How cannabis can help treat opioid addiction

If you or a loved one is suffering from opioid addiction, you know how helpless and out of control one may feel. While opioids can be highly effective in treating pain (at first), unfortunately they are highly addictive and lethal in overdose. This has led to a global opioid crisis affecting people from all walks of life demonstrating that pain and seeking relief are truly a shared human experience. Moreover, opioid addiction is extremely difficult to overcome.

 

In this article, we will cover some background information and then discuss five evidence-based ways in which cannabis (Cannabis sativa L; Pollio 2016) can provide hope.

  1. Cannabis works synergistically with opioids to more effectively relieve pain and decrease the risk of opioid addiction and overdose by allowing the use of lower doses of both the opioid and cannabis.
  2. Cannabis can safely and effectively substitute for opioids in treating pain, thereby eliminating opioid risks by not starting or continuing their use.
  3. Cannabis improves the efficacy of medications used to treat opioid addiction.
  4. Cannabis acts independently to make it easier for addicts to quit.
  5. Cannabis treats problems encountered while quitting such as pain, vomiting, insomnia and anxiety.

 

The Potential of Cannabis: Indirect Evidence

The passage of medical cannabis laws is associated with decreased opioid use and overdose, as evidenced by decreases in opioid prescriptions billed to private insurance (Raji 2019), Medicaid (Wen 2018) and Medicare Part D (Bradford 2018). Legalization of medical cannabis has also been documented to coincide with decreases in reported opioid overdoses, hospital admissions for opioid overdose (Shi 2017), death from opiate overdose (Powell 2018, Bachhuber 2014), positive tests for opioids in fatal motor vehicle crashes, and diagnoses of opioid addiction (Powell 2018). As important as the science is, real life stories of people who have rebuilt their

 

lives by overcoming opioid addiction with the help of cannabis are authentic, powerful and inspiring.

 

A Personal Account of Overcoming Opioid Addiction with the Help of Cannabis

A friend of mine, Rico Lamitte, used opioids to cope with pain from injuries suffered while playing NCAA Division I college football. The support staff and physicians gave him a wide variety of opioids and powerful non-opioid medications, including Vicodin (generic ingredients: hydrocodone, a semi-synthetic opioid analgesic, combined with acetaminophen), Norco (generic ingredients: hydrocodone and acetaminophen available at a higher dose), Vioxx (generic name: rofecoxiban, an advanced nonsteroidal anti-inflammatory pain reliever taken off the market because of increased risk of heart attack and stroke), Zoloft (generic name: sertraline, a selective serotonin reuptake inhibitor antidepressant), and Ambien (generic name: zolpidem, a nonbenzodiazepine sedative-hypnotic sleep medication). It was a common practice for doctors to give out opioids like candy, and the athletes were effectively used as guinea pigs to provide data to big pharmaceutical companies testing their drugs.

 

As happens with up to ¼ of people who use opioids for chronic pain (Banta-Green 2009, Boscarino 2010, Fleming 2007), Rico became addicted to opioids, shattering his dream of playing in the NFL. After graduating from college, he went on to work in corporate finance. The money was good, and with benefits Rico only had $40 copays for large prescriptions of opioids with multiple refills, instead of paying $800 on the street. He worked hard and played hard. This included drinking large volumes of alcohol, which does not mix well with the opioids, because they are both sedatives, and when used together can easily lead to stupor, respiratory depression, overdose and death. Eventually Rico hit rock bottom when he was diagnosed with a tumor, which is how his father died at a young age. Fortunately, the biopsy results came back benign, but this was his wake up call.

 

A friend, who was working in the cannabis industry in California, shared with Rico his knowledge of various cannabis strains and how they could be used to manage his pain and opioid addiction. Rico started to substitute cannabis for the opioids, and after about 7 months, he no longer felt the need or desire to use opioids. Rico believes cannabis truly saved his life. (You can watch Rico’s TEDx talk where he shares his story in more detail at: https://youtu.be/ fQ9iUTabam4). Rico went on to become a successful entrepreneur and leader in the cannabis

 

industry. Through his current company Canivision (https://www.canivision.com/), Rico helps educate people on the benefits of medical cannabis, as well as helping people from Black and Brown communities to succeed in the cannabis market. You can watch my interview with Rico and life coach Mila Diamond in which we discuss his journey of recovery and success at: < I will email a link to the edited version of the interview as soon as we get it back from the professional editing team >

 

Rico’s story is not unique. The myriad accounts of people getting off opioids with the help of medical cannabis as a stepping stone to sobriety are scattered throughout the long history of these two powerful medications.

 

Opioids & Cannabis: Historical Highlights

The earliest reference to opium, the natural opioid form, dates back to 3400 BCE, when opium poppies (Papaver somniferum) were cultivated in Mesopotamia and referred to as “Joy Plants” for their euphoric effects. Over two millennia later, traders introduced opium cultivation to Egypt, where it was insightfully used as medicine in low doses and for execution in overdose. Another millennium later, Alexander the Great brought opium from Greece to India and Persia.

 

About 400 CE, Arab traders introduced opium cultivation to China, where it flourished. Not much is documented about opium during the Middle Ages in Europe, likely due to the fact that the Spanish Inquisition branded the “Eastern drug” as evil.

