cbd oil gabapentin interactions for nerve pain

CBD Oil and Gabapentin: Can CBD be a Safe Substitute?

Gabapentin, a prescription drug sold under different brand names, like Neurontin, Gralise, and Horizant, is an anti-epileptic medication that offers respite from seizures and neuropathic (nerve) pain. Sometimes, doctors may prescribe it for patients with migraine headaches too.

Epilepsy, migraines, and other conditions associated with nerves or neuropathic pain are caused due to wrong signaling by the brain, which manipulates your body into feeling pain, even if there’s no injury or damage. Gabapentin helps in slowing down these erroneous neurotransmissions, thereby relieving the patient’s pain sensations.

Nevertheless, Gabapentin has been reported to have several adverse effects, including swelling, back or chest pain, shortness of breath, vomiting, urinary problems, lack of concentration, and even suicidal tendencies, especially in high doses.

Even the US Food and Drug Administration (FDA) has been forced to issue a warning about antiepileptic drugs (AEDs), like Gabapentin, causing serious breathing problems among patients with respiratory comorbidities (like COPD).

Another issue with gabapentin is that it provides only temporary relief. It doesn’t address the underlying problems of these ailments.

This has prompted many to look for safer, effective, and more reliable alternatives – that some found in Cannabidiol (CBD).

While some use CBD to alleviate Gabapentin’s side-effects, while helping in the overall therapy, others have replaced Gabapentin with CBD oil.

Can CBD Effectively Treat Epilepsy & Nerve Pain?

Despite the broad-spectrum of studies conducted on cannabidiol and its benefits, CBD remains one of nature’s mysteries.

It seems to help treat and alleviate symptoms and provide relief from many kinds of health problems – when even the strongest of prescription medications fail. However, it doesn’t cause any severe side-effects, as most potent drugs do.

Moreover, studies reveal that CBD doesn’t directly bind with most of the body’s receptors – not even with the endocannabinoid receptors, as THC, CBD’s psychotropic cousin, does. However, it does seem to have a good interaction with the 5-HT1A receptor.

The 5-HT1A receptor, a subtype of serotonin or 5-hydroxytryptamine (5-HT) neuroreceptor, interacts with serotonin, the body’s happy chemical, influencing several bodily functions associated with mood, cognition, reward, learning, memory, pain sensations, etc. Its activation is linked to the body’s anxiolytic, antidepressant, and antipsychotic mechanisms.

So, can CBD help ease epilepsy seizures and nerve pain?

Several years ago, when controlled studies to test the efficacy of Epidiolex on children with epilepsy was still being planned, a 2014 review focussed on the need to take a broader look at the potential use of CBD to address epilepsy and other neuropsychiatric disorders, like anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. This review was published in the medical journal Epilepsia.

Numerous other studies have been carried out on the effects of cannabidiol and medical marijuana on epilepsy and other neurological disorders. Most of these indicated that CBD could have a positive impact on treatments for epileptic seizures and neuropathic pain.

So, let’s find out what the scientific researchers have found so far…

  • For the first time in 2017, an Italian researcher, Emilio Perucca, found solid evidence of purified CBD having a positive impact on patients with two rare types of epilepsy – Dravet Syndrome and Lennox-Gastaut Syndrome. In his review, published in the Journal of Epilepsy Research, he reviewed three high-quality placebo-controlled adjunctive-therapy trials of a purified CBD product in patients with Dravet syndrome and Lennox-Gastaut syndrome.
  • In June 2018, the FDA approved the cannabidiol oral solution Epidiolex® for treating seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut and Dravet syndromes, in patients aged two years and older.

This was the first time that the FDA approved any cannabis-derived drug. This was also the first FDA-approved drug for the treatment of Dravet Syndrome patients.

  • In May 2019, a team of researchers from Florida Agricultural and Mechanical (A&M) University College of Pharmacy and Pharmaceutical Sciences, published a paper on the ‘Treatment of Seizures Associated with Lennox-Gastaut and Dravet Syndromes…’ in the Pharmacy and Therapeutics (P&T). Their findings concluded that the FDA-approved CBD oral solution (Epidiolex ®) is indeed “a new anti-epileptic drug (AED)… the first plant-derived CBD agent…for treating severe and difficult-to-treat forms of childhood epilepsy… (that exhibits) significant reduction…in the frequency of convulsive seizures…”
  • A September 2018 review, published in the Frontiers in Neurology by a team of Brazilian researchers, indicated that CBD improves seizure control in patients with treatment-resistant epilepsy. This review, which collated data from 11 studies, provides strong evidence of CBD’s potent therapeutic effects on 670 patients. This review also indicated that CBD-rich cannabis extracts are much more potent than purified CBD in treatment-resistant epilepsy.
  • In an April 2019 study on the use of CBD for treatment of epilepsy, published in the Molecules journal, suggested that CBD could be used on patients, suffering from AED-resistant epilepsies.

In 2016, when California became the first American state to allow the use of medical marijuana for certain ailments, several interesting studies were conducted.

