inhibition of adenylyl cyclase, decreased cAMP formation, as well as an increase in the activity of mitogen-activated protein kinases (MAPK) (Ibsen et al., 2017). New evidence is emerging that different ligands can differentially activate these pathways, suggesting biased signaling through the cannabinoid receptors CB1 and CB2 (Ibsen et al., 2017).
The CB1 receptor is distributed throughout the nervous system. It mediates psychoactivity, pain regulation, memory processing and motor control. CB1 is a presynaptic heteroreceptor that modulates neurotransmitter and neuropeptide release and inhibits synaptic transmission. Activation of CB1 results in the activation of inwardly rectifying potassium channels, which decrease presynaptic neuron firing, and in the inhibition of voltage-sensitive calcium channels that decrease neurotransmitter release (Morales et al., 2017). The CB1 receptor is strategically located in regions of the peripheral and CNS where pain signaling is intricately controlled, including the peripheral and central terminals of primary afferent neurons, the dorsal root ganglion (DRG), the dorsal horn of the spinal cord, the periaqueductal gray matter, the ventral posterolateral thalamus and cortical regions associated with central pain processing, including the anterior cingulate cortex, amygdala and prefrontal cortex (Hill et al., 2017). The principal endogenous ligand for the CB1 receptor is AEA. CB1 receptors are observed more often on the gamma-aminobutyric acid (GABA) inhibitory interneurons in the dorsal horn of the spinal cord, and weakly expressed in most excitatory neurons (Hill et al., 2017). CB1 receptors are also present in multiple immune cells such as macrophages, mast cells and epidermal keratinocytes.
The CB2 receptor is found predominantly at the periphery (in tissues and cells of the immune system, hematopoietic cells, bone, liver, peripheral nerve terminals, keratinocytes), but also in brain microglia (Abrams and Guzman, 2015). The receptors are responsible for the inhibition of cytokine/chemokine release and neutrophil and macrophage migration and they contribute to slowing down of chronic inflammatory processes and modulate chronic pain (Niu et al., 2017). Both CB2 and CB1 receptors on mast cells participate in the anti-inflammatory mechanism of action of cannabinoids (Facci et al., 1995; Small-Howard et al., 2005). Also, activation of CB2 receptors on keratinocytes stimulates the release of β-endorphin, which acts at μ opioid receptors on peripheral sensory neurons to inhibit nociception (Ibrahim et al., 2005). Under basal conditions, CB2 receptors are present at low levels in the brain, the spinal cord and DRG, but may be upregulated in microglia where they modulate neuroimmune interaction in inflammation and after peripheral nerve damage (Hsieh et al., 2011). CB2 receptor activation inhibits adenylyl cyclase activity and stimulates MAPK activity, but the effect on calcium or potassium conductance is controversial (Rahn and Hohmann, 2009; Atwood et al., 2012). Stimulation of CB2 receptors does not produce cannabis-like effects on the psyche and circulation. The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG) (Kano, 2014).
Endocannabinoids are arachidonic acid derivatives. AEA and 2-AG are synthesized separately, they have local (autocrine and paracrine) effects and are rapidly removed by hydrolysis by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively (Pacher et al., 2006; Starowicz and Przewlocka, 2012; Howard et al., 2013). Beside AEA, FAAH inhibition significantly elevates the levels of other fatty-acid amides such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the CNS and peripheral tissues (Lambert et al., 2002). Endocannabinoids, similarly to THC, appear to activate cannabinoid receptors. AEA and 2-AG are a partial and full agonist of CB receptors, respectively (Kano, 2014). They work as a part of a negative feedback loop that regulates neurotransmitter and neuropeptide release and thereby modulate various CNS functions, including pain processing (Vaughan and Christie, 2005).
The AEA is a full agonist at TRPV1 (AEA referred to as an ‘endovanilloid’) that activates TRPV1 which results in desensitization (Ross, 2003; Horvath et al., 2008; Starowicz and Przewlocka, 2012). AEA also activates GR55 (Ryberg et al., 2007), directly inhibits 5-HT3A receptors (Barann et al., 2002) potentiates the function of glycine receptors (Hejazi et al., 2006), inhibits T-type voltage-gated calcium channels (Chemin et al., 2001) and activates PPARs (Rockwell and Kaminski, 2004; Sun et al., 2007; Romano and Lograno, 2012; O’Sullivan, 2016).
Endocannabinoids, which are produced in neural and non-neural cells in the physiological response to tissue injury or excessive nociceptive signaling, suppress inflammation, sensitization and pain (Piomelli and Sasso, 2014; Maccarrone et al., 2015). Inhibitors of FAAH lead to elevated AEA levels and are intended for therapeutic use (Hwang et al., 2010). N-acylethanolamines such as PEA and OEA do not belong to endocannabinoids as they do not bind to cannabinoid receptors; they exhibit anti-inflammatory action via PPARs, and also inhibit pain through TRPV1 receptors. They are of interest to the field of cannabinoid pain research as they elevate levels of AEA through substrate competition at FAAH (Lambert et al., 2002).
There is a constant active exchange of substrates and metabolites between endocannabinoid and eicosanoid pathways. The enzyme FAAH breaks down AEA to arachidonic acid and ethanolamine or, alternatively, AEA can be directly transformed by cyclooxygenase-2 (COX-2) into proalgesic prostaglandins. As such, AEA may contribute to the analgesic properties of COX-2 selective NSAIDs. It was established that the metabolite of paracetamol combines with arachidonic acid by the action of FAAH to produce an endocannabinoid, which is a potent agonist at the TRPV1 and a weak agonist at both CB1 and CB2 receptors and an inhibitor of AEA reuptake (Bertolini et al., 2006).
At present, there are two synthetic cannabinoids on the market, dronabinol and nabilone, which may be of benefit in the treatment of pain (Abrams and Guzman, 2015). In general, their use in pain treatment is off-label. Dronabinol is a generic name for the oral form of synthetic THC (Marinol®). It is approved for the treatment of chemotherapy-associated nausea and vomiting, and anorexia associated with human immunodeficiency virus infection. Nabilone, a generic name for the orally administered synthetic structural analog of THC (Cesamet®), is approved for the treatment of chemotherapy-associated nausea and vomiting. Their medical use is mostly limited by their psychoactive side effects, as well as their limited bioavailability (Huestis, 2007).
Cannabis and Cannabis Extract
Cannabis delivered by way of inhalation (smoked or inhaled through vaporization), orally or oromucosally, produces a host of biological effects (Andre et al., 2016). Unfortunately, clinical trials conducted on cannabis are limited, and no drug agency has approved the use of cannabis as a treatment for any medical condition. Although there is no formal approval, cannabis is widely used for the treatment of pain. It is authorized by physicians where medical marijuana is legal (Health Canada, 2013).
Nabiximols, a generic name for the whole-plant extract with a 1:1 ratio of THC:CBD (2.7 THC + 2.5 CBD per 100 μL), an oromucosal spray (Sativex®) is approved as an adjuvant treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis (MS) who have not responded well to other therapy and who have demonstrated a significant improvement during an initial trial of Sativex® therapy. In addition, Sativex® is approved in Canada (under the Notice of Compliance with Conditions) as an adjuvant treatment for symptomatic relief of neuropathic pain in adults with MS, and as an adjuvant analgesic in adult patients with advanced cancer who suffer from moderate to severe pain that is resistant to strong opioids (Health Canada, 2013). An approval under the Notice of Compliance with Conditions means that a product shows potential benefit, possesses high quality and an acceptable safety profile based on a benefit-risk evaluation (Portenoy et al., 2012). Nabiximols is also approved in the United Kingdom and some European countries (e.g., Spain). The United States Food and Drug Administration (FDA) has not yet approved nabiximols as a treatment for any medical condition. Currently it is under investigation by the FDA under the Investigational New Drug Application (IND) for the treatment of cancer pain. Beside THC and CBD, nabiximols also contains other cannabinoids, terpenoids, and flavonoids.
Pharmacokinetics of Cannabis/Cannabinoids
Cannabis is mostly inhaled by smoking and to a lesser extent by vaporization. The pharmacokinetics of inhaled and oral cannabis differ significantly (Agurell et al., 1986; Huestis, 2007). Taken by mouth, THC is metabolized in the liver to 11-hydroxy-THC, a potent psychoactive metabolite. By inhalation, cannabis (THC) avoids the first passage metabolism in the liver, and the effect of inhaled cannabis is proportionate to the plasma levels of THC. The pharmacokinetic profile of the inhaled cannabis is similar to THC given by the intravenous route (Agurell et al., 1986). The pharmacokinetic profile of CBD is very similar to THC given by the same route of administration.
When inhaled, cannabinoids are rapidly absorbed into the bloodstream. The advantages of inhaled over oral cannabis are the fast onset of action (requiring minutes instead of hours), and rapid attainment of peak effect (in 1 h vs. several hours), which is maintained at a steady level for 3–5 h (vs. the variable effect, observed after oral administration, which lasts from 8 to more than 20 h) and less generation of the psychoactive metabolite (Agurell et al., 1986). The analgesic effect is experienced shortly after the first breath and can be maximized by self-titration (patients adjust cannabis dosage themselves). However, self-titration of oral cannabis is not recommended due to the unpredictable appearance of side effects. The main disadvantage of smoking cannabis is inhalation of combustion byproducts with possible adverse effects in the respiratory tract (Volkow et al., 2014; NASEM, 2017). Therefore, vaporization is considered a better alternative for the inhalation of cannabis. About 25–27% of the available THC becomes available to the systemic circulation after smoking (Carter et al., 2004; Zuurman et al., 2009). The bioavailability of inhaled THC varies considerably, probably due to differences in inhalation techniques and source of the cannabis product (Agurell et al., 1986; Huestis, 2007).
Dronabinol, nabilone, and nabiximols are currently available oral pharmaceutical preparations of cannabinoids with standardized concentrations or doses. The main limitation associated with the administration of oral cannabinoids is their poor pharmacokinetic profile characterized by slow, unpredictable and highly variable absorption, late onset of action, extended duration due to psychoactive metabolites and unpredictable psychotropic effects (Ohlsson et al., 1980; Huestis, 2007; Issa et al., 2014). Oral THC (extract, synthetic or cannabis-derived) bioavailability was reported to be 6–20% only (Wall et al., 1983; Agurell et al., 1986). Further efforts are aimed at improving the bioavailability of oral cannabinoids (Smith, 2015).
Tetrahydrocannabinol is characterized by high binding to plasma protein (95–99%) so that the initial volume of distribution of THC is equivalent to the plasma volume (Grotenhermen, 2003). However, the distribution changes over time, with the steady state volume of distribution being about 3.5 L per kg of body weight. This is due to the high lipophilicity of THC, with high binding to fat tissue. THC crosses the placental barrier and small amounts also cross into breast milk (Grotenhermen, 2003).
Tetrahydrocannabinol is metabolized by cytochrome P450 enzymes CYP 2C9, 2C19 and 3A4, (Huestis, 2007; Rong et al., 2018), and drugs that inhibit these enzymes (e.g., proton pump inhibitors, HIV protease inhibitors, macrolides, azole antifungals, calcium antagonists and some anti-depressants) can increase the bioavailability of THC. Conversely, drugs that induce hepatic enzymes responsible for THC metabolism (e.g., phenobarbital, phenytoin, troglitazone, and St John’s wort) will lower its bioavailability (Rong et al., 2018).
In chronic-pain patients on opioid therapy, vaporized cannabis increases the analgesic effects of opioids without affecting significantly the plasma opioid levels (Abrams et al., 2011) suggesting that the effects are probably due to pharmacodynamic rather than pharmacokinetic interactions.
Cannabinoids in Animal Models of Pain
Behavioral studies have shown that synthetic or plant-derived cannabinoid receptor agonists or endogenous cannabinoid ligands are effective in different animal models of acute pain (Dhopeshwarkar and Mackie, 2014). However, data obtained in humans, including volunteers with experimental pain and clinical trial patients, suggest that cannabinoids may be more effective for chronic rather than acute pain conditions (Kraft et al., 2008). Also, a number of targets identified in animal studies have not been confirmed in clinical trials. These include the absence of apparent clinical activity in clinical trials with CB2 agonists (Roche and Finn, 2010; Ostenfeld et al., 2011; Atwood et al., 2012; Pereira et al., 2013; Dhopeshwarkar and Mackie, 2014). In addition, FAAH inhibitors, although providing promising data in animal studies, did not demonstrate a significant efficacy against chronic pain in humans (Huggins et al., 2012; Woodhams et al., 2017). These discrepancies may be explained by species differences, differences in methodology and outcomes measured in the studies, as well as lack of selectivity of the ligands used (Dhopeshwarkar and Mackie, 2014). On the other hand, the outcome of a clinical trial of pain depends on the type of pain, trial design, target patient population, and several other factors (Gewandter et al., 2014). The effect of THC and other cannabinoids acting at CB1 receptors on motor activity in animals may easily be misinterpreted as pain-suppressing behavior (Meng et al., 1998). In humans, multiple emotional and cognitive factors influence the perception and experience of pain and this result in high inter-individual variability. However, pain in animals is mainly measured as a behavioral response to noxious stimuli, so that results obtained from animal studies are often more consistent. Also, volunteers with experimental pain respond more uniformly than patients with pathological pain, and pain pathways in healthy volunteers differ from those in patients (Olesen et al., 2012).
Due to CB1 receptor activation, the cannabinoid antinociception in animals may be accompanied by CNS side effects (e.g., hypoactivity, hypothermia and catalepsy) (Martin et al., 1991), which may translate into psychoactive side effects in humans (e.g., drowsiness, dizziness, ataxia, and fatigue).
A growing body of evidence indicates that in the treatment of chronic pain conditions, stimulation of the endocannabinoid system presents a promising approach that may prevent the occurrence of CNS side effects (Lomazzo et al., 2015). Several new strategies on how to preserve analgesic activity and avoid psychoactivity of cannabinoids have been proposed and tested in animals. They include inhibition of endocannabinoid uptake and metabolism in identified tissues where increased levels of endocannabinoids are desirable, administration of novel compounds that selectively target peripheral CB1 and CB2 receptors, positive allosteric modulation of cannabinoid CB1 receptor signaling, and modulation of non-CB1/non-CB2 receptors (TRPV1, GPR55, and PPARs) (Malek and Starowicz, 2016; Starowicz and Finn, 2017). In recent years, dual-acting compounds that provide FAAH inhibition (increased AEA and decreased arachidonic acid levels), TRPV1 antagonism (that prevents activation of the pro-nociceptive pathway by AEA), or COX-2 inhibition (that increases AEA and decreases prostaglandin levels), have offered the most promising results in chronic pain states in animals (Maione et al., 2007; Grim et al., 2014; Morera et al., 2016; Malek and Starowicz, 2016; Aiello et al., 2016; Starowicz and Finn, 2017). However, it is important to verify whether the efficacy of this multi-target strategy observed in rodent models of chronic pain and inflammation translates to humans and is not species-specific.