 

Depression complicates both opioid addiction and withdrawal. Fortunately, cannabis has been used to successfully treat depression throughout history. In 1621, English clergyman Robert Burton recommended its use in his book The Anatomy of Melancholy, while doctors in India during the same period were actively using it to treat their patients’ depression. (Kossen 2016)

 

By the 1700s, people began smoking opium in tobacco pipes, and opium dens — shops where opium is sold and smoked — became popular throughout Europe and China. This sparked an early opium epidemic, with rapidly rising levels of addiction, leading the Chinese Emperor Kia King to ban opium entirely by the turn of the 18th century.

 

In 1806, the German chemist Friedrich Sertürner isolated a substance from opium, which he called “morphine”, after the Greek god of dreams. With the advent of morphine, it was felt that opium had now been tamed into what was considered “God’s own medicine”. By 1819, writer John Keats and other English literary personalities experimented with opium strictly for recreational use. London physician Dr. John Clendinning successfully used cannabis to treat arthritis, neuropathic pain, and migraines, all medical problems for which opioids are largely ineffective and can even make the pain worse. In his1843 medical journal article (Clendinning 1843), Dr. Clendinning reported his therapeutic experiences improving the lives of his patients by prescribing cannabis tinctures, and also described the use of cannabis to help ease a patient’s morphine withdrawal.

 

Francis Rynd, an Irish surgeon, is generally credited as inventing the hypodermic needle for human use in 1844. The plunger syringe, invented almost a decade later in 1853, made intravenous and intramuscular injection possible. Use of the new technique spread rapidly, and even helped Florence Nightingale during an illness. She declared: “Nothing did me any good, but a curious little new-fangled operation of putting opium under the skin, which relieved [the pain] for 24 hours.” (Kotwal 2005).

 

In 1868, Sir John Reynolds, personal physician to Queen Victoria, began writing about his experience with cannabis as a superior painkiller in The Lancet (Reynolds 1868): “The bane of many opiates … is that the relief of the moment is purchased at the expense of tomorrow’s misery,” alluding to opioid withdrawal. “In no one case to which I have administered Indian hemp [a term used for cannabis in documents before the 1940s], have I witnessed any such results.” In a1890 article in the highly respected British medical journal The Lancet (Reynolds 1890), Reynolds wrote, “In almost all painful maladies I have found Indian hemp by far the most useful of drugs”. Cannabis was said to be the treatment of choice for Queen Victoria’s dysmenorrhea (menstrual pain) (Abrams 2015).

 

For US doctors, morphine quickly became the analgesic mainstay for relieving suffering, and was so commonly used during the Civil War that a massive number of soldiers became dependent on opiates. Their post-war morphine addiction became known as “soldier’s disease”. Cannabis was used along with opioids to treat the pain of treat war injuries and the diarrhea of dysentery (Barnes 1992).

 

 

Heroin was first synthesized in 1874 when English researcher C.R. Wright boiled morphine and acetic anhydride over a stove, producing this more potent form of morphine. Heroin became commercially available around the turn of the 19th century. By the end of the 19th century, two Opium Wars had been fought over the narcotic, by Britain, China and France.

 

Racism and the “War on Drugs” go hand-in-hand. Starting in 1890, newspapers owned by William Randolph Hearst and others began publishing stories about white women being seduced by Chinese men and their opium to invoke fear of the “Yellow Peril” disguised as a public health campaign. Harry Anslinger, a “crazy racist”(Abdelfatah 2019) high school dropout best known for demonizing cannabis, initially targeted alcohol stating that cannabis was not a problem, did not harm people, and even that, “There is probably no more absurd fallacy” than the idea it makes people violent (Anslinger 1933). Anslinger was appointed the founding commissioner of the Federal Bureau of Narcotics, but it was not until the end of alcohol Prohibition in 1933 that his focus and views on cannabis shifted — not based on objective evidence, which he ignored, but out of glaring self-interest. As part of Anslinger’s strategy to justify the existence and budget of the Bureau of Narcotics, he targeted minorities, especially Black Americans including jazz legend Billie Holiday, whom he had handcuffed on her deathbed (Hari 2015). Anslinger propagated repulsive lies, virtually all of which have been disproven, such as: “Two <racial slur> took a girl fourteen years old and kept her for two days under the influence of hemp. Upon recovery she was found to be suffering from syphilis.”(Inciardi 1986) and “Reefer makes <racial slur> think they’re as good as white men.”(Newton 2017)

 

At the beginning of the 20th century, morphine and heroin addiction rates rose to alarming levels resulting in passage of the Harrison Narcotics Tax Act, signed into law by President Woodrow Wilson in 1914. The Tax Act established federal taxation and regulation of opioids and cocaine and allowed Corsican gangsters to dominate the US heroin market through their partnership with Mafia drug distributors. The 1930s-1950s saw the development of multiple synthetic opioids, including oxycodone pills, long-acting methadone and super high potency fentanyl, by large pharmaceutical companies.