  • A May 2016 review, published in the Pharmacological Research, was one of those first papers, printed in a medical journal that focused on the need for considering CBD as an alternative AED. It did, however, draw attention to the need for more preclinical and clinical studies to establish the facts.
  • A 2016 study, published in the Innovations in Clinical Neuroscience, pointed towards medical marijuana’s potentials in epilepsy treatment. The researchers, however, expressed despair over the lack of sufficient research and facilities to conduct experiments owing to the legal issues surrounding marijuana.

Several more studies have been held on CBD’s efficacy in handling drug‐resistant epilepsy. This includes a March 2020 review, which established that “Cannabidiol is a multitarget drug”, which “may act on unconventional central and peripheral targets to control drug‐resistant epilepsy”.

These studies indicate that CBD does exhibit some anti-epileptic properties and could be used to control the severity and frequency of seizures, even when conventional drugs fail in their adequacy.

Meanwhile, several other researchers have shed light on CBD’s positive effects on chronic pain management.

  • Ethan B Russo discussed the role that cannabinoids can play in the management of difficult-to-treat pain disorders in his paper, published in the Therapeutics and Clinical Risk Management in 2008. He suggested that cannabinoids could offer significant ‘side benefits’ beyond analgesia, including anti-emetic effects. He further inferred that CBD also inhibits cancer-induced angiogenesis.
  • A February 2018 paper, published in the Canadian Family Physician magazine, also concluded that CBD could be prescribed for treating neuropathic pain, palliative cancer pain, CINV, and MS- or SCI-related spasticity in patients, where traditional medicines are not effective.

Does CBD interact with/inhibit Gabapentin in the body?

The FDA had issued an advisory, warning citizens against mixing CBD with other drugs, as it can impact the breakdown of those drugs, potentially causing serious side-effects.

CBD is generally known to interact during the first-pass effect, i.e. metabolism by a group of liver enzymes, known as Cytochrome P450 (CYP450). Studies show CBD inhibits many, if not most, of the CYP enzymes, including CYP2C9, CYP2C19, CYP3A4, CYP2D6.

  • A 2019 review, published in the Medicines, indicated that CBD alters the levels and effectiveness of certain enzymes in the body, leading to certain drugs undergoing delayed metabolism, thus increasing the risk of their retention in higher concentration and overdosing.

Nevertheless, Gabapentin is considered a better option over other AEDs, owing mainly to its lack of substantial metabolism in the human digestive system. Therefore, gabapentin doesn’t tend to interact with most other drugs and chemical substances.

  • A 2011 study, published in the Journal of Medical Sciences, indicated that Gabapentin isn’t metabolized in the human body, leaving no scope for drug interaction. It enters the bloodstream by bypassing the first-pass enzyme interaction and “more than 95%” gets excreted unchanged through urine.
  • Another 2017 study, published in the Journal of Experimental Pharmacology, indicated that Gabapentin only interacts with certain chemicals, like caffeine, losartan, ethacrynic acid (both anti-hypertensive drugs), phenytoin (anti-seizure medication), magnesium oxide, anti-malarial drugs, and morphine, but does not interact with cannabis or alcohol, among several other drugs and substances.

However, Gabapentin is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

  • In May 2017, researchers indicated that if CBD travels to the brain through the bloodstream, it could bind with the GABAA receptors and slow down the firing frequency of neurons.

This is very similar to the route Gabapentin follows in the body, possibly suggesting that CBD could still interact with Gabapentin, despite the latter not being metabolized by the body digestive enzymes – which is how most drugs usually interact with CBD.

The Last Word

When it comes to your health, it’s always best to let your doctor have the last word.

Neuropathic pain and epilepsy are two critical disorders that need proper medical care and attention.

Studies into any possible drug interaction are inconclusive, at best. Even if CBD doesn’t interact with Gabapentin in the liver, they may still do so in the bloodstream (as discussed in the earlier section). So, mixing the two chemical compounds may not be totally safe.

Even though CBD has been proven by many researchers to be a potent and safe substance that can aid in treatment-resistant epilepsy, it is still unwise to stop taking AEDs and start on CBD oil on your own.

Cannabis-based medicines and the perioperative physician

The increasing availability of cannabis for both recreational and medicinal purposes means that anaesthetists will encounter an increasing number of patients taking cannabis-based medications. The existing evidence base is conflicted and incomplete regarding the indications, interactions and long-term effects of these substances. Globally, most doctors have had little education regarding the pharmacology of cannabis-based medicines, despite the endocannabinoid system being one of the most widespread in the human body. Much is unknown, and much is to be decided, including clarifying definitions and nomenclature, and therapeutic indications and dosing. Anaesthetists, Intensivists, Pain and Perioperative physicians will want to contribute to this evidence base and attempt to harness such therapeutic benefits in terms of pain relief and opiate-avoidance, anti-emesis and seizure control. We present a summary of the pharmacology of cannabis-based medicines including anaesthetic interactions and implications, to assist colleagues encountering these medicines in clinical practice.