Cannabinoids have been studied in various types of neuropathic pain in animals, including chronic nerve constriction traumatic nerve injury, trigeminal neuralgia, chemotherapy- and streptozotocin-induced neuropathy, etc.
Both CB1 and CB2 receptors have been found to be upregulated in nervous structures involved in pain processing in response to peripheral nerve damage (Lim et al., 2003; Zhang et al., 2003; Hsieh et al., 2011), and this may explain the beneficial effects of cannabinoid receptor agonists on neuropathic pain. It has been shown that increased CB2 expression is accompanied by the appearance of activated microglia (Zhang et al., 2003). Both microglial activation and neuropathic pain symptoms can be suppressed by CB2 agonists (Wilkerson et al., 2012). Consistent with this, CB2 knockout mice and transgenic mice overexpressing CB2 are characterized by enhanced and suppressed reactivity of microglia and neuropathic pain symptoms, respectively (Racz et al., 2008). TRPV1 expression is also increased in glutamatergic neurons of the medial prefrontal cortex in a model of spared nerve injury (SNI) in rats (Giordano et al., 2012).
In different neuropathic pain conditions, systemic administration of synthetic mixed cannabinoid CB1/CB2 agonists produces antinociceptive effects similar to those of THC (Herzberg et al., 1997; Pascual et al., 2005; Liang et al., 2007). The CB2 selective agonists given intrathecally or systemically are also effective in several animal models of neuropathic pain (Yamamoto et al., 2008; Kinsey et al., 2011), but their antinociceptive effects are without development of tolerance, physical withdrawal and other CNS side effects that accompany CB1 agonism (Deng et al., 2015).
When given early in the course of diabetes, CBD attenuates microgliosis in the ventral lumbar spinal cord of diabetic mice, as well as tactile allodynia and thermal hyperalgesia. However, if given later in the course of the disease, CBD has a little effect on pain-related behavior (Toth et al., 2010).
A controlled cannabis extract containing numerous cannabinoids and other non-cannabinoid fractions such as terpenes and flavonoids demonstrated greater antinociceptive efficacy than the single cannabinoid given alone, indicating synergistic antinociceptive interaction between cannabinoids and non-cannabinoids in a rat model of neuropathic pain (Comelli et al., 2008). The anti-hyperalgesic effect did not involve the cannabinoid receptors but was mediated by TRPV1 and thus it most probably belongs to CBD.
In animals with neuropathic pain, increased levels of endocannabinoids (AEA and 2-AG) have been detected in different regions of the spinal cord and brain stem (Mitrirattanakul et al., 2006; Petrosino et al., 2007). However, they appeared to be differentially regulated in different models of neuropathic pain, depending on the characteristic of the pain and the affected tissues (Starowicz and Przewlocka, 2012). Genetic or pharmacological inactivation of FAAH/MAGL resulting in the elevation of endocannabinoid (AEA/2-AG) levels in the spinal cord and brain stem (Lichtman et al., 2004; Schlosburg et al., 2009; Long et al., 2009; Adamson Barnes et al., 2016) show promise for suppressing both neuropathic and inflammatory pain. In general, the antinociceptive effect of endocannabinoids is sensitive to antagonists of CB1 and CB2 receptors, TRPV1 channels and PPARα antagonism, indicating that multiple targets could be involved in the mechanism of their action (Kinsey et al., 2010; Caprioli et al., 2012; Piomelli, 2014; Adamson Barnes et al., 2016). The reduction in the side effects that accompany CB1 agonism, such as motor incoordination, catalepsy, sedation and hypothermia, suggests that mainly TRPV1, but not a cannabinoid receptor-dependent mechanism, mediate the analgesic properties of exogenously and endogenously elevated levels of AEA in neuropathic pain. In a rat chronic constriction injury (CCI) model, depending on the dose of URB597 (FAAH inhibitor) used, lower or higher elevation of endogenous AEA levels and CB1- or TRPV1-mediated analgesia were achieved, respectively (Starowicz et al., 2012). It has been suggested that endocannabinoids can increase the excitability of nociceptive neurons by reducing synaptic release of inhibitory neurotransmitters via CB1 receptors on dorsal horn neurons (Pernía-Andrade et al., 2009), as well as by agonist activity on TRPV1 (Ross, 2003).
Monoacylglycerol lipase inhibitors demonstrated CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility (Long et al., 2009). In a mouse model of neuropathic pain both CB1 and CB2 were engaged in the anti-allodynic effects of FAAH inhibitors, while only CB1 was involved in the anti-allodynic effect of the MAGL inhibitor (Kinsey et al., 2010). Also, unlike FAAH inhibitors, the persistent blockade of MAGL activity leads to desensitization of brain CB1 receptors and loss of the analgesic phenotype (Chanda et al., 2010) and physical dependence (Schlosburg et al., 2009). However, a new highly selective MAGL inhibitor, KML29, exhibited antinociceptive activity without cannabimimetic side effects (Ignatowska-Jankowska et al., 2014).
In CCI in mice, JZL195, a dual inhibitor of FAAH and MAGL, demonstrated greater anti-allodynic efficacy than selective FAAH or MAGL inhibitors, and a greater therapeutic window (less motor incoordination, catalepsy and sedation) than WIN55212, a cannabinoid receptor agonist (Adamson Barnes et al., 2016).
Co-administration of sub-threshold doses of FAAH inhibitor, PF-3845 and the non-selective COX inhibitor, diclofenac sodium, produced enhanced antinociceptive effects in rodent models of both neuropathic (CCI) and inflammatory pain (intra-plantar carrageenan) (Grim et al., 2014). Combined FAAH inhibition/TRPV1 antagonism is also an attractive therapeutic strategy because FAAH inhibition only produced biphasic effects, with antinociception via CB1 at low levels of AEA, and when AEA levels were higher, pronociceptive effects via TRPV1 (Maione et al., 2007; Malek and Starowicz, 2016).
Cannabinoids may attenuate neuropathic pain by peripheral action via both CB1 and/or CB2 receptors (Fox et al., 2001; Elmes et al., 2004). The peripherally acting cannabinoid agonist AZ11713908 reduced mechanical allodynia with a similar efficacy to WIN55,212-2, an agonist that entered the CNS (Yu et al., 2010). In addition, URB937, a brain impermeant inhibitor of FAAH, elevated anandamide outside the brain and controlled neuropathic pain behavior without producing CNS side effects (Clapper et al., 2010).
After identification of allosteric binding site(s) on the CB1 GPCR (Price et al., 2005), several CB1-positive allosteric modulators have been developed and tested in animals. They attenuated both inflammatory and neuropathic pain behavior without producing the CB1-mediated side effects of orthosteric CB1 agonists but did not produce tolerance after repeated administration (Khurana et al., 2017; Slivicki et al., 2017).
Different classes of cannabinoids (i.e., CB1 agonists, CB2 agonists, mixed CB1/CB2 agonists, endocannabinoids and endocannabinoid modulators) all suppressed pain behavior in various animal models of inflammatory pain (Clayton et al., 2002; Burgos et al., 2010; Starowicz and Finn, 2017). Since inflammatory pain is a characteristic of several chronic diseases, including cancer, arthritis, inflammatory bowel disease, sickle-cell disease, etc., cannabinoids appear to promise the lessening of severe pain in these diseases (Fichna et al., 2014; Abrams and Guzman, 2015; Turcotte et al., 2016; Vincent et al., 2016).
It is well known that CB2 receptor expression increases in microglia in response to inflammation and serves to regulate neuroimmune interactions and inflammatory hyperalgesia (Dhopeshwarkar and Mackie, 2014). However, the extent of CB2 expression in neurons is a subject of controversy (Atwood and Mackie, 2010; Atwood et al., 2012). It has been suggested that peripheral inflammation, unlike peripheral nerve injury, does not induce CB2 receptor expression in the spinal cord (Zhang et al., 2003). In contrast, Hsieh et al. (2011) demonstrated that the CB2 receptor gene is significantly upregulated in DRG and paws ipsilateral to inflammation induced by injection of complete Freund’s adjuvant (CFA).
Systemic or local peripheral injection of the CB2-selective agonist was reported to reduce nociceptive behavior and swelling in different animal models of inflammation (Quartilho et al., 2003; Elmes et al., 2005; Kinsey et al., 2011). In addition, the CB2-selective agonist did not produce hypothermia or motor deficit that are CB1-mediated side effects (Kinsey et al., 2011). Therefore, a CB2 receptor selective agonist is expected to have less psychomimetic side effects and lower abuse potential as compared to the available non-selective or CB1-selective cannabinoid agonists. In animal models of inflammatory disease, CB2 agonists slow the progression of diseases (Turcotte et al., 2016). In a murine model of rheumatoid arthritis, collagen-induced arthritis (CIA), CB2-selective agonists did not prevent the onset of arthritis, but did ameliorate established arthritis (Sumariwalla et al., 2004). JWH133, a selective CB2 agonist, inhibited in vitro production of cytokines in synoviocytes and in vivo reduced the arthritis score, inflammatory cell infiltration and bone destruction in CIA (Fukuda et al., 2014). Another CB2-selective agonist, HU-308, was shown to reduce swelling, synovial inflammation and joint destruction, in addition to lowering circulating antibodies against collagen I in CIA (Gui et al., 2015). Although approved in a range of preclinical models of pain, LY2828360, CB2 agonist, failed in a trial of patients with osteoarthritic knee pain (Pereira et al., 2013).
It was shown that formalin administration to the hind paw of rats induced AEA release into the periaqueductal gray matter (Walker et al., 1999). FAAH knockout mice and mice that express FAAH exclusively in nervous tissue, displayed anti-inflammatory and anti-hyperalgesic effects in both the carrageenan and CIA models, and the effects were prevented by administration of a CB2 but not a CB1 antagonist (Lichtman et al., 2004; Kinsey et al., 2011). FAAH inhibition may also reduce nociceptive behavior induced by lipopolysaccharide injection into the rat hind paw, and examination of the mechanism showed that both CB1 and CB2 were involved, but not TRPV1, PPARs, or opioid receptors (Booker et al., 2012). Oral administration of PF-04457845, a highly efficacious and selective FAAH inhibitor, produced potent antinociceptive effects in the CFA model of arthritis in rats, and it was shown that both CB1 and CB2 receptors were implicated in this effect (Ahn et al., 2011). In contrast to animal data, PF-04457845 failed to demonstrate efficacy in a randomized placebo and active-controlled clinical trial on pain in osteoarthritis of the knee (Ahn et al., 2011; Huggins et al., 2012). The possible explanations are development of tolerance to chronically elevated endocannabinoids or sensitization of TRPV1 receptors. A pronociceptive phenotype has been recently documented in FAAH knockout mice after administration of a challenge dose of TRPV1 agonist capsaicin (Carey et al., 2016). The increased nociceptive response was attenuated by antagonists of CB1 and TRPV1 receptors.
In a recent phase I trial, the FAAH inhibitor BIA-102474 caused death in one and severe neurological damage in five participants (Kaur et al., 2016; Moore, 2016). It has been suggested that specificity and non-selectivity of this molecule and several errors in the design of the study were responsible for its toxicity, and not targeting of FAAH per se (Huggins et al., 2012; Pawsey et al., 2016). More research is necessary to characterize both the efficacy and safety profiles of endocannabinoid-directed therapeutic strategies.
An increase in local endocannabinoid levels by inhibition with local peripheral administration of URB597 (an irreversible FAAH inhibitor) induced analgesia in a model of carrageenan-induced inflammation in rats that was inhibited by a PPARα antagonist but not by a CB1 receptor antagonist (Sagar et al., 2008). However, local administration of URB597 into osteoarthritic knee joints reduced pain via CB1 receptors [monosodium iodoacetate (MIA)-induced osteoarthritis in rats and the model of spontaneous osteoarthritis in Dunkin-Hartley guinea pigs] (Schuelert et al., 2011). A peripherally restricted FAAH inhibitor, URB937, also reduced inflammatory pain in rodents via CB1 receptors (Clapper et al., 2010).
It was shown that inhibition of fatty acid binding proteins (FABPs) reduced inflammatory pain in mice. This effect was associated with an upregulation of AEA and the effect was inhibited by antagonists of CB1 or PPARα receptors (Kaczocha et al., 2014).
Recent animal findings suggest that cannabinoids may have beneficial effect on affective-emotional and cognitive aspect of chronic pain (La Porta et al., 2015; Neugebauer, 2015; Kiritoshi et al., 2016). In mice with MIA-induced arthritis, selective agonists of both CB1 and CB2 receptors ameliorated the nociceptive and affective manifestations of osteoarthritis, while a CB1-selective agonist improved the memory impairment associated with arthritis (La Porta et al., 2015; Woodhams et al., 2017). This is in agreement with human studies of cannabinoids that indicate a significant improvement in secondary outcome measures, such as sleep and mood (Lynch and Ware, 2015).
The combined FAAH/COX inhibitor ARN2508 demonstrated efficacy against intestinal inflammation and was without gastrointestinal side effects (Sasso et al., 2015) because AEA, which is similar to prostanoids, has protective actions on the gastrointestinal mucosa.
Experiments with animal models of cancer pain support the use of cannabinoids in the treatment of cancer pain in humans. Systemic administration of non-selective, CB1 selective or CB2 selective agonist significantly attenuated mechanical allodynia in a mouse model which was produced by inoculating human oral cancer cell lines HSC3 into the hind-paw of mice (Guerrero et al., 2008). A mechanical hyperalgesia associated with decreased anandamide levels were found in plantar paw skin ipsilateral to tumor induced by injection of fibrosarcoma cells into the calcaneum of mice. The paw withdrawal frequency was reduced after local injection of anandamide (Khasabova et al., 2008). Also, one study reported that the efficacy of synthetic CB1- and CB2-receptor agonists was comparable with the efficacy of morphine in a murine model of tumor pain (Khasabova et al., 2011). An important finding is that cannabinoids are effective against neuropathic pain induced by exposure of animals to anticancer chemotherapeutics (vincristine, cisplatin, paclitaxel) (Rahn et al., 2007; Khasabova et al., 2012; Ward et al., 2014).