 

In 1902, the American doctor Thomas D. Crothers promoted cannabis’ “temporary removal of the worst symptoms” of opioid addiction (Crothers 1902). Released in 1944 after more than 5

 

years of research, the LaGuardia Report represented the first in-depth study into the effects of cannabis in the United States conducted by the New York Academy of Medicine commissioned by New York Mayor Fiorello LaGuardia. As part of their investigation, a group of prisoners addicted to opioids were given 15 mg of THC (Δ9-tetrahydrocannabinol, the most prominent ingredient in cannabis) three times daily in a prospective, placebo-controlled, matched cohort study. Compared to control patients, who received standard treatment, prisoners receiving THC experienced much less severe withdrawal symptoms and were observed to be in better condition on discharge from the hospital. A mountain of other evidence in the Report systematically contradicted claims made by the Federal Bureau of Narcotics that smoking cannabis results in insanity, deteriorates physical and mental health, promotes criminal behavior and juvenile delinquency, is strongly physically addictive, and is a “gateway” drug to the use of more dangerous drugs such as opioids and cocaine. (Laguardia 1944)

 

The Vietnam War was blamed for a surge in illegal heroin being smuggled into the United States, and the estimated number of heroin addicts rose to over 750,000. This contributed to President Nixon formally declaring the “War on Drugs” in 1970 with passage of the Controlled Substances Act which charged the Drug Enforcement Administration (DEA) and the Food and Drug Administration (FDA) with classifying controlled medications into five schedules. Both heroin and cannabis were placed in the most restrictive Schedule 1, declaring them to have a high potential for abuse, no accepted medical use and a high risk of addiction. In the case of cannabis, the extreme Schedule 1 classification was supposed to be temporary pending the report of the Shafer Commission on Marihuana [sic] and Drug Abuse, appointed by Nixon himself. After careful review of all available scientific evidence, the Commission called for decriminalization of cannabis (Shafer 1972), but the report was ignored, and cannabis has erroneously remained in Schedule 1 ever since (Clayton 2009), despite thousands of peer-reviewed studies demonstrating the unique medical benefits and safety of the plant (NAS 2017).

 

While pervasive throughout society, some opioid overdose deaths receive greater attention than others. Some of the celebrity deaths due opioid overdose include: singers Janice Joplin (1970) and Kurt Cobain (1994) who died of heroin overdoses, and comedian John Belushi (1982) and actor River Phoenix (1993) whose deaths resulted from overdoses of a combination of heroin and cocaine, known as a “speedball”. As we saw in Rico’s case, the multi-talented artist Prince suffered from severe pain and became addicted to the opioids that once gave him relief. In 2016,

 

Prince died of an overdose of pills he thought were Vicodin (containing hydrocodone, a mid- level opioid) but turned out to be laced with the ultra-potent synthetic opioid fentanyl (trade name: Duragesic). Actor Heath Ledger died in 2008 after taking the opioids oxycodone and hydrocodone along with the sedative diazepam (trade name: Valium), all of which tend to impair breathing — especially when combined with alcohol. Ledger was taking these powerful, controlled substances “to help with a busy schedule and lack of sleep”. (Onderdonk 2019) However, a recent study (Ahmad 2020) comparing drug overdose deaths by celebrities with non- celebrities between 1999 and 2017, found that while impressions from media reports might suggest that death from a drug overdose is more common in celebrities, the opposite is actually true. Celebrities died from an overdose of any opioid at a rate of only 253 per 100,000 persons compared to 820 for non-celebrities. The bottom line is that opioid addiction and overdose can happen to anyone. In contrast, as we will consider shortly, no one has ever died of a cannabis overdose.

 

The decade of the 1980s was characterized by “opiophobia,” in which doctors became overly cautious of prescribing opioids to patients because of the high addiction potential. The 1990s saw the pendulum swing back in the other direction as physicians began prescribing more opioids after noticing that pain was generally being undertreated (Bushak 2016, Meldrum 2016, Frontline 1998). This marked the start of our current opioid crisis, which we will discuss next.

 

The Opioid Crisis

Addiction

Opioid use disorder typically begins with the legitimate use of prescription opioids for pain relief (Martin 2017 Addict Behav), which still accounts for the majority of all opioid use. Anyone who takes opioids is at risk of developing addiction, and it is impossible to predict who is vulnerable to dependence on and misuse of these drugs. Doctors define drug addiction as an irresistible craving for a drug, out-of-control, compulsive use of the drug, and continued use despite repeated, harmful consequences in areas such as relationships, employment and the law.

 

In 2019 (the last year for which statistics were available as of the date this article was written), over 10 million people misused opioids in the US. The vast majority of people misused prescription pain relievers (SAMSA 2020). This has led to a global opioid crisis centered in the United States, where we consume 80% of all the opioids used in the entire world (Manchikanti

 

2008), despite making up only 4% of the population of the planet (US Census Bureau 2021). An estimated 20% of patients presenting to US physician offices with noncancer pain symptoms or pain-related diagnoses receive an opioid prescription (Daubresse 2013). A further humanitarian tragedy is that more 88% of the world’s population, who live in low- and middle-income countries, consume less than 10% of the pharmaceutical opioids and are deprived of access to controlled drugs for acute pain relief and other essential medical uses due to global shortages (Lemahieu 2020).

 

Unfortunately, people addicted to prescription opioids often go on to become dependent on heroin (Cicero 2014, Martin 2017 JAMA Psych, Martin 2017 Addict Behav), because heroin is more effective, longer lasting, cheaper and easier to access (Cicero 2014). In fact, four in five new heroin users started out misusing prescription painkillers (Jones 2013). This has accelerated since the DEA and states began tracking opioid prescriptions written by doctors.

 

Heroin use has risen sharply throughout the United States among men and women, most age groups, and all races and income levels, with some of the greatest increases occurring in demographic groups with historically low rates of heroin use, including women, people who are privately insured, and people with higher incomes (CDC Heroin 2020, Shiels 2017). Heroin is typically injected but can also be smoked and snorted. When people inject heroin, they are at increased risk of potentially fatal, long-term viral infections such as HIV, Hepatitis B and Hepatitis C, as well as serious bacterial infections of the skin, bloodstream, and heart (CDC 2020 Heroin).