Introduction

Cannabis use for medicinal purposes was first documented in 2900 BC in China, when Emperor Shen Nong described benefit for rheumatism and malaria (Pertwee 2015) and later in Ancient Egyptian texts (Pertwee 2015; Zlas et al. 1993). In the United Kingdom (UK), Queen Victoria’s personal physician Sir John Russell Reynolds issued a tincture containing cannabis for her Majesty’s menstrual cramps (David 2017), subsequently publishing his 30 years’ worth of experience with the drug (Reynolds 1890).

Discussion in medical journals, the mainstream and social media around the use of cannabis for medicinal and non-medicinal purposes has increased recently, especially following the legalisation of cannabis for recreational use in Canada (Government of Canada 2018a) and the UK government’s decision to make cannabis-based medicines (CBMs) available for prescription by doctors on the specialist register (Department of Health and Social Care 2018).

The actual, social and economic legitimisation of cannabis and its medicinal derivatives makes it likely increasing numbers of patients will present on this class of medicines. Perioperative physicians will require a sound understanding of their pharmacology and evidence base, and may wish to exploit this group of compounds for therapeutic purposes in the perioperative period.

A search of Pubmed was conducted in February 2019 utilising the search terms cannab* and the AND function for the following search terms individually; anaes*, marijuana, pain, nausea, surgery and pharmaco*. Abstracts were then screened for their applicability, with full texts reviewed. This was supplemented by a review of recent publications from governmental and regulatory organisations relating to CBMs, with backward reference searching. A search of individual governmental websites looking for legislation around cannabis and cannabinoid use was also undertaken in September 2019.

The pharmacology of novel psychoactive compounds (“legal highs”) is outside the scope of this review.

The global position

The availability of CBMs varies geographically and there is no global consensus on how cannabis and CBMs should be regulated. International stakeholders and regulators, including the United Nations (International Drug Policy Consortium 2016; Transnational Institute and Global Drug Policy Observatory 2016) and World Health Organisation (WHO) have been inconsistent in their approach. The WHO’s Expert Committee on Drug Dependences’ recent review (Ghebreyesus 2019) recommended to the United Nations Office on Drugs and Crime (UNODC) that the rescheduling within the International Drug Control Conventions occurs for cannabis and cannabis resin, dronabinol, tetrahydrocannabinol and extracts and tinctures of cannabis. They also repeated their recommendation to remove cannabidiol (CBD) preparations (with not more than 0.2% delta-9-THC) from the International Drug Control Conventions. The UNODC subsequently delayed its vote on these recommendations, but despite this, many countries are proceeding to legalise or reschedule cannabis and/or CBMs, broadening public availability, with the UK the most recent country to reschedule CBMs. Table 1 details the current status of cannabis and CBMs in selected countries for medical use. The recreational use of cannabis is currently legalised in Uruguay, Canada and certain states within the USA (United Nations Office on Drugs and Crime 2019).

Definitions of cannabis and cannabinoids

Cannabis

The Cannabis genus encompasses three major species; Cannabis sativa, Cannabis indica and Cannabis ruderalis. The number of identifiable extractable compounds has increased dramatically from 60 (Ashton 1999) to over 500 in the last 20 years (Beaulieu et al. 2016), of which over 100 are cannabinoids (Bie et al. 2018).

Cannabinoids

Cannabinoids are endogenous in humans, animals and plants, or synthetically produced, acting as ligands at the cannabinoid receptors. Cannabinoids can be psychoactive, for example delta-9-tetrahydrocannabinol (d9THC), delta-8-tetrahydrocannabinol (d8THC), cannabinol (CBN) or non-psychoactive, for example cannabidiol (CBD). Table 2 lists their classification, as well as examples of currently available CBMs (Pertwee 2015; Beaulieu et al. 2016; Zendulka et al. 2016; Yeon Kong et al. 2018; Hauser et al. 2018a; Barnes 2018; National Institute for Health and Care Excellence 2014; Rice and Cameron 2017; Krcevski-Skvarc et al. 2018).

Pharmacology of cannabinoids

Mode of action

The endocannabinoid system consists of both cannabinoid (CB) receptors and neurotransmitters, the plasma concentrations of which are normally at low levels. They are synthesised in the postsynaptic neurone (Hosking and Zajicek 2008) in response to stimuli including pain, stress, inflammation and are involved in the homeostasis of various body systems (Pertwee 2015). Antinociceptive effects occur via their actions as retrograde transmitters at presynaptic inhibitory CB1 receptors (Hauser et al. 2018a). Both CB1 and CB2 receptors are G protein coupled receptors (Gi,Go) with stimulation reducing cAMP production through the inhibition of adenylyl cyclase, resulting in an action on voltage gated calcium and potassium channels depressing neuronal excitability and reducing neurotransmitter release (Zendulka et al. 2016; Hauser et al. 2018a; Hosking and Zajicek 2008).

CB1 receptors are found in the cortex (thalamus, medulla, periaqueductal gray matter, descending pain pathways), spinal cord (descending pain pathways, dorsal horn) and peripherally on primary afferent sensory neurones where they outnumber the mu receptor, suggesting a potential mechanism for the modulation and treatment of neuropathic pain (Kumar et al. 2001).