Clinical Trials of Cannabis/Cannabinoids in Chronic Pain
Pain relief is the most commonly cited reason for the medical use of cannabis. In 2011, 94% of the registrants on the Medical Marijuana Use Registry in Colorado (United States) were using medical marijuana for chronic pain (Kondrad and Reid, 2013). However, cannabis is not the first drug of choice that a patient takes to relieve pain. As with many other analgesics, cannabinoids do not seem to be equally effective in the treatment of all pain conditions in humans. This is most probably due to the different mechanisms of pain (e.g., acute vs. chronic, or chronic non-cancer vs. chronic cancer pain) (Romero-Sandoval et al., 2017). Clinical studies have shown that cannabinoids are not effective against acute pain (Buggy et al., 2003; Beaulieu, 2006; Holdcroft et al., 2006; Kraft et al., 2008). Clinical data also indicate that cannabinoids may only modestly reduce chronic pain, like all presently available drugs for the treatment of chronic pain in humans (Romero-Sandoval et al., 2017).
Efficacy of Cannabis/Cannabinoids in the Treatment of Chronic Pain
Until recently, there was no consensus about the role of cannabinoids for the treatment of chronic pain. Several years ago, the European Federation of Neurological Societies recommended cannabinoids (THC, oromucosal sprays 2.7 mg delta-9-tetrahydrocannabinol/2.5 mg cannabidiol) as the second or third line of treatment of central pain in MS (Attal et al., 2010). More recently, the Canadian Pain Society supported their use as the third-line option for the treatment of neuropathic pain, after anti-convulsives, anti-depressants, and opioids (Moulin et al., 2014). In addition, Health Canada provided preliminary guidelines for prescribing smoked cannabis in the treatment of chronic non-cancer pain (Kahan et al., 2014). At the same time, the Special Interest Group on neuropathic pain of the International Association for the Study of Pain provided “a weak recommendation against the use of cannabinoids in neuropathic pain, mainly because of negative results, potential misuse, abuse, diversion and long-term mental health risks particularly in susceptible” (Finnerup et al., 2015).
There is a growing body of evidence to support the use of medicinal cannabis in the treatment of chronic pain. At present, there is a scientific consensus on the medicinal effects of cannabis for the treatment of chronic pain that is based on scientific evidence. The National Academy of Sciences, Engineering and Medicine (NASEM, 2017) has evaluated more than 10,000 scientific abstracts and established that there is “conclusive or substantial evidence” for the use of cannabis in treating chronic pain in adults. Also, there is “moderate evidence” that cannabinoids, in particular nabiximols, are effective in improving short-term sleep outcomes in patients with chronic pain (NASEM, 2017). The expert report NASEM supports more research to determine dose–response effects, routes of administration, side effects and risk-benefit ratio of cannabis/cannabinoid use with precision and make possible evidence based policy measure implementation. At the same time, the PDQ Integrative Alternative and Complementary Therapies Editorial Board (2018) states that pain relief is one of the potential benefits of cannabis/cannabinoids for people living with cancer (in addition to its anti-emetic effects, appetite stimulation, and improved sleep).
Chronic Non-cancer Pain
Lynch and Campbell (2011) and Lynch and Ware (2015) performed two systematic reviews of cannabis/cannabinoid use in chronic non-cancer pain (neuropathic pain, fibromyalgia, rheumatoid arthritis and mixed chronic pain) involving 18 randomized controlled trials published between 2003 and 2010, and 11 studies published between 2011 and 2014, respectively. All 29 trials included about 2000 participants and their duration was up to several weeks. Twenty-two of 29 trials demonstrated a significant analgesic effect and several also reported improvements in secondary outcomes (sleep, spasticity).
Whiting et al. (2015) performed a systematic review of the benefits and adverse events of orally administered cannabinoids and inhaled cannabis for a variety of indications (chronic pain was assessed in 28 studies, there were 2454 participants, the follow-up period lasted up to 15 weeks), and provided moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain.
The Canadian Agency for Drugs and Technologies in Health (2016) recently analyzed five systematic reviews (including two with meta-analyses) of nabiximols (THC:CBD buccal spray) for the treatment of chronic non-cancer or neuropathic pain (Lynch and Campbell, 2011; Lynch and Ware, 2015; Jawahar et al., 2013; Boychuk et al., 2015; Whiting et al., 2015). The length of the follow-up across the studies was from 1 to 15 weeks. In this review, there are inconsistencies with regard to both the effectiveness and safety of nabiximols. The authors concluded that treatment with nabiximols in the short term may be associated with pain relief and good tolerability when compared with placebo therapy, but there is still insufficient evidence to support its use in the management of chronic neuropathic and non-cancer pain.
The meta-analysis of individual patient data from 5 randomized trials (178 participants) presents evidence that inhaled cannabis may provide short-term reductions (>30% reduction in pain scores) in chronic neuropathic pain (diabetes, HIV, trauma) for 1 in 5–6 patients (Andreae et al., 2015). In these trials, the THC content ranged from 3.5 to 9.4%. A dose-related effect of cannabis was found, with higher THC contents producing more pronounced pain relief. In one study, pain relief was not dose-dependent and was achieved with a low concentration of cannabis THC [1.29% (vaporized)] (Wilsey et al., 2013). The follow-up periods ranged from days to weeks. Consistent with the results of this meta-analysis, a more recent, small, randomized, double-blind, placebo-controlled crossover clinical study demonstrated that vaporized cannabis (1–7% THC) in a dose-dependent manner reduced spontaneous and evoked pain in patients (16 subjects) suffering from painful diabetic neuropathy (Wallace et al., 2015). The analgesic effect was achieved at THC concentrations as low as 1–4%. In a more recent randomized, placebo-controlled, double-blind crossover study (38–41 participants pergroup), Wilsey et al. (2016) reported that low THC concentrations (2.9–6.7%) of vaporized cannabis effectively reduced chronic neuropathic pain after spinal cord injury or disease. It was found that higher plasma levels of THC and/or the THC metabolite significantly correlated with improvements in clinical symptoms of pain (Wilsey et al., 2016).
No recommendations regarding cannabinoid treatment of non-spastic and non-trigeminal neuralgic pain in adult patients with MS were reported in the systemic review of Jawahar et al. (2013). Results of another systematic review that analyzed the effectiveness of cannabis extracts and cannabinoids in the treatment of chronic non-cancer neuropathic pain suggested that cannabis-based medicinal extracts may provide pain relief in conditions that are refractory to other treatments (Boychuk et al., 2015). It was pointed out that further studies are required to estimate the influence of the duration of the treatment.
A recently published systematic review (Meng et al., 2017) considered 11 randomized controlled studies involving a total of 1219 participants in which oral cannabinoids (dronabinol, nabilone, and nabiximols) were compared with standard pharmacological and/or non-pharmacological treatments or placebo in patients with neuropathic pain (including MS). This study shows that oral cannabinoids are modestly effective in reducing chronic neuropathic pain and that for this effect a minimum of 2 weeks of treatment is required. The study also showed improvements in the quality of life, sleep and increased patient satisfaction. However, the quality of the evidence is moderate and the strength of recommendation for analgesic efficacy of selective cannabinoids in this clinical setting is weak. Of the different cannabinoids used, nabiximols and dronabinol but not nabilone demonstrated an analgesic advantage.
The authors of the most recent Cochrane Review on the efficacy, tolerability and safety of cannabis-based medicines (CBM; botanical, plant-derived, and synthetic) compared to placebo or conventional drugs for neuropathic pain in adults (16 randomized, double-blind controlled trials with 1750 participants) concluded that the potential benefits of CBM in neuropathic pain might be outweighed by their potential harms (Mücke et al., 2018). All CBMs were superior to placebo in reducing pain intensity, sleep problems and psychological distress (very low- to moderate-quality evidence). Between these two groups, no differences were found in improvements to health-related quality of life and discontinuation of the medication because of its ineffectiveness. There was no difference between CBM and placebo in the frequency of serious adverse events (low-quality evidence). Adverse events were reported by 80.2% of participants in the CBM group and 65.6% of participants in the placebo group (RD 0.19, 95% CI 0.12–0.27; P-value < 0.0001; I2 = 64%). CBM may increase nervous-system adverse events compared with placebo [61% vs. 29%; RD 0.38 (95% CI 0.18–0.58); number-needed-to-harm (NNTH) 3 (95% CI 2–6); low-quality evidence], as well as psychiatric disorders (17% vs. 5%: RD 0.10 (95% CI 0.06–0.15); NNTH 10 (95% CI 7–16); low-quality evidence]. Some of the adverse events (e.g., somnolence, sedation, confusion, and psychosis) may limit the clinical usefulness of CBM.
Four randomized controlled trials with 159 patients with fibromyalgia, osteoarthritis, chronic back pain and rheumatoid arthritis treated with cannabinoids (nabilone, nabiximols, and FAAH inhibitor) or placebo or an active control (amitriptyline), were included in a systemic review (Fitzcharles et al., 2016). The results were not consistent and did not reveal whether the cannabinoids were superior to the controls (placebo and amitriptyline). The authors concluded that there is insufficient evidence for the recommendation for cannabinoid use for pain management in patients with rheumatic diseases. Smoked cannabis has not been tested for pain relief in patients suffering from rheumatoid pain (Ko et al., 2016).
Chronic abdominal pain
In a randomized, double-blind, placebo-controlled parallel-design phase 2 study (65 participants), no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain due to surgery or chronic pancreatitis was found (de Vries et al., 2017).
Chronic Cancer Pain
Cancer pain is a chronic pain, often complex, consisting of nociceptive, inflammatory and neuropathic components. Severe and persistent cancer pain is often refractory to treatment with opioid analgesics (Abrams and Guzman, 2015).
Nabiximols has been considerably studied in patients with cancer pain. It has been conditionally approved in Canada and some European countries for the treatment of cancer-related pain. Currently, it is in phase 3 trials for cancer pain. A multicenter, double-blind, randomized, placebo-controlled study (177 patients) demonstrated that nabiximols (2.7 mg THC + 2.5 mg CBD) given for 2 weeks is superior to a placebo for pain relief in advanced cancer patients whose pain was not fully relieved by strong opioids (Johnson et al., 2010). A randomized, placebo-controlled, graded-dose trial with advanced cancer patients (88–91 per group) whose pain was not fully relieved by strong opioids, demonstrated significantly better pain relief and sleep with THC:CBD oromucosal spray following 35 days of treatment with lower doses (1–4 and 6–10 sprays/day), compared with placebo (Portenoy et al., 2012). In an open-label extension study of 43 patients with long-term use of the THC:CBD oromucosal spray there was no need for increasing the dose of the spray or the dose of other analgesics (Johnson et al., 2013). However, results of more recent studies differ from previous ones and are not promising for the use of nabiximols in the treatment of cancer pain. Namely, two studies (multicenter, randomized, double-blind, placebo-controlled, and parallel-group) conducted by GW Pharmaceuticals, the manufacturer of nabiximols, suggested that the effects of nabiximols in patients with cancer pain resistant to opioid analgesics were not different from placebo (Fallon et al., 2017). In fact, it was shown that nabiximols is superior to placebo in a patient sub-population studied in the United States, but not in sub-populations studied outside of United States, and this finding warrants further examination.
At present, there is insufficient evidence to support the approval of dronabinol and nabilone for the treatment of any type of pain, including cancer pain. In an observational study of patients with advanced cancer, nabilone improved management of pain, nausea, anxiety and distress when compared with untreated patients. Nabilone was also associated with a decreased use of opioids and other pain killers, as well as dexamethasone, metoclopramide, and ondansetron (Maida et al., 2008). Two studies examined the effects of dronabinol on cancer pain. In the first, randomized, double-blind, placebo-controlled, dose-ranging study involving ten patients, significant pain relief was obtained with 15- and 20-mg doses; however, a 20-mg dose induced somnolence (Noyes et al., 1975b). In a follow-up, single-dose study involving 36 patients, doses of 10 and 20 mg of dronabinol produced analgesic effects that were equivalent to doses of 60 and 120 mg of codeine, respectively (Noyes et al., 1975a). However, higher doses of dronabinol were found to be more sedating than codeine. It can be concluded that the effectiveness of cannabinoids in the treatment of chronic cancer pain is questionable. However, whether cannabinoids show some other improvements in cancer patients (sleep, quality of life) remains to be explored. More research is required to establish the role of cannabinoids in the treatment of cancer pain.
There are some case studies, but no published controlled clinical trials, on the use of inhaled cannabis for the treatment of pain in patients with cancer. Also, inhaled cannabis could be effective against chemotherapy-induced neuropathic pain in patients with cancer (Wilsey et al., 2013; Wilsey et al., 2016).
Tolerability and Safety of Cannabis/Cannabinoids in the Treatment of Chronic Pain
Short-Term Tolerability and Safety
Findings from available short-term clinical studies suggest that the safety profile of the short-term use (days to weeks) of cannabis/cannabinoids for pain treatment is acceptable. Their short-term use was associated with an increased risk of adverse events, but they were mostly mild and well tolerated (Wang et al., 2008; Lynch and Campbell, 2011; Andreae et al., 2015; Lynch and Ware, 2015; Whiting et al., 2015; Meng et al., 2017). The psychoactive effects of inhaled cannabis were dose-dependent, rare and mild in intensity (Andreae et al., 2015). The treatment with oral cannabinoids was associated with limited tolerability. They produce more cannabinoid-related side effects than placebo, but the side effects are mild to moderate and short-lived (Meng et al., 2017).
One systematic review of safety studies (23 RCTs and 8 observational studies) of medical cannabis and cannabinoids found that short-term use appeared to increase the risk of non-serious adverse events and that they represent 96.6% of all reported adverse events (Wang et al., 2008). Usually no difference in the incidence rate of serious adverse events was found between the group of patients assigned medical cannabis/cannabinoids and the control group. Psychiatric adverse effects are the most common reason for withdrawal of the treatment. The most commonly reported adverse effect was dizziness (15.5%), followed by drowsiness, faintness, fatigue, headache, problems with memory and concentration, the ability to think and make decisions, sensory changes, including lack of balance and slower reaction times (increased motor vehicle accidents), nausea, dry mouth, tachycardia, hypertension, conjunctival injection, muscle relaxation, etc. (Wang et al., 2008; Belendiuk et al., 2015). Tolerance to these adverse effects develops soon after the beginning of treatment. Cannabis/cannabinoids can cause mood changes or a feeling of euphoria, dysphoria, anxiety and even hallucinations and paranoia. They can also worsen depression, mania or other mental illnesses. Due to lack of cannabinoid receptors in the brainstem areas controlling respiration, lethal overdoses from cannabis do not occur.