 

Overdose

The opioid addiction epidemic has led to a rapid increase in deaths from overdose (Scholl 2018, Wilson 2020), such that opioids now account for over 70% of all overdose deaths (Wilson 2020). Overdose has become the leading cause of death for people under 50 years old in the USA. According to the Centers for Disease Control and Prevention (CDC), in 2017 over 130 Americans died every day from an opioid overdose, which is almost one person every ten minutes (Wilson 2020). COVID-19 has led to an acceleration in the rise of opioid overdose deaths (CDC 2020 COVID-19), due in part to increased isolation, decreased interaction between patients and healthcare providers, worsening of mental health problems and financial insecurity.

 

From 1999-2018, almost half a million people died in the US from opioid overdoses (WONDER 2020 Data Analysis). Opioid overdose deaths have increased almost six fold during that time, and the meteoric rise can be understood as occurring in three distinct waves. The first wave resulted from a rapid increase in opioid prescriptions written by doctors in the 1990s (Paulozzi 2011). The second wave, beginning in 2010, is attributed to heroin (Rudd 2014), with annual overdose deaths involving heroin mushrooming by nearly five times, from about 3 thousand in 2010 to 15 thousand in 2018 (WONDER 2020 Heroin). The third wave began in 2013, with significant increases in overdose deaths involving synthetic opioids, particularly illegally manufactured fentanyl (Gladden 2016, O’Donnell 2017 Trends, O’Donnell 2017 Fentanyl).

Fentanyl is about 100 times stronger than morphine, and overdose deaths have sky-rocketed from about 2600 in 2012 to over 31,000 in 2018. Fentanyl can be found in combination with heroin, counterfeit pills, and cocaine (DEA 2020 Fentanyl).

 

How Opioids Work: The Body’s Opioid System

The opioid system has been observed in all vertebrate animals studied, and its effects in the human body are vast, involving almost every physiological system (Stevens 2009). The opioid system in the human body is composed of a family of opioid receptors located on cell membranes and endogenous opioids, compounds manufactured by the body, that bind to the opioid receptors and produce an effect. The most famous endogenous opioids are the endorphins, because for decades they were presumed to account for the “runner’s high” phenomenon described as a state of euphoria and reduced pain occasionally experienced during prolonged strenuous exercise (Fuss 2015). However, recent research has led to a fascinating new theory of “runner’s high” that we’ll revisit below.

 

Exogenous opioids, such as morphine, heroin and fentanyl, are foreign substances introduced into the body from outside that are able to produce effects by binding to the same receptors as the endogenous opioids. Opioids exert their effects through many different mechanisms in many different areas of the body. For our discussion, we will focus on the ability of exogenous opioids to relieve pain, to suppress breathing, to affect nausea and vomiting, anxiety and depression and impair sleep with both chronic use and in withdrawal, and to produce reward leading to craving, tolerance and addiction.

 

Opioid Effects on the Human Body

 

Pain

High concentrations of opioid receptors are present in neurons in many areas throughout the nervous system. Opioids relieve suffering by dampening pain signals as they are transmitted from peripheral nerves to the spinal cord on their way to the brain (Dhaliwal 2020). Opioid- induced hyperalgesia: Hyperalgesia is an increase in pain sensitivity (Mercadante 2003) despite increasing doses of opioids (Mercadante 2005) and is a relatively newly recognized adverse effect. Long-term use and high doses of opioids have been associated with the development of hyperalgesia, but it’s mechanism appears to be complex and is not yet well understood. Recent studies in opioid addicts have confirmed that chronic opioid use results in the abnormal pain perception of hyperalgesia (Pud 2006). The bottom line is: Chronic opioid use can make the pain worse.

 

Breathing

Opioid receptors are abundant along the entire respiratory system from the respiratory center in the brain, to peripheral chemical and pressure receptors in the nerve pathway carrying signals from the brain to the lungs, to mechanoreceptors of the airways and lungs. Stimulation of these opioid receptors leads to slow, irregular breathing that impairs the inhalation of oxygen and exhalation of carbon dioxide waste, which can rapidly escalate to the point at which the person stops breathing and dies. This is how an opioid overdose kills.

 

Nausea & Vomiting

Opioids cause nausea and vomiting through multiple mechanisms primarily by binding to opioid receptors in the chemoreceptor trigger zone in the brain, central and peripheral areas that inhibit gut motility, and in the vestibular apparatus in the temporal lobe of the brain and inner ear that is responsible for detecting changes in equilibrium. The role of the brain’s cerebral cortex is unclear, but may be related to a patient recalling previous episodes of nausea and vomiting after opioid therapy (Herndon 2002).

 

Constipation & Diarrhea

Opioid use is well known to produce constipation that can be so severe that patients are taken to surgery — sometimes it may be indicated and sometimes this common opioid adverse side effect is missed as the cause of the patient’s severe abdominal pain. The opposite problem occurs when

 

opioids are stopped, and diarrhea is a hallmark of opioid withdrawal syndrome. These problems are due to the tremendous influence of the body’s endogenous opioid system on gut motility.

 

Anxiety & Depression

There is a high density of opioid receptors in the emotional center (limbic system) of the brain that regulates mood and may explain why anxiety and depression are prominent in opioid withdrawal. Sustained use of opioids decreases structural plasticity and neurogenesis (formation of new neurons) in the hippocampus (Lutz 2013), part of the emotional center of the brain. This could also help explain the detrimental effect of chronic opioid exposure on mood regulation, leading to disordered mood states and social isolation.