CB2 receptors are involved in immunomodulation, with receptors distributed in the spleen, macrophages and Kupffer cells. It is increasingly recognised that the endocannabinoid system plays a crucial role in the maintenance of microglial activity through actions at CB1 and CB2 receptors, reducing neuro-inflammation (Bie et al. 2018; Bilkei-Gorzo et al. 2018). Relatively few CB2 receptors are found in the nervous system (Lucas et al. 2018), but they are inducible in the dorsal horn following inflammation or injury, with increased receptor concentration found in neuropathic pain models and receptor activation limiting the acute inflammatory process contributing to nociceptor sensitisation (Bie et al. 2018; Hosking and Zajicek 2008).

Exogenous and endogenous cannabinoids have differing effects at the CB1 and CB2 receptors. THC is an agonist at both, whilst CBD is a non-competitive antagonist at CB1 receptors at high concentrations, an inverse agonist at CB2 receptors and causes allosteric modulation of both CB receptors (Pertwee 2015; Lucas et al. 2018; Expert Committee on Drug Dependence 2018). The cannabinoid compounds, particularly CBD, have additional actions within the nervous system through signalling at a multitude of other receptors. This includes adenosine, serotonergic, adrenergic, nicotinic acetylcholine, glycine, nuclear peroxisome proliferator activated receptors (PPARs) and transient receptor potential (TPRV) ion channels (Capsaicin target). Anaesthetists should also note their actions at the opioid, NMDA and gamma amino butyric acid (GABA) receptors (Zendulka et al. 2016; Hauser et al. 2018a; Expert Committee on Drug Dependence 2018; Meng et al. 2017; Koppel et al. 2014).

Opioid system interaction

The cannabinoid and opioid systems are closely linked, with the activation of both opioid and cannabinoid receptors mediating common intracellular signalling mechanisms (Manzanares et al. 1999; Abrams et al. 2011; Scavone et al. 2013; Cohen et al. 2019; Pertwee et al. 2010). Opioid and cannabinoid receptors are found within the same cells and neurones in the central nervous system, with cannabinoids acting at kappa and delta receptors to increase endogenous opioid synthesis and release. Notably, the administration of opioid antagonists has been shown to block some of the effects of delta 9THC (Manzanares et al. 1999). The presence of opioid and cannabinoid receptors in noradrenergic pathways may have a role in the treatment of opiate withdrawal (Scavone et al. 2013).

NMDA system interaction

The NMDA receptor NR1 subunit is closely coupled to CB1 receptors, with the histidine triad nucleotide binding protein 1 (HINT 1) thought to be the pivotal modulator, exerting a negative control on NMDA receptors. HINT-1 gene deletion results in loss of CB1 inhibition of the NMDA receptor (Rodríguez-Muñoz et al. 2016). CB1 receptors have both presynaptic (reduced release of glutamate into synaptic cleft) and post-synaptic (intracellular NMDA signalling) effects (Rodríguez-Muñoz et al. 2016).

NMDA receptor activity stimulates the release of endocannabinoids, resulting in negative feedback reducing NMDA receptor numbers. It has been postulated that exo-cannabinoids are more potent inhibitors of the NMDA receptor than endocannabinoids (Pacheco et al. 2019; Ferreira et al. 2018), with exo-cannabinoids causing neural dysfunction and NMDA receptor hypofunction through alteration in the balance of NMDA-CB receptor regulation (Rodríguez-Muñoz et al. 2016).

The endocannabinoid system also regulates NMDA receptor activity by preventing over activation, neuroprotection from excitotoxicity and downregulating their activity (Rodríguez-Muñoz et al. 2016; Pacheco et al. 2019; Sánchez-Blázquez et al. 2014).

Gamma amino butyric acid

Gamma amino butyric acid (GABA) and CB1 receptors are closely localised in multiple cortical regions, including the hypothalamus, hippocampus and cortex (Cohen et al. 2019; Lotsch et al. 2018). CB1 receptors are expressed on GABAergic neurons, helping to regulate astrocyte and microglial activity, and hence neuroinflammation (Bilkei-Gorzo et al. 2018).

In preclinical studies, cannabinoids inhibit GABA release, through activation of CB1 receptors (Pertwee 2015; Laaris et al. 2011). They inhibit GABA uptake from the CNS extracellular space (Laaris et al. 2011), and cause allosteric modulation of GABA receptors (Bakas et al. 2017). Limited human studies show altered levels of GABAergic functions with chronic cannabis use, which may contribute to psychological effects (Cohen et al. 2019).

Pharmacokinetics

Absorption

The absorption of vaporised cannabinoids is rapid, with peak plasma concentrations observed within 10 min. THC’s bioavailability after inhalation ranges from 10 to 35%, and CBD 31% varying with device used and size of the particles (Kumar et al. 2001; Lucas et al. 2018; Karschner et al. 2011).