Long-Term Tolerability and Safety
As cannabis/cannabinoids are intended for treating chronic pain conditions, their long-term tolerability and safety has to be precisely determined, as do the potential health effects of recreational cannabis use (Mattick, 2016). The brain develops a tolerance to cannabinoids, and long-term studies with cannabinoids need to answer the question whether pain can be constantly controlled with these drugs, or whether tolerance and a hyperalgesic response can occur. However, at present there are few well-designed clinical trials and observational studies for long-term medicinal cannabis use that have examined tolerability and safety (mostly in MS patients and in use of oral cannabinoids).
One controlled (open-label) study has evaluated the safety and tolerability of cannabis (a standardized botanical cannabis product that contains 12.5% tetrahydrocannabinol) used for 1 year in 215 patients (from seven clinics across Canada) with chronic non-cancer pain (Ware et al., 2015). There was a higher rate of adverse events (mostly mild to moderate with respect to the nervous system and psychiatric disorders) among cannabis users when compared to controls, but not for serious adverse events at an average dose of 2.5 g botanical cannabis per day. The conclusion of the authors of this study is that cannabis is tolerated well and relatively safe when used long-term. The beneficial effect persists over time, indicating that cannabis use for over 1 year does not induce analgesic tolerance.
The effectiveness and long-term safety of cannabinoid capsules (2.5 mg dronabinol vs. cannabis extract containing 2.5 mg THC, 1.25 mg CBD vs. placebo) in MS (630 patient) was studied in a 1-year randomized, double-blind, placebo-controlled trial follow-up of a randomized parent study (Zajicek et al., 2005). The number of patients who withdrew due to side effects was similar between groups. Also, serious side effects were similar in the placebo and active groups and were related to the medical condition. Generally, there were no safety concerns reported in this study.
The safety and tolerability of nabiximols long-term use in different conditions (cancer pain, spasticity and neuropathic pain in MS patients) has been studied in a series of trials of up to 2 years duration (Wade et al., 2006; Rog et al., 2007; Johnson et al., 2013; Serpell et al., 2013). All were uncontrolled, open-label extension trials. Adverse events and serious adverse events were cannabinoid-related with no safety concerns reported. Also, there was no evidence for a loss of effect in the relief of pain with long-term use.
Taking into account all long-term safety studies, cannabis appears to be better tolerated than oral cannabinoids (Romero-Sandoval et al., 2017). This interpretation is based on a single study with cannabis (Ware et al., 2015) and should therefore be taken with caution.
Long-term adverse effects of medical cannabis are difficult to evaluate. They mainly come from studies with recreational cannabis use (Mattick, 2016). However, there are many differences between medical cannabis and recreational cannabis users as regards the amounts used, the existence of comorbidities, the mode of drug delivery (Wang et al., 2008), etc. Thus, the adverse effects of recreational cannabis use cannot be directly extrapolated to medical cannabis use. The safety of medical and recreational cannabis should be evaluated separately. There is evidence that long-term cannabis use is associated with an increased risk of addiction, cognitive impairment, altered brain development and an increased risk of mental disorders (anxiety, depression, and psychotic illness) with adolescent use, and adverse physical health effects such as cardiovascular disease, chronic obstructive pulmonary disease and lung cancer (Volkow et al., 2014; Mattick, 2016). It is well established and documented that CBD may lower the risk for developing psychotic illness that is related to cannabis use (Iseger and Bossong, 2015).
Cannabis-use disorders (CUD) are defined in the Diagnostic and Statistical Manual of Mental Disorders (Hasin et al., 2013) and in the International Statistical Classification of Diseases and Related Health Problems (ICD-11). It was estimated that 9% of those who use cannabis develop CUD (Budney et al., 2007). Risk factors (e.g., cannabis use at an earlier age, frequent use, combined use of abused drugs) for the progression of cannabis use to problem cannabis use (CUD, dependence, and abuse) (NASEM, 2017; Hasin, 2018) are more common among recreative than among medical cannabis users. CUD are associated with psychiatric comorbidities. About one half of patients treated for CUD develop withdrawal symptoms such as dysphoria (anxiety, irritability, depression, and restlessness), insomnia, hot flashes and rarely gastrointestinal symptoms. These symptoms are mild when compared with withdrawal symptoms associated with opioid use. Most of the symptoms appear during the 1st week of cannabis withdrawal and resolve after a few weeks (Gordon et al., 2013; Volkow et al., 2014).
A number of studies have yielded conflicting evidence regarding the risks of various cancers associated with cannabis smoking (Health Canada, 2013). Recently, NASEM (2017) has stated, with a moderate level of evidence, that there is no statistical association between cannabis smoking and lung cancer incidence.
Before grant approval, drug agencies need to be sure that the benefits of medicine outweigh the risks. As the benefits and risks of medical cannabis have not been thoroughly examined, individual products containing cannabinoids have not been approved for the treatment of pain (Ko et al., 2016). Nonetheless, a number of chronic-pain patients use cannabis/cannabinoids for pain relief. Some replaced partially or completely the use of opioids with cannabis/cannabinoids (Boehnke et al., 2016; Lucas and Walsh, 2017; Lucas, 2017; Piper et al., 2017), and others continued to use prescription opioids. Observational studies have found that state legalization of cannabis is associated with a decrease in opioid addiction and opioid-related over-dose deaths (Hayes and Brown, 2014; Powell et al., 2018). Previous studies suggested that the analgesic effects of cannabis are comparable to those of traditional pain medications (Wilsey et al., 2013). However, data on the comparative efficacy and safety of cannabis/cannabinoids versus existing pain treatments, including opioids, are missing. Also, more studies are needed on potentially beneficial or problematic combinations of cannabis/cannabinoids and available analgesics. Further research is expected to provide an answer to the question whether cannabis/cannabinoids can be an effective and safe substitute for opioid therapy in the treatment of chronic pain (Nielsen et al., 2017). New high-quality, long-term exposure trials are required to determine the efficacy and safety of long-term use of medicinal cannabis in the treatment of pain (Hill et al., 2017; Piomelli et al., 2017; Romero-Sandoval et al., 2017). The design of trials should be improved to ensure that they are blinded, placebo-controlled with active comparator, with consistency of pain diagnosis, long-enough duration of treatment, evaluation of the dose-response, homogeneity of the patient population and inclusion of quality of life as an outcome measure (Ko et al., 2016; NASEM, 2017; Piomelli et al., 2017).
Current research evidence supports the use of medical cannabis in the management of chronic pain in adults (NASEM, 2017). As its use in the treatment of chronic pain increases, additional research to support or refute the current evidence base is crucial to provide answers to questions concerning the risk-benefit ratio for medical cannabis use in pain treatment. The implementation of monitoring programs is mandatory and provides an opportunity to accumulate data on the safety and effectiveness of long-term use of medical cannabis in the real world (Hill et al., 2017; Romero-Sandoval et al., 2017). This is important for evidence-based policy making and implementation (Nosyk and Wood, 2012).
The key findings are summarized below:
Cannabinoids and cannabis are old drugs but now they are a promising new therapeutic strategy for pain treatment.
Cannabinoids (plant-derived, synthetic) themselves or endocannabinoid-directed therapeutic strategies have been shown to be effective in different animal models of pain (acute nociceptive, neuropathic, inflammatory). However, medical cannabis is not equally effective against all types of pain in humans.
A recent meta-analysis of clinical trials of medical cannabis for chronic pain found substantial evidence encouraging its use in pharmacotherapy of chronic pain. Also, it was shown that medical cannabis may only moderately reduce chronic pain, similar all other currently available analgesic drugs. However, controlled comparative studies on the efficacy and safety of cannabis/cannabinoids and other analgesics, including opioids, are missing.
Inhaled (smoked or vaporized) cannabis is constantly effective in reducing neuropathic pain and this effect is dose-related and can be achieved with a concentration of cannabis THC lower than 10%. Compared to oral cannabinoids, the effect of inhaled cannabis is more rapid, predictable and can be titrated. Compared to inhaled cannabis, the effectiveness of oral cannabinoids in reducing the sensory component of neuropathic pain seems to be less convincing and oral cannabinoids in general may be less tolerable. However, data suggest that they may improve secondary measures such as sleep, quality of life and patient satisfaction.
There are no controlled clinical trials on the use of inhaled cannabis for the treatment of cancer or rheumatic (osteoarthritis, rheumatoid arthritis, and fibromyalgia) pain.
Whether oral cannabinoids reduce the intensity of chronic cancer pain is not completely clear. Recent long-term studies of nabiximols are not encouraging.
Sparse literature data show that oral cannabinoids have inadequate efficacy in rheumatological pain conditions. Also, oral cannabinoids do not reduce acute postoperative or chronic abdominal pain.
In general, the efficacy of medical cannabis in pain treatment is not completely clear due to several limitations. Clinical trials are scarce and most were of short duration, with relatively small sample sizes, heterogeneous patient populations, different types of cannabinoids, a range of dosages, variability in the assessment of domains of pain (sensory, affective) and modest effect sizes. Therefore, further larger studies examining specific cannabinoids and strains of cannabis, using improved and objective pain measurements, appropriate dosages and duration of treatment in homogeneous patient populations need to be carried out.
The current review of evidence from clinical trials of medicinal cannabis suggests that the adverse effects of its short-term use are modest, most of them are not serious and are self-limiting.
Long-term safety assessment of medicinal cannabis is based on scant clinical trials, so the evidence is limited, and the safety interpretation should be taken cautiously. More research is needed to evaluate the adverse effects of long-term use of medical cannabis.
In view of the limited effect size and the low but not unimportant risk of serious, adverse events, a more precise determination of the risk-to-benefit ratio for medicinal cannabis in pain treatment is needed to help establishing evidence-based policy implementation.
Current evidence supports the use of medical cannabis in the treatment of chronic pain in adults. Monitoring and follow-up of patients is obligatory.
Cannabis has been a friend to humankind since before the written word, providing fiber for cordage and cloth, seeds for nutrition, and roots, leaves and flowers for ritual and healing. During the Neolithic period, our ancestors discovered uses for every part of cannabis, which was one of the first agricultural crops, perhaps the first, ever to be grown and harvested some 12,000 years ago.
Agriculture, strictly speaking, is not a natural phenomenon. It is an expression of human ingenuity, an invention that has been described as the basis—literally the ground—of modern civilization. “The onset of agriculture was probably one of the most dramatic and important developments in human history,” writes Swiss scientist Jürg Gertsch, who explores the profound consequences of dietary changes brought on by food cultivation in a recent article in the British Journal of Pharmacology.
The interplay between diet and the endocannabinoid system is key to understanding today’s obesity and diabetes crises.
Gertsch’s provocative thesis is that chronic metabolic disorders, currently a worldwide pandemic, are rooted in “a mismatch between ancient genes and high caloric diets” that ensued with the introduction of agriculture. “The multimillion year evolutionary process during which nearly all genetic change reflected the life circumstances of our ancestors [was] suddenly disturbed” when “carbohydrate farming” supplanted the “hunter-gatherer diet rich in animal food,” says Gertsch, who maintains that “the interplay between diet and the endocannabinoid system” is key to understanding today’s obesity/diabetes crisis and its potential remediation.
The endocannabinoid system, an ancient biological signaling network, regulates numerous physiological processes, including intestinal function, glucose metabolism, and the stress response. A dysregulated endocannabinoid system is implicated in metabolic and bowel pathologies and many other diseases. Gertsch discusses the different, yet complementary, roles of the cannabinoid receptors—CB1 and CB2—pertaining to diet, digestion, and energy metabolism.
Mammalian CB1 receptors are concentrated in the brain and the central nervous system. They are also present in taste buds and the enteric nervous system (the gut-brain axis). Tetrahydrocannabinol (THC), marijuana’s main psychoactive component, boosts appetite and food intake by binding to the CB1 receptor—a phenomenon playfully known as “the munchies.” But CB1 receptors, as Gertsch points out, “can exert paradoxical effects on food intake,” facilitating essential nourishment as well as metabolic imbalance.
CB1 receptor signaling triggers a newborn’s suckling instinct. Mother’s milk is well endowed with arachidonic acid, a basic building block of the brain’s own marijuana-like compounds, anandamide and 2-AG. These endogenous cannabinoid compounds bind to the same cell receptors—CB1 and CB2—that mediate many of the effects of marijuana. Found in eggs, meat, and dairy products, arachidonic acid intake increases endocannabinoid levels in different tissues and is crucial for pre- and post-natal brain development.
Early hominids lived a precarious wilderness existence, requiring significant physical exertion (hunting and gathering) for survival. Famine, microbial infection, traumatic encounters with predators, fight or flight—all were hallmarks of a pre-agriculturist, subsistence lifestyle. Given the metabolic demands of their large brains and strenuous daily activities, our ancestors needed to consume energy-dense, nutrient-rich food.
In addition to heightening one’s sense of smell and stimulating appetite, CB1 receptor signaling “may facilitate survival after excessive physical activity, stress and trauma by restoring homeostasis, suppressing negative memories and reducing anxiety at the level of the central nervous system,” writes Gertsch, who explains that “CB1 receptor activation is associated with increased energy intake and decreased energy expenditure by controlling neural pathways.”
AND CB1 TAKETH AWAY
Combined with rigorous, day-to-day aerobics, the hunter-gatherer diet did not engender obesity, metabolic problems or cardiovascular disease. But the high-fat hunter-gatherer diet, which served our ancestors well, changed significantly with the advent of cultivated food. “Carbohydrate farming incited the most important dietary transition, which is still ongoing to the present day,” says Gertsch. There is a continuum, he maintains, between plant carbohydrate cultivation of yore and today’s over-starched, over-sweetened and over-processed Western diet.
Grain, carbs, sugar, alcohol, high fructose corn syrup: What started as the basis of civilization has spiraled into a mass-marketed refined sugar binge. “Dietary carbohydrates once essential for the cognitive and social development of Paleolithic humans gradually turned into a metabolic stress factor as a function of their glycemic indices,” Gertsch explains. “Epidemiological evidence points toward a pandemic diet-induced glucose toxicity due to excess sugar intake.”