 

Sleep

Regular, chronic use of opioids is known to interfere with sleep via several mechanisms. Opioids can cause changes in sleep architecture including a reduction in both sleep efficiency and deeper Stages 3 and 4 levels of sleep (Xiao 2010), as well as less rapid eye movement (REM) sleep and dreaming (Teichtahl 2001). These effects lead to poor sleep quality and daytime sleepiness (Xiao 2019, Cao 2018, Teichtahl 2001, Wang 2005, Dunn 2018). The opioids themselves have also been shown (Parker 2006) to contribute to depression and even enhance pain, both of which are leading causes or poor sleep. Furthermore, multiple studies have demonstrated that chronic use of opioids is associated with an increase in central sleep apnea, due to decreased drive to breath in the brain (see Breathing above) and obstructive sleep apnea, resulting from deep sedation and muscle relaxation causing obstruction of the airway, decreased blood oxygen and repetitive arousals from sleep (Chowdhuri 2017, Farney 2018).

 

Opioid Addictive Effects

Reward & Craving

Stimulation of opioid receptors in the reward center of the brain results in the release of dopamine, the happy neurotransmitter that leads to positive reinforcement and a strong desire for more dopamine reward (Toubia 2019).

 

Tolerance & Addiction

Prolonged use of opioids leads to an irreversible breakdown of the endogenous opioid system due to reduced production of endogenous opioids. The body decides that if it is given a lot of

 

exogenous opioids from the outside, it doesn’t need to produce endogenous opioids and opioid receptors. The endogenous opioid system becomes unable to perform its many functions, including controlling pain. This causes opioid users to rely on exogenous opioids to mimic the actions of the failed endogenous opioid system, leading to increased risk of uncontrollable pain made worse by their opioid use, dependence, and eventually addiction (Dhaliwal 2020).

 

Note to Reader

If you are taking opioids, and you have developed tolerance and have had to increase your dose to effectively relieve your pain, please ask your doctor for help. There are other, safer options available to help you make a change and continue feeling well. Do not stop opioid medications without a doctor’s help. Quitting these drugs abruptly can cause severe side effects, including anxiety, depression, poor sleep, and pain that is worse than it was before you started taking opioids. A doctor specializing in the use of medical cannabis can help you taper off opioids gradually and safely.

 

When are Opioids Appropriate?

The primary indication for treating pain with opioids is in acute pain of moderate to severe intensity, immediately following a significant injury or surgical procedure (e.g. involving bones or joints). Opioids should be prescribed only when necessary, in the lowest effective dose, and for the shortest duration required (Pino 2020).

 

For chronic pain, opioids are considered appropriate first line therapy in the setting of cancer, palliative care and end-of-life care. In other cases of chronic pain, nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred treatment options. Current clinical guidelines from the American Academy of Pain Medicine, American Pain Society, and the Centers for Disease Control and Prevention state that long-term prescription opioids should only be considered for patients with chronic pain when the expected benefits are anticipated to outweigh the potential harms (Chou 2009, Dowell 2016). Evidence supporting these restrictive recommendations are summarized as follows:

 

  •       No evidence shows a long-term benefit of opioids in pain and function versus no opioids for chronic pain.

 

  •       Extensive evidence shows the possible harms of opioids (including addiction, overdose, and motor vehicle injury).

 

  •       Extensive evidence suggests some benefits of nonpharmacologic and nonopioid pharmacologic treatments compared with long-term opioid therapy, with less harm.

 

 

Non-Opioid Drugs for Pain

CDC guidelines recommend using non-opioid medications as first line treatments for both acute and chronic pain. A 2020 systematic review (McDonagh 2020) of the scientific evidence evaluated the benefits and harms of non-opioid drugs in randomized controlled trials of patients with specific types of chronic pain, considering the effects on pain, function, quality of life, and adverse events.

 

In the short term, improvement in pain and function was small with anticonvulsants, moderate with antidepressants in diabetic peripheral neuropathy, post-herpetic neuralgia and fibromyalgia, and small with nonsteroidal antiinflammatory drugs (NSAIDs) in osteoarthritis and inflammatory arthritis. In the intermediate term, limited data showed evidence of benefit for memantine (trade name: Namenda) in fibromyalgia and for serotonin norepinephrine reuptake inhibitor (SNRIs) antidepressants in low back pain and fibromyalgia.

 

Virtually all medications have side effects, though non-opioids present fewer risks compared to opioids. Small to moderate increases in the number of subjects who withdrew from the studies due to adverse events were found with the SNRIs duloxetine and milnacipran, the anticonvulsants pregabalin and gabapentin, and the NSAIDs. Large increases were seen with the anticonvulsant oxcarbazepine. NSAIDs have increased risk of serious gastrointestinal bleeding, liver dysfunction, and cardiovascular adverse events. Although helpful for some patients, these medications are often inadequate and have serious side effects. This demonstrates the need for effective, safe alternatives. The evidence indicates that cannabis can be one of those alternatives.