Oral bioavailability of CBM is low, at 2–20% for both CBD and THC (Lucas et al. 2018; Karschner et al. 2011; Anderson and Chan 2016) mainly due to extensive first pass metabolism (Lucas et al. 2018). Onset of action is 0.5–2 h due to slow intestinal absorption resulting in a longer duration of action (Kumar et al. 2001; Bridgeman and Abazia 2017).

An oromucosal spray preparation (nabiximols; Sativex ®) has a reported bioavailability similar to oral THC or intermediate between the oral and inhaled routes (Lucas et al. 2018; Expert Committee on Drug Dependence 2018; Karschner et al. 2011; Anderson and Chan 2016).

Transdermal administration is reported, with the permeability of CBD and CBN higher than d9THC and d8THC (Therapeutic Goods Administration 2017), but their hydrophobic nature means transdermal absorption is poor and requires permeation enhancement (Lucas et al. 2018).

Distribution

Volume of distribution varies by cannabinoid studied, with a VD of 32 L/kg for CBD (intravenous administration), and 3.4 L/kg for THC (inhalation administration) (Lucas et al. 2018), which is said to follow a three-compartment model (Heuberger et al. 2015). Cannabinoids are highly lipid soluble (Kumar et al. 2001) with rapid penetration through the blood–brain barrier (Ashton 1999), the placenta and into breast milk (Lucas et al. 2018). This also leads to accumulation in fatty tissue, with continued activity following cessation.

Metabolism

The cannabinoids are mainly hydroxylated and glucuronidated in the liver by the cytochrome P450 family of isoenzymes (Kumar et al. 2001; Lucas et al. 2018; Karschner et al. 2011; Ujváry and Hanuš 2016). Some metabolites are equipotent to the parental compounds (Yeon Kong et al. 2018; Rong et al. 2017). THC is metabolised to over 80 metabolites by various isoenzymes, including CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2A6, CYP2C9 and CYP3A4. Inhibition of CYP3A4 may result in clinically apparent interactions with oxycodone (Pertwee 2015; Zendulka et al. 2016; Hauser et al. 2018a; Lucas et al. 2018).

CBD is metabolised to over 100 metabolites by isoenzymes CYP1A1, CYP1A2, CYP3A4, CYP2C9 and CYP2D6, the most abundant metabolite being the hydroxylated 7-COOH CBD derivative (Lucas et al. 2018; Ujváry and Hanuš 2016). Inhibition of CYP2D6 and CYP3A4 results in interactions with oxycodone, benzodiazepines and haloperidol (Hauser et al. 2018a; Karschner et al. 2011; Ujváry and Hanuš 2016). Oral CBD increases clobazam (and active metabolite) plasma levels (CYP2C19 interaction) (Ujváry and Hanuš 2016), resulting in dose reductions of clobazam in recent randomised controlled trial (RCTs) (Thiele et al. 2018). Prolonged use of CBD results in CYP1A1 induction (Ujváry and Hanuš 2016).

Cannabinol is metabolised via CYP2C9 and CYP3A4, with no evidence cytochrome P450 interactions (Zendulka et al. 2016).

The significance of these interactions is uncertain as they have occurred either in vitro or in excess of clinically relevant concentrations.

Elimination/excretion

Clearance of cannabinoids is estimated to be 38.8 L/h to 53 L/h (Heuberger et al. 2015), with long terminal half-lives due to their lipophilicity. In regular users, this is extended, with measurable plasma concentrations of THC over 24 h after last administration. Fifteen percent of cannabinoid metabolites undergo enterohepatic recycling, prolonging their action (Ashton 1999).

THC and metabolites are mainly excreted in faeces (65–80%) and urine (20–35%) (Ashton 1999; WHO Expert Committee on Drug Dependence 2018). THC’s elimination half-life is 56 h in occasional and 28 h in chronic users (Ashton 1999) with urinary metabolites measurable 14 days post exposure (Vandrey et al. 2017). Nabilone’s (Cesamet ®; synthetic THC) elimination half-life is shorter than THC, at 2–4 h, yet 16% of a single dose is reportedly measurable at 7 days post administration (Ashton 1999).

CBD metabolites and unchanged drug are mainly excreted in the urine with an elimination half-life of 2–5 days (Lucas et al. 2018; Anderson and Chan 2016; Ujváry and Hanuš 2016).

Pharmacodynamics (of relevance to the perioperative physician)

Cardiovascular system

Tachycardia due to CB1 agonism in cardiac myocytes has been reported (Kumar et al. 2001; Lucas et al. 2018), but was not noted following intravenous administration of d9THC (Vandrey et al. 2017). Bradycardia, hypotension, an increased cardiac output and myocardial oxygen demand have been described (Dickerson 1980; Bryson and Frost 2011). These effects are potentially exacerbated by sympathomimetic agents although the mechanism of action is unclear (Lucas et al. 2018). Effects may be cannabinoid specific, with CBD (Expert Committee on Drug Dependence 2018) not reported to effect heart rate or blood pressure, and THC possibly having anticholinergic effects through depletion of acetylcholine stores (Dickerson 1980).