The endocannabinoid system is deeply implicated in this unhealthy worldwide trajectory. Linked to both motivation and reward, CB1 receptor signaling encourages sugar consumption by enhancing neural responses to sweet flavors. It has been shown that chronic CB1 receptor activation in mice causes obesity-related insulin resistance. Aberrant CB1 activity reinforces a metabolically skewed feedback loop: In obese humans, high endocannabinoid levels are found in the liver, pancreas, adipose tissue, and skeletal muscle, where they contribute to insulin resistance, decreased glucose uptake, oxygen depletion, and cardiometabolic distress.
“The generation and excess use of sugars could be seen in analogy to the detrimental impact of the first distilled alcohol on humans. The sudden availability of excess sugars in combination with fats in diet may have led to a collision of genes that evolved to cope with high energy demands due to constant physical activity,” says Gertsch. “Excessive consumption of high-energy palatable food without physical activity contributes to obesity.” Which, in turn, leads to metabolic syndrome, heart disease, and other degenerative conditions.
CB2 TO THE RESCUE
CB1 and CB2 cannabinoid receptors play different roles with respect to diet and nutrition. In animal studies, CB2 receptor activation generally causes the opposite effects of CB1. Whereas CB1 receptors promote appetite and food consumption, CB2 receptors tend to inhibit food intake.
Expressed primarily in immune cells, adipose (fatty) tissue, and the peripheral nervous system, CB2 receptors confer broad anti-inflammatory effects in various disease models. Noting that obesity is a low-grade inflammatory condition, Gertsch discusses the “protective role of CB2 receptors in diet-induced metabolic malignancies.” Preclinical research indicates that CB2 receptor activity can prevent or ameliorate diabetes-associated peripheral neuropathy and pro-inflammatory obesity. CB2 signaling is also protective against brain damage from strokes, concussions, and neurodegenerative ailments.
Gertsch suggests that the contemporary “mismatch between ancient genes and high caloric diets” might be reconciled in part by CB2’s ability to mediate the effects of secondary plant metabolites (terpenes, flavonoids and other polyphenolic compounds) that are found in kitchen spices, leafy greens, and other vegetables. “Dietary secondary metabolites from vegetables and spices are able to enhance the activity of CB2 receptors and may provide adaptive metabolic advantages and counteract inflammation,” Gertsch reports.
Beta-caryophyllene (BCP), for example, is a seemingly ubiquitous aromatic terpene present in many spices (black pepper, cloves, rosemary, etc.) and bitter greens, as well as in numerous cannabis varietals. This versatile plant compound conveys significant health benefits by directly activating the CB2 receptor and via other molecular pathways. BCP has been shown to stimulate insulin production and inhibit tumor growth in human cell lines. Mounting evidence suggests that a steady diet of BCP-rich foods could prevent or mitigate non-alcoholic fatty liver disease through CB2-mediated channels. Eating green leafy vegetables and spices rich in essential oils “may counteract metabolic stress induced by excessive carbohydrate intake,” Gertsch advises.
HEALTHY FATS, HEALTHY PEOPLE
Several scientific studies have explored the link between the intake of polyunsaturated fatty acids (PUFAs) and the endocannabinoid system. Docosahexaenoic acid (DHA), an omega-3 fatty acid, is the principal long chain PUFA found in the human brain. Omega oils are considered “essential” fatty acids because they can’t be produced by the body in sufficient amounts and therefore must be ingested. Dietary DHA and eicosapentaenoic acid (EPA), another long chain PUFA, support neurological function, retinal development, and overall health by up-regulating CB1 receptor gene expression.
Preclinical research has shown that administering DHA and EPA prevented glucose intolerance and low-grade inflammation of white adipose tissue in obese mice.
The manifold health benefits of omega-3 PUFAs — prominent in oily fish, walnuts, flax and hempseeds, for example — include the prevention of heart disease, dementia, cancer cell proliferation, insulin resistance, and depression.
The manifold health benefits of omega-3 PUFAs—prominent in oily fish, walnuts, flax and hempseeds, for example—include the prevention of heart disease, dementia, cancer cell proliferation, insulin resistance, and depression. Low levels of DHA and EPA can lead to premature aging, as well as mental illness. Nutritional omega-3 dietary deficiency “abolishes endocannabinoid-mediated neuronal functions” and is associated with neuropsychiatric disease, according to a 2011 report in Nature Neuroscience. Alzheimer’s sufferers and children with attention deficit hyperactivity disorder tend to be deficient in omega-3 fatty acids.
A healthy balance of omega-3 fatty acids and grain-derived omega-6 fatty acids is fundamental for preventing and managing obesity and metabolic syndrome. But a well-balanced ratio of PUFAs is typically lacking in a carb-heavy Western diet that favors greater omega-6 intake at the expense of omega-3. Gertsch suggests that it is possible “to reprogram energy metabolism” by increasing omega-3 and decreasing the amount of omega-6 in one’s diet: “Generally a lower omega-6 to omega-3 ratio is desirable in reducing the risk of many of the chronic diseases of high prevalence in industrial society or societies with high carbohydrate intake.”
A 2014 paper by Japanese scientists reported that the ratio of dietary omega-6 to omega-3 fatty acids influences how CB1 receptors regulate fear memory. The upshot is that altering the omega-6/omega-3 ratio in one’s diet could improve treatment regimens for anxiety and PTSD, as well as for metabolic disorders. Human beings have evolved in such a way as to have “an advanced capacity to digest and metabolize higher fat diets,” says Gertsch, who concludes that a “low-carb, high fat diet should be the most effective measure against obesity”—with the caveat that a high fat diet must be combined with regular physical exercise, much like in the hunter-gatherer days before agriculture.
Given what scientists know about how the endocannabinoid system functions, there is a strong basis for adopting a high fat, low carb diet with lots of fresh vegetables and spices, both as a general health practice and a remedy for many maladies.
Martin A. Lee is the director of Project CBD and the author of Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific.
Copyright, Project CBD. May not be reprinted without permission.
While cannabis is being legalized in more and more states, both the adverse and beneficial effects of its use are starting to be better understood. The active compound in cannabis, THC (tetrahydrocannabinol) is widely known to have effects on the brain, producing the “high” that many users are seeking. However, the other more adverse effects cannabis can have on the body are less widely known. In this blog, I want to focus mainly on how cannabis can affect your hormones, primarily through the pituitary, thyroid, and adrenal glands, and the reproductive system.
The Endocannabinoid System (ECS) and How It Works
Endocannabinoids are molecules naturally produced in the body in small amounts that act on cannabinoid receptors and play important roles in various processes. There are 2 types of cannabinoid receptors in the body, CB1 and CB2, and a few orphan receptors that also bind with the endocannabinoids. These are the same receptors that THC binds and activates (and CBD, which I won’t cover here). The ECS is involved in regulating fertility, pregnancy, appetite, pain-sensation, mood, memory, energy balance, homeostasis, and the immune system. The ECS is also responsible for “runner’s high” through spikes in endocannabinoids circulating in the blood to the brain, where it is involved in locomotor activity through interactions with the cerebellum and affects the reward center of the brain through transduction of dopamine release.
Cannabis’s Effects on the Hypothalamus-Pituitary-Adrenal (HPA) Axis
The HPA axis controls the stress response ultimately through the release of cortisol. When different regions of the brain sense a stressor (whether emotional, chemical, physical, or pathogenic), neural signals are sent to the hypothalamus which triggers the release of corticotropin-releasing factor (CRF) and vasopressin (VP) which couple to stimulate the pituitary to manufacture and release adrenocorticotropic hormone (ACTH) into the bloodstream. When ACTH reaches the adrenal glands it binds to receptors in specific regions of the gland to stimulate the release of cortisol into the bloodstream. When the stressor is removed (e.g., low blood glucose returns to normal, emotional stress is resolved, and physical exercise, chemical, or pathogenic stressors are reduced), cortisol negatively feeds back to the hypothalamus and pituitary to shut down further stimulation of CRF and ACTH.
Acute high cortisol is essential for optimal health, since cortisol helps control blood sugar levels, regulates metabolism, reduces inflammation, controls salt and water balance which influences blood pressure, and assists with memory formation. However, persistent high cortisol caused by excessive stressors will eventually have a negative impact on health. Prolonged release of high levels of cortisol reduces the sensitivity of the negative feedback loop that controls cortisol levels and reduces its effectiveness .
It has been shown that THC increases circulating cortisol levels after use . For infrequent cannabis users, this increase in cortisol can cause increases in blood pressure and anxiety . In long-term users, sustained increase of cortisol blunts the body’s natural reactions to changes in cortisol and can affect a woman’s libido and menstrual cycle . Long-term use also has the potential to blunt the morning spike of cortisol, referred to as the Cortisol Awakening Response (CAR). Upon waking, cortisol levels spike, slowly declining throughout the day. This spike of cortisol is important in facilitating the body to wake up. If this spike is blunted, it becomes difficult to shake off sleep and function normally.
Cannabis’s Effects on the Hypothalamus-Pituitary-Thyroid (HPT) Axis
The HPT axis is responsible for maintaining metabolic rate, heart and digestive functions, muscle control, brain development, and bone health. Briefly, the hypothalamus releases thyrotropin-releasing hormone (TRH) which then binds with the pituitary gland, stimulating the release of thyroid-stimulating hormone (TSH). TSH then stimulates the release of thyroxine (T4) and triiodothyronine (T3) from the thyroid. T4 exerts a negative feedback with the hypothalamus to regulate how much is circulating in the bloodstream.
THC inhibits secretion of TSH from the pituitary gland mostly through regulation of TRH release in the hypothalamus . This effect is dose-dependent, meaning the more you consume, the more it depresses the TSH levels . This decrease in TSH levels causes a decrease in synthesis of T4 and T3 in the thyroid gland and consequent lower circulating T4 and T3 levels . Low circulating T4 and TSH levels can lead to symptoms of pituitary hypothyroidism including fatigue, weight gain, cold intolerance, depression, decreased libido, and abnormal menstrual cycles.
Cannabis’s Effects on the Hypothalamus-Pituitary-Gonadal (HPG) Axis
The HPG axis oversees the body’s functions related to reproductive health and regulates our hormones to maintain optimal function and health of all tissues throughout the body (brain, connective tissue, cardiovascular, reproductive organs, immune system, etc.). Briefly, the hypothalamus secretes gonadotrophin-releasing hormone (GnRH) which stimulates the pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
FSH and LH are important in regulating gonadal function in both sexes. In women, FSH and LH are important for pubertal development and ovarian function and play an important role during the menstrual cycle. In men, FSH is essential to the function of the testes and their production of sperm (spermatogenesis) and LH stimulates the production of testosterone. Cannabis use directly impacts many parts of the HPG axis. THC indirectly decreases the secretion of GnRH by the hypothalamus through regulation of the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) , and through the transduction of dopamine, which is shown to decrease GnRH signaling . In women, THC inhibits folliculogenesis, the maturation of the ovarian follicle, and ovulation, through the regulation of cellular energy produced in the mitochondria, cAMP . During ovulation, the body releases a surge of endocannabinoids in the ovary; excess cannabinoids from cannabis consumption can disrupt the ovulatory surge and lead to an irregular cycle . THC also inhibits steroidogenesis by preventing the conversion of pregnenolone to progesterone . In men, THC has been shown to decrease sperm count, reduce serum testosterone and LH levels, reduce sperm motility, and inhibit the processes needed to facilitate sperms’ ability to achieve conception . These effects can lead to a decrease in fertility in both men and women, but fertility can return with cessation of use.
In summary, chronic cannabis consumption can have effects on the adrenal, thyroid, and reproductive systems that can potentially affect energy, behavior, and reproductive health. Fortunately, after stopping long-term, chronic use, the body can restore normal function, hopefully mitigating these effects. THC also has an impact on the developing fetus so stopping cannabis use while trying to conceive will help both you and your developing child .
If you are a habitual cannabis user and your energy level and sex-drive are lackluster, it may be wise to periodically test your levels of adrenal hormones (cortisol, DHEA-S), sex hormones (estradiol, progesterone, and testosterone), and thyroid hormones (T4, T3, TSH, TPOab) to make sure THC isn’t blunting your edge. Simple and convenient saliva and blood spot tests can help determine if cannabis use is impacting your overall health.
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As a Holistic Clinical Pharmacist, I am always looking for holistic and natural approaches to health for people and pets. CBD or Cannabidiol is the perfect natural cannabinoid supplement to compliment good lifestyle choices and the desire for quality of life.
CBD hemp oils have become more common and as mainstream products are being marketed to pet owners, you may ask, “Should I give my Pet CBD oil?”
My answer is a definite “Yes!!! …but” because not all products are created equally and there are some things consumers should be aware of before purchasing a CBD product.
The good news is pets can benefit from CBD in much the same way humans do. Our furry friends, as well as most animals, have an Endocannabinoid System (ECS) that is responsible for maintaining homeostasis or balance within the body – including regulation of the communication between cells, the body’s immune response, and autonomic functions like appetite, sleep, and metabolism. Basically, the ECS helps the body maintain itself.
Cannabinoid supplements interreact with this system meaning that your pet will potentially derive benefits from CBD in similar ways to their human “parents” do. CBD’s benefits come from its ability to affect the body’s naturally occurring regulatory processes by interacting with the Endocannabinoid System. This chemical communication system includes CB1 receptors, mostly found in the brain, and CB2 receptors found all over the body, including in the gut and immune cells.
Because of this similarity between this system in humans and other animals, many owners have started taking advantage of the availability of CBD products in hopes of treating their pet’s Arthritis, Anxiety, fear of people, fear of loud noises, traveling stress, seizure disorders, GI disorders, chronic pain, inflammation, and even cancer. Animals, however, can be very sensitive to cannabinoids.
One of the leading experts and writer of Medical Marijuana and Your Pet, Dr. Robert Silver, DVM, MS, CVA, writes “Studies on dogs, conducted in the 1970’s, helped us to understand the working of the endocannabinoid system,” and “ it was determined that dogs, as compared to all of the other species studied, have the greatest number of endocannabinoid receptors in their cerebellum and brain stem, which govern coordination and other basic necessary functions like breathing and heart rate. Due to this high density of endocannabinoid receptors in its brain, dogs are extremely sensitive to THC.”
This extreme sensitivity to THC in dogs limits the ability to use traditional medicinal marijuana in our pets, which would quickly turn them into furry THC-zombies. This also means consumers must be very careful that the CBD products they buy DO NOT contain THC. Legally products can be marketed as “THC-Free” so long as they contain less than 0.3% THC which still may be far too high for our THC-sensitive furry friends.
Dogs can easily overdose on THC and have a severe negative reaction called Static Ataxia, which includes: glazed eyes, excessive drooling, loss of bowel and bladder control, rapid breathing, falling over, and an inability to get up again.