 

Non-Pharmacologic Analgesic Alternatives

 

CDC guidelines also recommend using non-pharmacologic interventions as first line treatments for both acute and chronic pain. A 2020 systematic review (Skelly 2020) of the scientific evidence on the effectiveness and safety of various methods of treating pain without the use of medications identified the following interventions that showed improved function and/or pain:

 

  • Low back pain: Exercise, psychological therapy, spinal manipulation, low-level laser therapy, massage, mindfulness-based stress reduction, yoga, acupuncture, multidisciplinary rehabilitation.
  • Neck pain: Exercise, low-level laser therapy, mind-body practices, massage, acupuncture.
  • Knee osteoarthritis: Exercise, cognitive behavioral therapy.
  • Hip osteoarthritis: Exercise, manual therapies.
  • Fibromyalgia: Exercise, cognitive behavioral therapy, myofascial release massage, mindfulness practices, tai chi, qigong, acupuncture, multidisciplinary rehabilitation.
  • Tension headache: Spinal manipulation.

 

Serious harms were not observed with any of the non-pharmacologic interventions.

 

The fact that opioids, non-opioid medications, and non-pharmacologic analgesics are generally only mildly effective and often inadequate, with adverse medication side effects that can be serious and even fatal, demonstrates the urgent need for safe and effective alternatives. Cannabis may fit that bill by successfully relieving a person’s suffering with minimal risks. Recent studies have revealed how cannabis works in the body and how it may help solve the opioid crisis.

 

How Cannabis Works: The Endocannabinoid System

The human body is made up of multiple different physiological systems, such as the immune system, gastrointestinal system, and the focus of our discussion here: the nervous system. The endocannabinoid system, discovered in the 1980s, is a master system that helps regulate the other physiological systems in the body to promote balance — the way a symphony conductor directs the instruments in an orchestra to produce beautiful music.

 

The endocannabinoid system is composed of cannabinoid receptors scattered throughout the body on cell walls and within mitochondria inside cells in various physiological systems. Two endocannabinoid receptors have been named so far: CB1 and CB2. CB1 receptors are

 

widespread but more prominent in the brain and spinal cord (Pertwee 1997). CB2 receptors tend to be peripheral and concentrated in organs of the immune system, such as the spleen, thymus and blood cells (Pacher 2006). The endocannabinoid system has been identified in almost every brain structure and organ system in the human body (Fride 2002, Fride 2006), and in some ways resembles the opioid system discussed above.

 

Endocannabinoids (endogenous cannabinoids) are compounds produced on demand by cells and released into the intercellular space, where they bind to endocannabinoid receptors on adjacent cells producing local effects specific to the physiologic system. Two endocannabinoids have been named: anandamide (from ananda the Sanskrit word for bliss, also known as arachidonoylethanolamide) and 2-AG (2-arachidonoylglycerol). The endocannabinoid system is present throughout the animal kingdom and has even been observed in primitive organisms, such as sea urchins, as well as humans and other animal species (Schuel 2005).

 

The reason the cannabis plant produces so many different effects on the body is because compounds in the plant, known as phytocannabinoids (phyto meaning plant in Greek), are able to bind to the same endocannabinoid receptors as anandamide and 2-AG. Over 100 phytocannabinoids have been identified in the plant (Mehmedic 2010), but THC (Δ9- tetrahydrocannabinol) and CBD (cannabidiol) are by far the most abundant. Unlike endocannabinoids that are made by the body on demand and rapidly metabolized thereby producing transient, focused effects, phytocannabinoids, like THC, are sequestered in adipose tissue (fat) and released slowly over extended periods of time leading to longer-lasting stimulation of cannabinoid receptors (Iversen 2003). This can be concerning when considering negative side effects.

 

Runner’s High

Elaborating on the traditional theory attributing the “runner’s high” phenomenon to endorphin secretion as mentioned above in the section on How Opioids Work: The Body’s Opioid System, recent data show that endurance exercise activates the endocannabinoid system (Sparling 2003). Exercise of moderate intensity dramatically increased concentrations of the endocannabinoid anandamide measured in the blood. This new information does not merely substitute one neurotransmitter for another but recognizes multiple mechanisms likely involved in the complex “runner’s high”

 

experience of analgesia (pain relief), sedation (post-exercise calm), anxiolysis, and enhanced sense of wellbeing (Dietrich 2004).

 

The Entourage Effect

Cannabis-based medicines derived from the whole plant, which contains about 700 different compounds many of which produce medical effects, have been shown to be superior to medicines limited to a single isolated compound, such as CBD (Gallily 2015, Comelli 2008, Comelli 2009). This demonstrates the phenomenon known as the “entourage effect”, in which the effect of the whole plant is greater than the sum of its parts. This is because many of the compounds are synergistic, meaning they help each other work better together. It is like you get a bonus when you use them together, like 1+1=3. The medically active compounds found in the cannabis plant fall primarily into three classes: cannabinoids (> 100 identified), terpenoids (> 200 identified) and flavonoids (about 20 identified). In this article, we will focus primarily on potential synergy between various cannabinoids and terpenoids, because very little is currently known about the effects of flavonoids in cannabis.

 

Cannabinoids

In general, cannabinoids are identified by their ability to bind to the cannabinoid receptors CB1 and CB2, though many cannabinoids interact with other receptor systems as well. The major cannabinoids are THC and CBD, and their non-psychoactive acidic precursor forms THCA (tetrahydrocannabinolic acid) and CBDA (cannabidiolic acid) as they occur in the raw cannabis plant. In fact, THC and CBD are only formed when cannabis is exposed to heat and light, so consuming the raw plant is not intoxicating. There are many minor cannabinoids, and we will explore the relevance of three of them: CBG (cannabigerol), CBC (cannabichromene), and CBN (cannabinol).