Central nervous system

Effects are well described largely in relation to their abuse as a recreational drug, including psychomotor impairment, sedation, dizziness, euphoria, disorientation and confusion. Effects may be enhanced if administered with other CNS depressant drugs, for example opioids or benzodiazepines, and have been observed in a clinical setting (Kumar et al. 2001; Lucas et al. 2018).

The behavioural and long-term psychological effects (including dependence) of cannabis are widely reported (Pertwee 2015; Kumar et al. 2001; Nugent et al. 2017), and not reiterated here. Some evidence suggests the abuse potential of CBMs, likelihood of withdrawal phenomena and mental health morbidity is low (Pertwee 2015; Aragona et al. 2009), but trials are of short duration and do not examine long term effects. Evidence suggests chronic cannabis use impairs learning, memory and attention, and causes complex mental health disorders (Pertwee 2015; Nugent et al. 2017; National Academies of Sciences Engineering and Medicine 2017; Campbell et al. 2018). Further research is needed to determine relevance to CBM use.

Respiratory system

There is no clear evidence of respiratory system effects when administered by routes other than smoking. This may be due to the absence of cannabinoid receptors in the brainstem (Kumar et al. 2001).

Perioperative practitioners should be alert to the recent warning from the FDA around the use of vaping THC oil (US Food and Drug Administration 2019). This followed on from a multitude of reports of severe pulmonary disease development associated with vaping of THC products (Layden et al. 2019). Any patient presenting in the perioperative period with new onset respiratory disease and a history of vaping THC should therefore be thoroughly evaluated with this kept in mind.

Immune system

Animal studies suggest that high-dose cannabinoids impair cell-mediated and humoral immunity (Kumar et al. 2001), and low-dose CBD causes immune stimulation (Expert Committee on Drug Dependence 2018). The clinical relevance in humans is unclear.

Interactions of note for the perioperative physician

Induction agents/volatiles

Effects of cannabinoids on dosing of volatile and intravenous anaesthetic agents is equivocal, with evidence limited to animal studies, case reports and two limited human studies.

Ether anaesthesia is prolonged in mice and rats by cannabidiol, d8THC and d9THC (Chesher et al. 1974). Halothane anaesthesia is prolonged and dose requirements reduced in dogs after THC administration (Stoelting et al. 1973), with similar effects noted in mice with isoflurane administration (Schuster et al. 2002). Little is known about the interaction between cannabinoids and modern inhalational anaesthetics.

Animal studies have shown cannabidiol, d8THC and d9THC prolong barbiturate anaesthesia in mice and rats (Chesher et al. 1974) and THC administration increases the doses of thiopentone and propofol required for sedation (Brand et al. 2008). A cannabis extract premedication in dogs resulted in quicker onset and longer lasting anaesthesia with propofol (Kumar et al. 2010). One postulated mechanism is the increased Andamide (endocannabinoid) levels in the brain with propofol, with the inhibition of the enzyme fatty acid amide hydrolyses (FAAH), which normally terminates Anandamides activity, thought to be key (Schelling et al. 2006).

There is limited evidence of the effect of cannabinoid exposure on anaesthesia in humans. Case reports suggest increased anaesthetic requirements with non-medicinal cannabis use (Richtig et al. 2015; Symons 2002). A prospective trial found significantly increased propofol dosing for induction and LMA insertion in cannabis users versus controls (Flisberg et al. 2009). Studies utilising bispectral index monitoring (BIS) found no differences between cannabis users and non-users with the bolus dose of propofol required to achieve a BIS of < 60 (Flisberg et al. 2009). Higher BIS values have been noted for patients under steady state volatile anaesthesia who were administered nabiximols (Sativex®) as a premedication versus controls (Ibera et al. 2018).

These results should be interpreted cautiously given the limited number of participants, the applicability of extrapolating animal studies to human practice, use of unknown quantities of non-prescribable CBMs (except one study) and uncertainties about prior cannabis consumption (Flisberg et al. 2009). Additionally in the electroencephalogram (EEG)/depth of anaesthesia studies, it is unclear if the effects are a result of cannabinoids on the EEG or the effect of cannabinoid-anaesthetic interaction.

In summary, there is minimal evidence base as to the effects of the current agents, with animal studies relating to older agents only (ether, halothane, isoflurane). The evidence for intravenous agents is conflicting and of poor quality, but propofol requirements may be higher. There is a current research opportunity for investigation into the interaction with newer agents in humans.

Opioids

Cannabinoid agonists facilitate endogenous opioid signalling and increase concentrations of endogenous opioids (Scavone et al. 2013; Abrams 2016).

In animal studies (Abrams 2016; Maguire and France 2018), cannabinoids and opioids are synergistic, with the analgesic efficacy of cannabinoids not reduced when opioid antagonists are administered. Human findings are variable; statistically significant reductions in pain scores, and similar opioid pharmacokinetics (with the exception of a reduced Cmax in the morphine group) pre and post vaporised cannabis use was found in chronic opioid users (morphine/oxycodone) (Abrams et al. 2011). In contrast, a small study found higher pain scores and greater rescue analgesia requirements post operatively in cannabis users, versus non-cannabis users (Jefferson et al. 2013). Chronic cannabinoid and cannabis users undergoing orthopaedic procedures showed higher post-operative pain scores without a significant increase in post-operative opioid consumption (Liu et al. 2018). All these studies have limited numbers of participants, and methodological issues that may confound the results.