CBD has become the cannabinoid of choice for many clients because it is non-toxic and well tolerated in animals, but the dangers of THC are less widely known.
Now you may ask, “How do I choose a CBD Hemp Oil product for my pet?”
First and foremost, you must buy the product from a reputable source. A reputable source is one that does third party lab testing on their finished products and can produce a Certificate of Analysis to prove that the products actually contain what is on the product labels. Since 2015 the FDA has sent warning letters to CBD manufacturers who claim there is more CBD in the bottle than there actually is. Up to 75% of CBD products were found in one study to be mislabeled and misbranded.1
Our LabNaturals CBD Full Spectrum CBD Hemp Oils have proven ZERO THC per third party testing, which makes them an excellent choice, especially dogs who are naturally much more sensitive to THC’s psychotropic effects.
Since LabNaturals CBD products are third party tested for potency, purity, and consistency, you can rest assured that our CBD hemp oils are consistent with their labeled strengths. We have Certificates of Analysis available upon request for each of our products. Our oils are free from contaminants – like mold, mildew, and microbes, and are grown without chemicals or pesticides, and are free of heavy metals – protecting your pet’s health and safety over the long-term use of these products.
Second, make sure to purchase CBD oil from a business with professional expertise in health, wellness, and supplementation. It is also important to have someone check your animal’s medications for potential interactions. Finding a pharmacist well versed in both CBD and pet medications is best to be sure that all information is accurate. Our LabNaturals CBD is not your vape shop’s CBD! LabNaturals PCR CBD products contain full spectrum hemp oil creating an entourage effect where the cannabinoids work together for greater potential benefits. They are also derived from the whole medicinal industrial hemp plant grown, processed, and produced in accordance with the 2014 FARM BILL, Section 7606.
Third, we use a “Low and Slow” “micro-serving” process of building up the serving size in our clients which applies to both humans and animals. This allows us to find the right serving size for the client’s needs. We also consider the pet’s size, species, and weight starting at a serving of 0.25-0.5mg of CBD/kg/day and this serving may be increased on a weekly basis until desired benefits are achieved.
You should feel confident that my 37 years of clinical pharmacy experience is reflected in every handpicked product in my pharmacy, Murray Avenue Apothecary, including our only brand of CBD products LabNaturals CBD Full Spectrum Plant Oils. This new brand of CBD builds on our already popular LabNaturals Skin Care line which provides affordable, non-toxic, and eco-friendly anti-aging and acne products.
At Murray Avenue Apothecary we are pharmacists for humans and our furry family members and we have done our research into the exciting new world of CBD and cannabinoid supplementation. If you have questions we will always do our best to answer them as completely as possible. We ensure the purity, consistency, and safety of all our products and compounds because that is exactly what you and your pets deserve.
Discover more about LabNaturalsCBD products by visiting our LabNaturalsCBD.com
Lab Naturals CBD Pet Testimonial:
"Our Bullmastiff/German Shepherd rescue, Hardy, came to us with a host of lovable quirks, but his anxiety made it difficult for him to enjoy life to the fullest. We tried an expensive prescription separation anxiety medication, but the results were just fair. We switched to LabNaturals CBD and it has made a world of difference! He no longer anxiously follows us from room to room or paces around our home, we've been able to trim his nails, and he is overall a more relaxed and happy dog.
What I appreciate most is that he does not seem "sedated," his fun and sweet personality still shines through. Using LabNaturals' product has allowed us to get Hardy's anxiety level diminished to the point of being able to start working on the behavioral modification techniques needed to treat the root of his anxious processes."
1. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017;318(17):1708–1709. doi:10.1001/jama.2017.11909
Cannabidiol and CBD oil seem to be everywhere these days, despite the confusing legal status of this prolific compound. But how much do we actually know about CBD?
CBD became illegal before it was discovered.
Cannabis was effectively outlawed by the federal government in 1937 with the passage and implementation of the Marihuana Tax Act. The Act explicitly stated that cannabis resin or any extract from the resin was considered to be “marihuana” (i.e. the Evil Weed). Cannabidiol (CBD) is found in the resin, nowhere else in the plant. (Tetrahydrocannabinol – THC, aka The High Causer – is also concentrated in the resin along with a slew of other therapeutic compounds.) In effect, CBD, a nonintoxicating cannabis component, was prohibited by federal law before anyone actually knew that CBD existed.
It wasn’t until 1940 that Roger Adams, a University of Illinois chemist, first identified and synthesized CBD. Two years later, he was awarded a patent for his unique method of isolating CBD. Adams observed that CBD had pain-killing properties and he contributed to the 1944 La Guardia Report on the Marihuana Problem, which debunked many of the scaremongering reefer madness claims promoted by the Federal Bureau of Narcotics. By the time Adams retired in 1957, he had published 27 studies on CBD and other plant cannabinoids. He was subsequently honored by the American Chemical Society, which established the prestigious Roger Adams Award in recognition of his life’s work. Israeli scientist Raphael Mechoulam picked up where Adams left off and elucidated the precise molecular structure of CBD in 1963. And he did the same for THC in 1964.
CBD oil makes brain cells grow.
Cannabidiol (CBD) not only protects brain cells – it also stimulates the growth of new brain cells, a process known as “neurogenesis.” New neurons are continually being created in two areas of the hippocampus: the subgranular zone of dentate gyrus and subventricular zone of lateral ventricles. These brain regions are densely populated with cannabinoid (CB1) receptors. Activation of CB1 receptors stimulates the creation of new neurons, a process that underscores the central role of endocannabinoid system the in embryonic and adult neurogenesis, according to a 2019 study by a team of Brazilian scientists.
CBD and THC both promote neurogenesis.
Whereas THC binds directly to CB1, CBD boosts CB1 signaling through other pathways. Both CBD and THC are “neurogenic” substances that promote neurogenesis. “The pro-neurogeneic effects of CBD might explain some of the positive therapeutic features of CBD-based compounds,” German scientists reported in 2010. The antidepressant properties of CBD, THC and several other compounds are contingent on enhanced neurogenesis and neuroplasticity, the ability to adapt to stress and injury – unlike “chronic alcohol exposure [which] reduces endocannabinoid activity and disrupts adult neurogenesis,” Spanish researchers disclosed in 2015. It’s worth noting that preclinical research shows that a low dose of CBD increases neurogenesis, but higher doses decrease neurogenesis.
CBD oil is not intoxicating, but it is psychoactive.
When Project CBD formed 10 years ago to educate the medical marijuana community and the public at large about cannabidiol, we typically referred to CBD as “non-psychoactive,” and it subsequently became the mantra of the upstart CBD industry. “CBD is not psychoactive, it doesn’t get you high” – that’s always been a key selling point about CBD. According to politically correct drug war dogma, the cannabis high is a bad side effect. At Project CBD, we’ve since come to an understanding that while CBD most certainly is not an intoxicant, it’s misleading to call it non-psychoactive. When a clinically depressed patient or a PTSD sufferer consumes a CBD-rich tincture and has a very good day for the first time in a long while, it’s apparent that CBD is a powerful mood-altering molecule. Cannabidiol won’t make a person feel euphoric or dysphoric like THC does, but CBD can impact the psyche in positive ways.
Best of all, when combined THC and CBD confer a greater-than-additive therapeutic effect. Accordingly, it makes sense to medicate using a CBD-rich remedy with as much THC as a person is comfortable with. For some people that means as little THC as possible. Those who are very sensitive to cannabis may have a genetic variant that impedes their ability to metabolize THC, which stays active in their system longer. About 20 percent of Caucasians express a polymorphism of the gene that encodes the cytochrome P450 isoform that breaks down THC. About ten percent of those of African descent and five percent of Asians also have this genetic anomoly, which makes them supersensitive to THC. Those who don’t like to get high have the option of utilizing a non-intoxicating CBD-rich product with a minuscule amount of THC.
CBD and THC bring out the best in each other.
CBD oil companies often tout cannabidiol for its ability to neutralize THC’s psychoactive effects. But this emphasis distracts attention from one of CBD’s greatest gifts: It enables a person to manage marijuana’s tricky psychoactivity in a way that suits one’s particular needs and sensitivities. That might mean reducing the high without eliminating it entirely. Finding the optimal balance between CBD and THC is a key challenge of cannabis therapeutics. CBD and THC are the power couple of the cannabis plant; they work best together.
“CBD increased some effects of an ineffective THC dose to the level of an effective one.”
Extensive clinical research has demonstrated that CBD combined with THC is more beneficial for neuropathic pain than either compound as a single molecule. Scientists at the California Pacific Medical Center in San Francisco found that a CBD-THC combo has a more potent anti-tumoral effect than either compound alone when tested on brain cancer and breast cancer cell lines. And according to a 2010 study in the British Journal of Pharmacology, CBD potentiates THC’s anti-inflammatory properties in an animal model of colitis: “CBD increased some effects of an ineffective THC dose to the level of an effective one.” In other words, a low, non-intoxicating dose of THC on its own might not be effective therapeutically. However, when combined with CBD a non-intoxicating dose of THC may result in a desired therapeutic outcome. That’s great news for those seeking the medical benefits of cannabis without the buzz.
CBD is a promiscuous compound.
The canonical endocannbinoid system consists of two cannabinoid receptor subtypes (CB1 and CB2); two principal endocannabinoid ligands (anandamide and 2-AG) that activate these receptors; and various proteins that regulate the biosynthesis, transport, and metabolic breakdown of our endogenous cannabinoids. CBD, it turns out, has little binding affinity for either cannabinoid receptor, but instead conveys effects through a bewildering array of molecular pathways. According to Mayo Clinic neurologist Eugene L. Scharf (writing in 2017), the scientific literature has identified more than 65 molecular targets of CBD, including various G-protein coupled receptors that activate or inhibit serotonin, adenosine and opioid signaling. CBD binds to several so-called orphan receptors (GPR3, GPR6, GPR12, GPR18, GPR55 …) and also interacts with GABAa receptors; nuclear receptors (PPARs); several members of the transient receptor potential (TRP) channel family of ionotropic receptors; and various ligand-gated ion channels, such as glycine (GlyR), nicotinic acetylcholine (nACh), and sodium channels (NaV).
That’s a lot of scientific mumbo-jumbo for a little molecule, but there’s more. CBD functions as a negative allosteric CB1 receptor modulator, which means that CBDinterferes with THC’s ability to signal through CB1 without entirely blocking it. This appears to be one of the ways that CBD lowers the ceiling on THC’s intoxicating effect. In addition, CBD acts through various receptor-independent conduits to confer therapeutic outcomes. As Paula Morales and Patricia H. Reggio report in Medicinal Chemistry, CBD’s promiscuous nature “offers novel prospects for the treatment of neurological, oncological, and inflammatory diseases.”
source: Project CBD
The Opioid Epidemic is everywhere and even though it is no longer dominating the TV news cycle doesn’t mean it has gone away. It is affecting our friends, families, and our neighbors every single day.
Let’s revisit this important topic and enhance our commitment to take part in the solution to this national health emergency.
In over 37 years of pharmacy practice I have witnessed many people afflicted with chronic pain and neuropathic pain who have turned to and have been prescribed dangerous and addictive opioids.
While not everyone who takes a prescription opioid will wind up an addict, the risk is all too real. The health risks associated with these drugs are great, and addiction and overdoses are a daily occurrence. It is particularly important for you to avoid opioids when trying to address long-term and chronic pain, as your body will create a tolerance to the drug. Over time you’ll require greater and greater doses at more frequent intervals to achieve the same pain relief; this is how the addiction process begins. This is the recipe for the disaster that is the Opioid Epidemic and could have lethal consequences for you or a loved one. Please don’t risk it!
Please continue reading to find out about CBD – the “green” light in the darkness of opioid addiction – because by replacing addictive, toxic, and dangerous opioid use with natural, non-toxic CBD oil we can attempt to make a major difference in the Opioid Epidemic, both here in western Pennsylvania and across the nation.
“In 2012, paramedics responded to about 900 calls for overdoses in the city [of Pittsburgh]; in 2016, it was 2,300… During 2016, 613 people died from overdoses in Allegheny County, compared with 424 in 2015...” and only 290 in 2012. (1)
Nationwide the numbers are even more startling. According to the Department of Health and Human Services, on an average day in the U.S. more than 650,000 opioid prescriptions are dispensed (2) and 78 people die from an opioid-related overdose. This includes overdoses involving prescription opioids and illicit opioids such as heroin. (3)
The economic impact is estimated in the billions with 55 billion dollars spent on health and social costs related to prescription opioid abuse each year (5) and 20 billion dollars in emergency department and inpatient care for opioid poisonings. (6) These numbers are growing every day.
To prevent you or someone you love from becoming addicted to prescription painkillers, or worse, becoming another potential victim of an opioid overdose, you must get educated today!
Let’s take a closer look at the nationwide Opioid Epidemic, opioid abuse, and offer a groundbreaking healthy alternative to help manage pain.
What is an Opioid?
Opioids are a class of drugs that include the illicit drug heroin as well as the legally prescribed pain relievers oxycodone, hydrocodone, codeine, morphine, fentanyl, and others. Opioids are chemically related and interact with opioid receptors on nerve cells in the brain and nervous system to produce pleasurable effects and relieve pain. (4)
The American Society of Addiction Medicine defines addiction as “a primary, chronic and relapsing brain disease characterized by an individual pathologically pursuing reward and/or relief by substance use and other behaviors.” It is important to remember that opioid addictions are physical. With every use the brain craves more stimulation of the opioid (Mu) receptors and the body becomes physically dependent on that simulation to continue functioning properly. If a heavy user stops suddenly the withdrawal symptoms can be life threatening.
This physical addiction means that the opioid user needs these drugs and when their prescriptions run out or become too expensive, they may turn to cheaper, more accessible, street drugs like heroin.
“There’s very little difference between oxycodone, morphine and heroin,” says Dr. Deeni Bassam, board-certified anesthesiologist, pain specialist and medical director of the Virginia-based Spine Care Center. “It’s just that one comes in a prescription bottle and another one comes in a plastic bag.” (7)
Heroin is often cheaper and easier to obtain than opioids and so has become a popular alternative. Chemically, Heroin and OxyContin are very similar and provide a similar kind of high. OxyContin is as dangerous and equally as addictive as pure heroin. More often than not though, drug dealers cut heroin with other drugs and the results can be deadly.