 

THC

THC, the most common phytocannabinoid in the plant, binds to the cannabinoid CB1 and CB2 cannabinoid receptors. THC is analogous to the body’s own endocannabinoid anandamide and is primarily responsible for cannabis’ psychoactive, intoxicating “high”. THC underlies many of the effects of cannabis as an analgesic pain reliever, muscle relaxant, anti-inflammatory, antiemetic (anti-nausea), antispasmodic (Pacher 2006), bronchodilator (Williams 1976), and neuroprotective antioxidant (Hampson 1998).

 

 

CBD

CBD is the most common phytocannabinoid in hemp, a form of cannabis defined legally as having less than 0.3% THC. CBD is the second most common cannabinoid in cannabis strains containing higher levels of THC and has the advantage of being non-intoxicating (Mehmedic 2010). CBD does not interact with the endocannabinoid system by mimicking endocannabinoids and binding to CB1 and CB2 receptors the way THC does. It partially binds to CB2 receptors in certain cells (Tham 2019), but mostly influences the way in which other cannabinoids bind to CB1 and CB2 receptors. This explains why CBD is known to temper potential negative effects of THC, such as intoxication, sedation, anxiety and tachycardia (Nahas 1985), while augmenting THC’s analgesic, anti-nausea, and anti-carcinogenic properties (Russo 2006). CBD also interacts with the endocannabinoid system indirectly by inhibiting the breakdown of anandamide, thereby amplifying the effects of this endocannabinoid made by the body (Bisogno 2001). However, most of CBD’s effects are distinct from the endocannabinoid system. CBD is an incredibly prolific compound targeting at least 76 molecular systems within the human body (Mlost 2020). This explains its wide range of effects in the human body and makes CBD a veritable treasure trove of pharmaceutical possibilities.

 

Terpenoids

A class of aromatic compounds produced by the cannabis plant known as terpenoids can also affect the human body. Terpenoids convey smell to plants and enhance plant health, for example, by attracting bees and friendly insects, and repelling unfriendly insects and grazing animals.

Many terpenoids have demonstrated medical benefits, though they are typically present in much smaller amounts — usually less than 3%, compared to cannabinoids, such as THC, which can test at over 30% in some US strains (Russo 2011). Fortunately, terpenoid compounds are very potent, and concentrations above 0.05% are considered pharmacologically significant (Adams 2010). Cannabis terpenoids with potential therapeutic relevance to our discussion of opioid addiction include β-myrcene, linalool, ß-caryophyllene, limonene, and α-terpineol.

 

The ways in which cannabis affects the human body are legion, but as we did in considering the relevant physiological effects of opioids, we will focus on the ability of cannabis to relieve pain, and to affect breathing, nausea and vomiting, diarrhea, anxiety, depression, sleep, reward and craving, and tolerance and addiction.

 

 

Effects of Cannabis on the Human Body

Pain

The ability of THC to bind cannabinoid CB1 and CB2 receptors analogous to the endocannabinoid anandamide made by the body underlies many of its activities as an analgesic, muscle relaxant, antispasmodic and anti-inflammatory (Pacher 2006, Rahn 2009). The ability of THC to relieve pain is often due to its moderate inflammation, because multiple chemicals released in the inflammatory process cause pain as our body’s way of telling us that an area, such as a joint, is ill or injured. THC has 20 times the anti-inflammatory power of aspirin, and twice that of the steroid hydrocortisone (Evans 1991). THC can be a powerful analgesic because it is capable of affecting multiple other pain mechanisms as well (Baron 2018). In fact, administration of THC around the brain and spinal cord produces analgesia similar to opioids. (Manzanarez 2006)

 

Exogenous and endogenous cannabinoids are also known to work in multiple pain pathways including the opioid system (Raichlen 2012). THC enhances pain relief that occurs when endogenous opioids and exogenous opioid medications bind to opioid receptors (Smith 2007, Smith 1998, Fine 2013, Welch 1993). THC also stimulates the body to produce more endorphins and increases levels of other endogenous opioids in brainstem regions involved in pain processing (Cichewicz 2004, Cichewicz 2003, Manzanarez 1998).

 

CBD relieves many different types of pain (Costa 2007) because it acts through a vast number of analgesic mechanisms, only a few of which we have space to consider here. CBD interacts with the opioid system by actually binding to opioid receptors itself, and like THC, also enhances the binding of other compounds to opioid receptors (Pertwee 2008). The anti-inflammatory effects of CBD (Malfait 2000) eclipse those of THC by an order of magnitude and have been shown to be several hundred times more potent than those of aspirin when measured in standard animal tests and isolated cell assays (Formukong 1991).

 

CBD is a neuroprotective antioxidant more potent than Vitamin C (ascorbate) and Vitamin E (tocopherol; Hampson 1998). CBD is particularly effective in relieving recalcitrant neuropathic pain due to diabetes and nerve injury, fostering improved thermal perception and nerve growth factor levels in numb limbs while decreasing oxidative damage (Comelli 2009). Because CBD

 

increases levels of anandamide made by the body by inhibiting its breakdown, CBD helps relieve pain indirectly via the endocannabinoid system’s CB1 and CB2 receptors. By binding to lesser known cell receptors (GPR55 and GPR18), CBD may be able to play a unique therapeutic role in disorders of cell migration, such as endometriosis (McHugh 2010, Russo 2011), the excruciating pain from which is notoriously difficult to treat, sometimes leading to hospital admission for IV opioid analgesia and surgery (Dückelmann 2021). Endometriosis affects 1 in 10 women, and up to 50% of them have difficulty becoming pregnant.