In summary, cannabinoids and opioids are synergistic for both wanted and unwanted effects. Chronic cannabis users may have higher pain scores; it is unclear whether this is pathophysiological or a behavioral component of drug use.

Ketamine

Ketamine induces endogenous cannabinoid release (Pacheco et al. 2019; Ferreira et al. 2018), which may partially explain its role in anti-nociception. The psychomotor side effects of ketamine are enhanced with CBD administration, but no adverse behavioural or cardiovascular effects have been noted (Hallak et al. 2011).

Gabapentinoids

Gabapentin’s mechanism of action is via α2δ subunits on voltage-dependent calcium channels, with reduction in neural transmission. Similarly, activation of the CB receptor results in inhibition of the voltage dependent calcium channel (Pertwee 2015; Lile et al. 2016). Animal studies have shown the synergistic action of gabapentin and THC when used for the treatment of neuropathic pain, at the expense of increased side effects of THC (Atwal et al. 2017).

Human studies are limited; in multiple sclerosis, the combination of THC and gabapentin improved pain scores in neuropathic pain (Turcotte et al. 2015). High-dose gabapentin for management of cannabis tolerance produces THC like effects, and when gabapentin was used in combination with THC, these effects were seen to be increased, suggesting overlap of pharmacological actions (Lile et al. 2016).

In summary, the gabapentinoids and cannabinoids have overlapping pharmacological actions, with increased therapeutic and side effects when combination dosing is used.

Dexmedetomidine

There is limited evidence regarding potential interactions between cannabinoids and Dexmedetomidine. Animal studies have shown that a synthetic THC derivative (CP55,940) has additive or synergistic analgesic effects when administered with Dexmedetomidine, depending on the nociceptive stimulus utilised (Tham et al. 2005). The study failed to explain the mechanism of this apparent synergy; however, given the similar intracellular signalling mechanisms (calcium, potassium and cyclic AMP) activated by these medications and the close locality of the target receptors in the periaqueductal grey and substantia gelatinosa, receptor interaction is postulated (Tham et al. 2005).

Given the lack of current evidence around interactions in humans, further research should focus on this area.

Medical conditions where cannabinoids are recommended

A variety of National and Governmental organisations have provided reviews on the use of CBMs, producing recommendations with a varying hierarchy of evidence (Department of Health and Social Care 2018; Ghebreyesus 2019; Therapeutic Goods Administration 2017; Health Products Regualtory Authority 2017; National Academies of Sciences Engineering and Medicine 2017). Here, we review the commoner indications for CBMs.

Chronic pain

Information on the use of cannabinoids for chronic pain comes from trials, systematic reviews (SR), meta-analyses (MA) and organisational reports. The outcomes vary, and are limited by factors including study design, moderate to high risk of bias (Hauser et al. 2018a), limited participants (most recent SR/MA (Stockings et al. 2018a) identified 104 studies, 21 with > 100 participants), short duration of exposure to the cannabinoid (median eight weeks (Stockings et al. 2018a)) and varying definitions of “chronic pain”. Many studies within these systematic reviews are notable for high withdrawal rates in the treatment arms (Stockings et al. 2018a; Mucke et al. 2018).

The most recent SR concluded that the number needed to harm (NNTH) for cannabinoid use in chronic pain was 6 (opioids NNTH = 5) (Stockings et al. 2018a) with a number needed to treat (NNT) of 24 (30% reduction in pain). This compares unfavourably with opioids (NNT 4.3), pregabalin (7.7) and tricyclics (NNT 3.6) (Stockings et al. 2018a). When the pain intensity reduction (versus placebo) was pooled, it was equivalent to a 3 mm reduction on a 100 mm visual analogue scale. Taken with a higher risk of an adverse event and trial withdrawal (Stockings et al. 2018a), the authors suggested that whilst there was moderate evidence for pain reduction with cannabinoids compared with placebo (higher quality evidence for MS and neuropathic related pain), it seemed unlikely that cannabinoids are highly effective for chronic non-cancer pain.

Other SR/MAs make varying comments on the strength of the evidence, including weak recommendations (Meng et al. 2017), low strength (Rodríguez-Muñoz et al. 2016), moderate (Therapeutic Goods Administration 2017; Mucke et al. 2018; Whiting et al. 2015) (30% reduction pain relief), moderate to high (Aviram and Samuelly-Leichtag 2017), strong or “conclusive” (Abrams 2018) evidence for the use of cannabinoids in chronic pain. Others suggest a moderate to high risk of bias, concluding the evidence base is insufficient to make well found conclusions about the use of CBMs for cancer and non-cancer pain (Hauser et al. 2018b). Additionally, a large observational cohort study in Australia disputed cannabis use as an adjunct to reduce opiate consumption (Sánchez-Blázquez et al. 2014).