One of the most popular drugs to spike heroin with is Fentanyl, a drug originally developed as an elephant tranquilizer. Cut into heroin, it was meant to deliver a stronger and more extended high, but as Dr. Karen Hacker, the director of the Allegheny Health Department said, “Fentanyl is like a whole new ballgame. People are dying the first time they try it.” (8)
Most heroin sold on the streets now contains some Fentanyl and some stamp bags now contain mostly Fentanyl, which can be 100 times stronger than heroin and 10,000 to 100,000 times stronger than morphine. (8,9)
Drug overdose is the leading cause of accidental death in the U.S., with 52,404 lethal drug overdoses in 2015. Opioid addiction is driving this epidemic of overdoses, with 20,101 deaths related to prescription pain relievers, and 12,990 overdose deaths related to heroin in 2015. (10) It is estimated that in 2015, 2 million Americans had a substance use disorder involving prescription pain relievers and 591,000 had a substance use disorder involving heroin. (11)
Dr. Robert Califf, who at the time was commissioner of the U.S. Food and Drug Administration (FDA), said, “The public-health crisis of opioid misuse, addiction and overdose is one of the most challenging issues [the FDA] has faced during my time as commissioner. Solving this issue is critical to our future. It’s time to put more resources into the development of non-opioid, non-addictive medications to help people who are in serious, debilitating pain.” (12)
At Murray Avenue Apothecary, we are always looking for holistic and natural approaches to pain management. In light of the Opioid Epidemic we redoubled our efforts to find safe and effective solutions for our clients. Almost two years ago during a phone call with my physician-friend she told me she could not take Dilaudid for post-op neck surgery pain. She said she had found a non-opioid solution and I was intrigued.
The solution? CBD Hemp Oil!
This led me, and my staff, into exhaustive research about medical marijuana, state drug laws, and CBD manufacturers.
What is CBD? How does it work? And most importantly, how can we provide it to the people who need it most!?
There are many different varieties of the cannabis plant. Hemp, sometimes called industrial hemp, refers to the non-psychoactive (less than 0.3% THC) varieties of Cannabis sativa L. Both hemp and marijuana come from the same cannabis species but are genetically distinct and are further distinguished by use, chemical makeup, and cultivation methods.
CBD or Cannabidiol (Canna-Bi-Diol) is a naturally occurring compound in the hemp plant and is one of a class of molecules called cannabinoids. Tetrahydrocannabinol (THC) is the cannabinoid that produces the euphoric and psychotropic effects of Marijuana. Typically, hemp has very little THC naturally. CBD is non-psychoactive and does not cause intoxication. CBD contains ZERO THC.
Our bodies, and those of almost all animals, have an endocannabinoid system with hundreds of CB receptors. It is the greatest system you’ve never heard about. These CB receptors are located all over your body including in the brain, skin, connective tissue, glands, immune cells, digestive tract, and reproductive organs. They play an important role in human health and homeostasis or balance. THC has a strong affinity for CB1 receptors found in high concentrations in the brain and therefore cause the psychoactive effects of marijuana.
The endocannabinoid system strongly suggests that the human organism is actually designed to make good use of the cannabis plant. In other words, the phytocannabinioids in the cannabis plant triggers something that's been inside us since the dawn of mankind. The endocannabinoid system exists in other mammals, reptiles, fishes, and more, suggesting it is truly an ancient biological system.
Dr. Margaret Gedde, a Stanford-trained pathologist and award-winning researcher, said, "When I started hearing the results patients were getting, I realized that the reason why [marijuana] could do so many different things in the body without being toxic is because it is acting through this natural endocannabinoid system in our bodies. That's when I said 'Wow. This is huge. There's nothing like this in medicine. There's nothing that I can prescribe that comes close to what this can do for people.’” (13)
“Although the endocannabinoid system has been known to interact with other systems…its interaction with the opioid system is now well established. These two systems share neuroanatomical, neurochemical, and pharmacological characteristics.” (14,15) This means the same receptors all over your body that interact with opioid chemicals also interact with the CBD. This important connection means that not only does CBD offer potential potent pain relief, it may also be used to wean patients off of their Opioids.
We have developed an Opiate Weaning Protocol at Murray Avenue Apothecary that works closely between the patient, physician, and pharmacist to safely and effectively achieve the desired results. Please have your Physician contact our Pharmacists to work together as a team to help with your opioid prescription weaning protocol. We are here for you!
“PEOPLE NEED CBD!”
Gedde added, “So many pain medications are damaging to the stomach, to the gut. The cannabis doesn't hurt the gut. It helps heal the gut. People are so relieved … There's nothing else that does that. It won't hurt the organs. It won't hurt the liver. It won't hurt the kidneys. Ibuprofen… people can't stay on that for months and years. They can stay on cannabis. As we know as well, there is no known lethal dose for cannabis, whether it's THC or CBD. A person couldn't die from it even if they were trying really, really hard. There's nothing you can say that about. It offers so much to people on a medical level."
LabNaturals CBD – Hemp derived CBD
At Murray Avenue Apothecary we carry our own brand of CBD products called LabNaturals Broad Spectrum PCR Plant Oil. CBD stands for “Phytocannabinoid Rich” and describes an oil containing CBD and other cannabinoids. Our plant oil products are derived from the whole hemp plant grown, processed, and produced in accordance with the 2014 FARM BILL, Section 7606. These products deliver healthful benefits, without the psychoactive or “high” effect associated with this type of botanical. There is no detectable THC in our LabNaturals CBD products so urine drug test screens should be negative, however we cannot guarantee this because not all tests are THC specific and all cannabinoids are molecularly similar. You should be aware of your employer’s drug testing policy.
Every LabNaturals CBD product is third party tested to ensure purity, potency, and consistency. In a study published in the Journal of the American Medical Association, 84 commercially available CBD products on the internet were chemically analyzed by an independent lab. The researchers found that ONLY 31% of the products tested contained the precise amount of CBD advertised on the label!
Without third party testing there is no way to ensure quality and consistency or that a product is correctly labeled and does not contain toxic chemicals and residues. We provide Certificates of Analysis with proof of nondetectable THC, solvents, pesticides, and heavy metals for each product. These Certificates of Analysis also confirm the actual amount of CBD in the bottle to be sure our labeling is accurate. This makes LabNaturals CBD an appealing and trustworthy option for people looking for potential relief from inflammation, pain, anxiety, depression, seizures, spasms, and other conditions.
There are over 40 examples of health conditions we found that may show benefit from CBD use including ADHD, Arthritis, Diabetes, Alcoholism, MS, Chronic Pain, PTSD, Depression, Osteoporosis, Epilepsy, and more. (19) CBD has been studied for its antiemetic, analgesic, antiepileptic, and immunomodulatory effects. CBD has also been studied in settings of mood disorders(16,17,18). CBD has demonstrable neuroprotective and neurogenic effects, and its anti-cancer properties are currently being investigated at several academic research centers in the United states and around the world. (19)
Our LabNaturals CBD Broad Spectrum Plant Oil comes in a variety of products including liquids, topicals, and capsules. Pets need pain relief too and we have created CBD Liquids just for our furry family members!
All of our LabNaturals CBD Plant Oil products are available Over-the-Counter (OTC) and do not require a Medical Marijuana card.
We are now carrying several OTC products including:
• CBD Broad Spectrum Plant Oils - Light, oily liquids that are to be delivered orally by dropper and come in a variety of strengths. Place under the tongue, hold for 2-3 minutes for enhanced absorption, and swallow.
• CBD Broad Spectrum Plant Oil Capsules - 10mg or 25mg - Small water-soluble softgel capsules that are taken orally.
• CBD Broad Spectrum Plant Oil Pain Balm - 500mg per Jar - A smooth and spreadable balm applied topically to painful areas like arthritic joints and painful damaged nerve areas.
• CBD Broad Spectrum Plant Oils for Pets - Light, oily liquids that are to be delivered orally on treats or food and are perfectly sized for our furry family members.
• CBD Chewing Gum -10mg per Piece - Sugar-free gum that delivers CBD through the oral mucosa by chewing each piece for ten minutes. Many of our arthritic clients love this gum!
• CBD Water -10mg per Bottle - 500mL of H2O with electrolytes and CBD. Also available by the case at a lower price.
Our General Serving Guidelines are to Start LOW & Go SLOW!
Everyone is different and everyone’s internal balance system is different. Some people are only a little “out of balance” and other people are way “out of balance.” Some people are very sensitive to substances and others are less responsive. There is no magic number, no formula, and no test to determine how “out of balance” you are. The good news is we have a great method to discover your “happy place” or “optimal dose.” We call this process “micro-servings.”
Many people need less CBD than they think they do, and more is not always better. By starting low and slowly increasing until you find your personal perfect balance you may get optimal benefits without wasting money on excess CBD.
Please Note: The amount of body fat, duration and severity of condition, GI/Liver function, individual biochemical makeup, and endocannabinoid balance may affect outcome. Some clients feel an immediate response, others take more time. Be patient, it may take months to fully rebalance your Endocannabinoid system.
Some Potential Minimal Side Effects include a temporary headache, potential feelings similar to dizziness and fatigue.
Many people feel more mentally alert and focused with CBD so we suggest starting it in the AM.
ATTENTION: Some medications may interact or impact serving size. Please call 412-421-4996 or 412-586-4678 to speak to a Pharmacist about any medications you are taking or visit us at 4227 Murray Avenue.
CBD products are not recommended for use in pregnant women because of the role the Endocannabinoid system plays in reproduction and infant development.
For all these reasons, it makes sense to buy CBD from a pharmacy and a pharmacist with 37 years of experience and expertise instead of from a random website or vape shop. I’ve done the research, I know biochemistry, and I know how to balance it!
Why did we choose our LabNaturals Broad Spectrum Plant Oil over other brands?
• No Detectable THC
• No Detectable Solvents
• No Detectable Pesticides
• No Detectable Heavy Metals
• Organically Farmed in accordance with Industrial Regulations (Reg. #69763)
• Broad Spectrum Entourage Effect
• Available over-the-counter (OTC) – no card or prescription needed
• Products are tested both internally and independently for potency, purity, and consistency.
• Hydrogenated Water Extraction Process and Supercritical CO2
The Opioid Epidemic has reached unfathomable proportions and is killing our family members, friends, and neighbors every day! Natural therapies, including CBD supplementation, may provide an alternative, non-toxic treatment to Opioid addiction.
What do you have to lose?
Please share this article with those who need it most and please stop by Murray Avenue Apothecary to speak with our CBD specialists. You can also learn more about our products and view a price list at www.LabNaturalsCBD.com
To Your Health and Healing,
Susan Merenstein, RPh/Owner
For More Information on CBD Please Consult the Following Paper from The National Institutes of Health: PACHER P, BÁTKAI S, KUNOS G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological reviews. 2006;58(3):389-462. doi:10.1124/pr.58.3.2.
The huge popularity of cannabidiol (CBD), a non-intoxicating component of cannabis, has helped to destigmatize the plant and restore its reputation as an important medicinal herb. But bogus science and inept reporting continue to distort how we understand the benefits and risks of CBD and cannabis.
A recent article by Mike Adams in Forbes online rang alarm bells by asserting that CBD “could be damaging our livers in the same way as alcohol and other drugs.” This sensational claim was based on a dubious study of CBD and liver toxicity conducted by researchers (Ewing et al) at the University of Arkansas in Little Rock – except the damage discussed in the study was unrelated to alcohol toxicity and “our livers” actually refers to mouse livers.
The Little Rock study made no mention of humans, which is a hugely important distinction. Moreover, in the real-world CBD consumers are not ingesting 0.25% of their body weight – the maximal dose that Ewing et al used in their study of liver toxicity.1
Nevertheless, according to Forbes, “People that use CBD are at an elevated risk for liver toxicity.” And “[CBD] may actually be just as harmful to their livers” as “conventional pain relievers, like acetaminophen.” These statements are clearly unsupported by the current literature.
The breathless reporting in Forbes focuses on a single, flawed, preclinical study and exaggerates it to the point of falsehood. Yet if there’s a saving grace of the Forbes article, it’s that it gets much less wrong than the study itself. The study is freely available from Molecules, a journal published by the Multidisciplinary Digital Publishing Institute (MDPI).
A close examination of the Molecules study reveals a Pandora’s box of strange statements, problematic publishing and unreasonable experimental design. On the first page, the abstract makes a claim that is fundamentally impossible, stating that, with chronic administration of CBD, “75% of mice gavaged with 615 mg/kg developed a moribund condition.” But there were only 6 animals that received this dose! One doesn’t need an advanced degree in science or math to recognize that something is amiss. Seventy-five percent of six equals 4.5.
According to the Little Rock researchers, four-and-a-half mice died because of the dangerous drug known as CBD, while somehow one-and-half mice survived.
Reading on, it only gets worse.
The experimental set-up is succinct. Scientists force-fed mice a single dose of CBD, ranging from the supposedly “low” dosage of 246 mg/kg up to a mega-dose of 2460 mg/kg CBD. That means for every kilogram of body weight, they gave the mice about 2.5 grams of CBD, which had been formulated as a hexane extract2 from cannabis supplied by the National Institute on Drug Abuse (NIDA). Hexane, it bears mentioning, is a neurotoxin.
“According to the Little Rock researchers, four-and-a-half mice died because of the dangerous drug known as CBD.”
The maximum human dosage recommended for the CBD-isolate Epidiolex is 20 mg/kg, which is over 100x less than what the Little Rock researchers force fed their experimental mice. They also tried smaller doses (ranging between 61.5 to 615 mg/kg) of CBD, which was given daily for 10 consecutive days.
Despite these ridiculous dosages, Ewing et al.3 claim their study accurately represents human experience, insisting that the equivalent human dose is 12.3 times lower because of allometric scaling (which we will discuss momentarily). This is – at best – an unverified assumption. More likely, it’s just plain wrong.
Before presenting their results in Molecules, the introduction tips the authors’ hand, revealing that the study is a hit piece against CBD, not legitimate scientific work.
When it comes to cited evidence, a double standard is obvious. The authors disparage the significance of positive medical findings about CBD (such as CBD’s anti-inflammatory and antioxidant properties) by citing only in vitro research.4,5 Yet a sentence later, they tout a score of harms allegedly attributable to CBD based on… in vitro and preclinical work. Even these claims are muddled by misinterpretation.
The Little Rock authors claim: “numerous reports have demonstrated neurological, cardiovascular and reproductive toxicities subsequent to CBD use.” Yet, eight of the nine sources cited to buttress this claim do not involve humans. Only one of the citations is based on human research, and it did not show toxicity. The human study, led by Saoirse O’Sullivan, actually showed a decrease in blood pressure after consuming CBD (600 mg or roughly 10 mg/kg). O’Sullivan and her colleagues at the University of Nottingham concluded that perhaps “CBD has a role in the treatment of cardiovascular disorders.” Yet the Arkansas team misrepresents O’Sullivan’s work as proof that CBD is cardiotoxic.