Globally, regulatory bodies have come to different conclusions. The Health Products Regulatory Authority (HPRA) of Ireland does not support CBMs as a treatment in chronic pain (Health Products Regualtory Authority 2017). The European Pain Federations recent position paper recommended CBMs be considered for chronic neuropathic pain, but as a third line agent, and stated there was insufficient evidence for CBMs for non-neuropathic chronic non-cancer pain (Hauser et al. 2018a). This is in direct contrast to the National Academies of Science Engineering and Medicine (NASEM) review on the health effects of cannabis and cannabinoids (National Academies of Sciences Engineering and Medicine 2017) which concluded that there was conclusive or substantial evidence for the use cannabis or cannabinoids for the treatment of pain in adults.

In summary, CBMs have a higher NNT than opioids, pregabalin or TCA, with a clinically insignificant pooled pain reduction of 3 mm on 100 mm VAS, and are thus unlikely to be effective in chronic, non-cancer pain, non-neuropathic pain. Additionally, other problems include study design and high withdrawal rates in intervention arms, with Cannabinoids demonstrating a higher risk of adverse events.

Nausea and vomiting secondary to chemotherapy

Nabilone (UK) and dronabinol (USA) are used to treat intractable post-chemotherapy nausea and vomiting (Abrams 2018), with the HPRA of Ireland recently permitting its use for this indication (Health Products Regualtory Authority 2017).

Reviews of cannabinoids for this indication have found them to be better than placebo (Whiting et al. 2015; Smith et al. 2015; Layeeque et al. 2006) of similar (Smith et al. 2015; Lewis et al. 1994) or better efficacy than antiemetics (dopamine antagonists) (Whiting et al. 2015), but with patients preferring CBMs (Smith et al. 2015). These reviews do not compare CBMs with steroids or serotonin (5HT3) antagonists. One randomised controlled trial utilising ondansetron as a comparator (Meiri et al. 2007) was stopped early due to recruitment difficulties, and had numerous methodological limitations including being underpowered for the authors conclusion that dronabinol was as efficacious as ondansetron.

The quality of evidence for the use of CBMs in preventing chemotherapy induced nausea and vomiting has been described as low (Whiting et al. 2015; Smith et al. 2015), “sometimes effective” (Therapeutic Goods Administration 2017) or conclusive/substantial evidence of benefit (Abrams 2018).

In summary, no completed studies have utilised modern antiemetics as a comparator, but cannabinoids are better than placebo, and display equivalent efficacy with dopamine antagonists. Further research will help determine the appropriate usage of CBM for nausea and vomiting.

Multiple sclerosis

Nabiximols (Sativex®) is licensed for multiple sclerosis (MS)-induced spasticity (Department of Health and Social Care 2018), which affects 17% of MS sufferers, with a similar proportion using cannabis for symptom control (Rice and Cameron 2017).

Previous MA/SR have produced various conclusions on the strength of the evidence of CBMs in MS-induced spasticity, ranging from low quality to conclusive evidence (Therapeutic Goods Administration 2017; Health Products Regualtory Authority 2017; Rice and Cameron 2017; Koppel et al. 2014; Whiting et al. 2015; Abrams 2018). A recent systematic review of reviews (Nielsen et al. 2018) for the use of cannabinoids in MS concluded that whilst the quality of the evidence from included studies was very low to low, five of the eleven reviews concluded that there was sufficient evidence for reduction in spasticity and/or pain in MS. However, the authors stated that despite the positive findings, the effect was small (Nielsen et al. 2018).

In summary, CBMs have a small positive effect on muscle spasticity, but the evidence quality is low.

Epilepsy

The United States Food and Drug Administration (FDA) (US Food and Drug Administration 2018) has recently approved cannabidiol oral solution (Epidiolex®) for the treatment of two forms of rare epilepsy in children aged over 2 years of age; Lennox-Gastaut syndrome and Dravet syndrome (Thiele et al. 2018; Devinsky et al. 2018; Devinsky et al. 2017). Most evidence is on the use of CBD, with the overall quality of the evidence in adults being limited (Koppel et al. 2014; Abrams 2018; Gloss and Vickrey 2014; Stockings et al. 2018b). Meta-analysis results pool effects in adults and children, with conclusions being influenced by the aforementioned paediatric studies (Sánchez-Blázquez et al. 2014; Devinsky et al. 2018; Devinsky et al. 2017; Gloss and Vickrey 2014; Stockings et al. 2018b). Outside of the USA, CBM use for epilepsy is not recommended in the UK (Department of Health and Social Care 2018), Ireland (Health Products Regualtory Authority 2017) and only once conventional treatments have failed in Australia (Therapeutic Goods Administration 2017).

In summary, the evidence base supports the use of CBD in children with certain neurological conditions, but not in adults.

Other

The NASEM review has considered CBMs for the treatment of other conditions, as detailed in Table 3 (Abrams 2018).