When contacted by Project CBD, O’Sullivan said, “Our research study showing that CBD causes a small reduction in resting and stress-induced blood pressure does not support the authors claim that we demonstrated cardiovascular toxicity of CBD. In fact, most of our work is about the potential protective effects of CBD in the cardiovascular system.”
In contradiction to the claims Arkansas researchers made about her lab’s work, Dr. O’Sullivan says their work suggests protective effects of CBD in the cardiovascular system.
The madness of citations continues to develop with the Arkansas researchers noting that one trial of Epidiolex (an FDA-approved pharmaceutical CBD isolate extracted from cannabis) demonstrated 93% of CBD users experience adverse events (aka side effects). Wow! CBD must be problematic for nearly everyone! Until you read the primary source, which states that adverse events “were reported in 93% of the patients in the cannabidiol group and 75% of the patients in the placebo group” [emphasis added]. These patients take many anti-epileptic drugs in addition to their CBD treatment. The relevant number is the fraction of side effects attributable to CBD, not the total number. But the authors chose to ignore such subtleties in favor of aggrandizing harm. As a consequence, they overlook an opportunity to review problems that CBD could actually cause, according to this Epidiolex trial.
Reading on, halfway through the second page (of the 17-page Molecules article), problems continue to pile up. The authors appear to undermine their own conjured fears: according to one lab’s analysis, dosages of “commercially-available products ranged from as little to 2.2 mg to as much as 22.3 mg, further amplifying concerns of potential toxicity.” First of all, the lab report states the smallest amount was 1.3 mg, not 2.2 mg.6 Secondly, 22.3 mg is not a large dose by any means. Humans have been reported to ingest up to a couple thousand milligrams of CBD without ill effect.
By the time the reader arrives at the results section of the Molecules article, the study’s credibility has been thoroughly demolished by the issues described above. And then there are the results. According to this section, huge doses (738-2460 mg/kg) of CBD caused problems, including altered levels of liver enzymes and gene expression related to metabolism. In the chronic administration group, the two highest doses caused similar problems. Dosages this high are unheard of in human studies. Some mice in the chronic administration group died from CBD treatment, but the authors neglect to mention how many. The only number reported is the impossible four-and-a half-mice mentioned in the abstract.
NEW DATA, SAME OLD STORY
“Regardless of your feelings on this particular study, it is hard to argue with dead mice,” the Forbes article blithely asserts. Nonsense. Not enough attention is paid to that last word – mice. Even if we suspend our disbelief and look past every problem described thus far, a dead mouse (or half a mouse) isn’t proof of what happens to a human.
The search for a lethal dose of cannabinoids is nothing new – one of the earliest efforts to kill an animal with a gigantic dose of THC was described in a 1972 paper by scientists at the Mason Research Institute in Worcester, MA. In their quest to prove the dangers of THC, they attempted to kill almost 400 rats, a couple dozen beagle dogs, and some rhesus monkeys. The rat dosages ranged from 225-3600 mg/kg of orally administered THC, a higher amount than the CBD dosage used in the Little Rock experiment.
Early trials failed to find a lethal dose of THC in monkeys - even when they were dosed with nearly 1% of their bodyweight.
It turned out that rats could be killed by THC, though it took roughly 1000 mg/kg. Interpreting this with allometric scaling, we expect that monkeys would have a lethally toxic response to 500 mg/kg of THC (see table below for approximate scaling factors). This translates to about 10 grams of pure THC for a human. But it’s wrong. The researchers weren’t able to overdose the monkeys7 – not with an allometrically scaled dose, nor when they tried a much higher dosage of 9000 mg/kg (or just under 1% of the monkey’s bodyweight).
In a typical 65 kg human, 1% of body weight would amount to 585 grams of THC. That’s over a pound of pure THC. And that concentration wasn’t enough for a lethal outcome.8 The dose used in monkeys is the one most likely to translate to humans, and it underscores – if anything – the importance of not extrapolating from one species to another.
Small animals, like a mouse or humming bird, are more active than large animals, like a human or raven. It’s not just a matter of physical movement – metabolism is also faster among small animals. So a mouse will clear drugs out of its system more quickly than a human. This is one major reason why drug dosages are not the same between lab animals and humans in the clinic.
Allometric scaling is a useful rule of thumb that helps to overcome this issue. It assumes that drug doses can roughly be scaled from one animal to another based on their body weight and body-mass index (BMI).
This scaling factor is often used to find a starting dosage for drugs that have never been tested on humans, which is not the case for CBD, a compound with a well-established human safety record that the Little Rock scientists and the Forbes journalist studiously avoid mentioning.
Using allometric scaling to reinterpret preclinical work needs to be justified. And, in fact, allometric scaling of toxicity may not pertain to cannabinoids.9 The linear scaling factor is predicated on properties that these oily compounds do not possess. For example, it works best when the drug of interest floats freely in the bloodstream, yet over 99% of CBD (and THC) is protein-bound, not free. Furthermore, the ridiculously high doses in this study will saturate the body’s metabolic machinery, preventing relevant dose-extrapolations.
Without a doubt, the dose used in a mouse experiment does not translate directly to human dosing. However, by choosing a flawed scaling factor, the authors’ report of “human equivalents” becomes irrelevant. Recall that the THC study indicates we could increase a primate dose to 10x larger than the rat dosage without toxicity, the opposite of what allometric scaling suggests.
All this just underscores the importance of limiting conclusions to what we can establish. The Little Rock study shows that ingesting huge doses of CBD – on the order of 0.25% of one’s weight – is harmful to mice. It says nothing about humans. It says nothing about realistic dosing. What it does say is little more than a reflection of the authors’ biases.
How did this problematic article get published in Molecules? Isn’t peer review supposed to correct flawed science?
Ideally peer review is challenging and constructive, forcing scientists to do better research. But unfortunately, not all peer review aspires to the same goal.10 Peer review can also be a venue for reinforcing old boy networks and engaging in political power plays hidden behind anonymity. In some cases, peer review is just a rubber stamp of acceptance so long as the authors pay hefty “article processing charges.”
Science journals, much like the input provided by peer reviewers, vary in quality. MDPI, which publishes the journal Molecules, has been called a predatory publisher.11 MDPI has been criticized for publishing unsound articles, though this is too great a controversy12 to tackle here. Even if such allegations are true, it doesn’t mean that good work can’t end up in one of MDPI’s 213 journals. But it underscores the importance of checking scientific work, rather than diligently repeating and amplifying whatever claims are presented.
Another red flag: The turnaround from submission to acceptance of the Molecules article claiming CBD causes liver toxicity was 18 days, which, while not impossible, is nevertheless very quick.13 Unlike some other journals, Molecules does not report when – or if – reviewers requested revisions to the article. But in this case, revisions had to be requested, because the reference list states that some citations were accessed after the submission date: see references 25-27. These citations were viewed on the same day that Molecules accepted the article. At best, this means a revised draft was submitted and accepted on the same day, making it difficult to believe that a proper peer review was performed. The Little Rock authors did not immediately respond to a request for comment on this issue.
CBD AND ACETAMINOPHEN
Can we call this article one bad study and move on? Well, no, because Molecules has already published another similar article. The same journal and the same irrelevance, with a few more authors and a few more unbelievable claims.
The most recent study, published in Molecules a month after the first liver toxicity article, doesn’t improve on much. In their second report, they assess a potential interaction between CBD and acetaminophen (sold as Tylenol or paracetamol) in female mice.
Similar to the first study, they use hexane, a neurotoxin, to extract cannabinoids from NIDA-supplied cannabis. The amount of residual solvent is listed as < 0.5%, or 5000 μg/g. Such a product would not be legal to sell in California’s regulated marijuana market, which has set a limit of 290 μg/g of hexane in cannabis extracts. The authors did not immediately reply to a request for clarification of the hexane content.14
The doses of CBD employed in the second Little Rock study are quite a bit lower than the first, since acetaminophen stresses the liver significantly on its own. A new oddity is the choice of administration. The researchers set up a feeding tube to administer high doses of CBD, but instead decided to inject 400 mg/kg acetaminophen into the mice. The authors do not state how this dosage would be allometrically scaled to a human taking Tylenol.
Three of the eight mice treated with acetaminophen and the supposedly low dose of CBD (116 mg/kg) died within a few hours. Curiously, none of the mice that were force fed a higher dose of CBD died. The Little Rock researchers explained this peculiar outcome by invoking the biphasic effect, also known as hormesis or a U-shaped dose-response curve, which refers to the existence of a sweet spot for optimal dosing. Outside of a particular dosage range – too low or too high – cannabinoids can lose their efficacy and even cause the opposite of an expected effect.
Cannabinoids often have a biphasic dose-response, but it’s unreasonable to claim without further explanation that this applies to CBD’s alleged toxicity. Imagine if you had drunk a poison and the cure was to drink a lot more of the same poison. That is essentially how the authors try to justify their results.
We could once again go through every citation, but the biases that undermine this publication are clear from the discussion, as Ewing et al. try to have it both ways. The consistency of their results (with a select choice of citations) shows that the model is accurate. The inconsistencies with other studies disprove any others’ claims to the safety of CBD.
The discussion after the first Molecules study displays the same bias. Positive preclinical results that suggest medical benefits don’t establish much, but absurd preclinical harms demonstrate that CBD “poses a risk for liver injury.” Ewing et al.’s research is valid because sometimes it seems to be consistent with data found in other papers. Yet when their findings contradict other research, it calls “into question [CBD’s] claimed ‘antioxidant’ properties” and other potential benefits.
One problem with these far-fetched studies that purport to demonstrate CBD’s harmful effects is that they undermine serious research into real risks.15 High doses of CBD – usually around 20-50 mg/kg – can cause issues with the liver, but there are important caveats. Numerous publications from the makers of Epidiolex have shed light on potential risks of CBD. Project CBD has been reporting on these dangers for years.16
One issue is CBD’s ability to inhibit drug-metabolizing enzymes. This usually occurs when someone is taking hundreds or thousands of milligrams of CBD per day.
While stress to the liver can be caused by CBD’s interaction with other drugs, it’s unreasonable to see temporary, reversible stress and insist that CBD is hepatotoxic.
Of greater concern is the reported elevation in liver enzymes called ALT and AST. This occurs in roughly 5-15% of kids in Epidiolex trials, and nearly every report involves the concurrent use of valproate, a powerful anti-epileptic drug that can cause problems in and of itself.17 This could be viewed as a severe drug-drug interaction. However, many neurologists indicate that the combination of CBD and valproate can be an effective epilepsy treatment. Thus, doctors find it is worth adding CBD to a treatment regime that includes valproate, with the understanding that patients’ liver function will need to be monitored. The co-administration of CBD and clobazam, which also has a high likelihood of drug interactions, is another combination that pediatric neurologists find works well – at least anecdotally.
So, people try CBD along with their other medications, but they stop or reduce the dose if there are liver problems (which needs to be monitored by a doctor, not the patient). These issues resolve when people stop taking CBD or reduce their dose, according to many reports. Once there is an awareness of the risk, it can be simple for a doctor to manage.
Calling such problems “damage” is an overstatement – an elevation in liver enzymes is indicative of stress on the liver that could cause damage if it continues unabated. Currently, there are no reports of lasting harm when CBD treatment was ceased.
It’s unreasonable to see temporary, reversible stress when cannabidiol is combined with other drugs and insist that this shows CBD is hepatotoxic.
MORE RESEARCH IS NEEDED
All three articles – the one in Forbes and both papers by Ewing et al. – conclude with the predictable mantra “more research is needed.” (A recent follow-up story in Forbes by Mike Adams called yet again for “more research,” while repeating the same distortions about liver toxicity.) “More research” is an easy fallback phrase, because no one is going to argue that we should know less about our medicine. But “more” is the wrong word. Better research is what’s needed. Better reporting, which checks scientists’ claims rather than ignorantly amplifying them. Better studies, which seek to assess the human consequences of CBD consumption. And better thinking, especially when it comes to interpreting human and non-human research.
Preclinical research is at once frustrating and exciting. It provides a precisely controllable environment to test ideas, a scientist’s sandbox. But the outcome is always indirect – unless someone is seeking to treat a sick pet mouse, results from animal models of human disease can only provide ideas and guidance for follow-up in humans, not definitive conclusions.
The issue here is not one bad study in a science journal. It is the pernicious manifestation of investigator bias. Ewing et al. see the worst in any report on CBD. CBD reduces blood pressure in humans? They’ll call it toxic to the cardiovascular system. CBD slightly decreases the weight of mice? They spark fears it causes you to waste away. But if one dares to say it may help someone fall asleep, or reduce their arthritic pain or opioid cravings, well that’s just anecdotal, it’s just preclinical, it’s just a few isolated reports.
Imagine if their eager trust were extended to the much more plentiful medical research on CBD. If we were to interpret all mouse studies on cannabinoids as applicable to humans, we would find hundreds of papers showing that THC and CBD kill tumors, quell an overactive immune system, reverse Alzheimer’s, heal traumatic brain injuries, and so on. In fact, quite a few animal studies show that CBD is protective in certain liver diseases, like alcohol-induced steatosis and nonalcoholic fatty liver disease.
Regarding claims that CBD causes liver damage, the Forbes writer failed to probe key questions.
Ultimately, some of the preclinical work will translate to human experience, though most of it won’t. That is what motivates so much excitement among cannabis advocates, who are pushing back against the racial and social consequences of terrible drug policy, while also promoting cannabis therapeutics that may improve poorly-treated medical conditions. Clearly epilepsy is one such example. Multiple sclerosis is another. Neuropathic pain and reduced need for opioids is a third area with substantial evidence. For autoimmune and other inflammatory diseases there is good reason to hope, though not certainty. And, of course, there will be risks: not everyone benefits from cannabis use and some harms will inevitably emerge.
Instead of holding scientists accountable, some journalists merely act as stenographers, repeating and amplifying allegations instead of scrutinizing them. The need for a controversial, engaging story often overtakes the desire for accurate reporting. Regarding claims that CBD causes liver damage, the Forbes writer failed to probe key questions. Are the research methods valid? Do the researchers apply consistent standards in their assessment of evidence? Are the conclusions a reasonable interpretation of the results? And what ever happened to the one-and-a-half mice that survived the massive doses of CBD?
source: Project CBD