 

CBD binds to TRPV1 pain receptors analogous to the analgesic capsaicin (trade names: e.g. Salonpas and Qutenza) but without the noxious effect (Bisogno 2001). Originally isolated from chili peppers (genus Capsicum), capsaicin relieves pain by stimulating nerve endings on surfaces such as the skin and oral mucosa. Capsaicin is indicated for treating arthritis, musculoskeletal pain, peripheral neuropathy and postherpetic neuralgia caused by shingles (Fattori 2016).

Interestingly, the pleasurable and even euphoric effects some people feel from ingesting chili peppers containing capsaicin (Gorman 2010) have been postulated by some to represent pain- stimulated release of endorphins, opioids made by the body.

 

Furthermore, combining CBD with THC was found to increase analgesic efficacy of cannabis in treating a variety of types of pain, leading the British drug company GW Pharmaceuticals to invest hundreds of millions of dollars in the development of a purified medication derived from the cannabis plant with a CBD:THC ratio of 1:1 called nabiximols (trade name: Sativex).

Nabiximols, an oromucosal spray, has been approved for use in treating pain in over 30 countries and is currently being evaluated by the US FDA. CBD proved (Berenbaum 1989) to be a critical factor in the ability of nabiximols to successfully treat intractable cancer pain in patients unresponsive to opioids achieving a 30% reduction in pain from baseline. A high-THC extract devoid of CBD failed to distinguish from placebo (Johnson 2010). This represents true synergy and an excellent example of the “entourage effect”, because the CBD–THC combination was shown to provide a larger effect than a summation of those from the compounds separately.

 

THCA (tetrahydrocannabinolic acid) and CBDA (cannabidiolic acid), have been found to relieve pain and inflammation quite effectively by binding to non-endocannabinoid receptors (TRPA1, TRPV1 and TRPM8) (De Petrocellis 2008; Rock 2018). A beneficial property of THCA and CBDA is that they are non-psychoactive and therefore excellent options for daytime use,

 

when patients may have responsibilities and need to be fully functional. Because these acid precursor forms convert to THC and CBD with exposure to heat, they need to be extracted without raising the temperature and cannot be vaped, smoked or incorporated into baked edibles. THCA and CBDA are commonly taken as sublingual tinctures or incorporated into a smoothie in their raw form.

 

Several minor cannabinoids have been shown to relieve pain by working at multiple different receptor types while likewise producing no intoxication, making them additional options for use during the day. The analgesic effects of CBG (cannabigerol) are due to its ability to strongly bind to the α-2 adrenoreceptor (Formukong 1988). CBC (cannabichromene) binds to the cannabinoid CB2 receptor and potentiates some effects of THC (Udoh 2019) resulting in modest analgesic and anti-inflammatory activity (Davis 1983). CBN (cannabinol) is a breakdown product of THC formed when cannabis is exposed to oxygen over time. CBN has been shown to relieve pain due to burns, which is notoriously excruciating and usually requires prolonged use of risky, high doses of potent, long-acting opioids. CBN also exerts its analgesic effects by binding to alternative receptors (TRPV2 and CGRP) (Zygmunt 2002, Qin 2008). While non-intoxicating, CBN is sedating (see Sleep below), and may therefore be best reserved for nighttime use. These minor cannabinoids have been difficult to obtain, however, they are becoming more widely commercially available. Some formulations can even be obtained by patients living in states without medical cannabis laws via the internet, especially if they are combined with CBD.

 

Several terpenoids have also been shown to have analgesic properties. β-Myrcene diminishes inflammation (Lorenzetti 1991) and was found to relax muscles and relieve pain in mice.

Interestingly, the analgesic effects of β-myrcene can be blocked by naloxone (Rao 1990), the antidote to an opioid overdose. This phenomenon suggests that β-myrcene may relieve pain in part by acting on opioid receptors.

 

ß-Caryophyllene relieves pain by strongly binding to the cannabinoid CB2 receptor and is also non-psychoactive. ß-Caryophyllene has potent anti-inflammatory and analgesic effects and modulates the immune system (Klauke 2014), making it particularly helpful in painful inflammatory conditions such as arthritis, for which opioids are sometimes prescribed (Vijayalaxmi 2015). ß-Caryophyllene has been found to be comparable in potency to powerful nonsteroidal anti-inflammatory drugs (NSAIDs), such as phenylbutazone (trade name:

 

Butazolidine; Basile 1988), etodolac (trade name: Lodine) and indomethacin (trade name: Indocin; Ozturk 2005). These prescription NSAIDs are rife with serious adverse side effects, including ulcers and potentially fatal gastrointestinal bleeding. In stark contrast, ß-caryophyllene protects the stomach lining (Tambe 1996). In fact, cannabis extracts were used in the past to treat duodenal ulcers in the United Kingdom (Douthwaite, 1947).

 

α-Terpineol has also been shown to relieve pain and inflammation. A Brazilian study (Oliviera 2012) showed significant analgesic effects of α-terpineol administered 30 minutes before application of mechanical pain in the hind paws of mice. Relief probably resulted from inhibition of the release of painful inflammatory molecules and impaired transmission of pain signals from the peripheral nerves to the spinal cord. The study also demonstrated the ability of α-terpineol to decrease inflammatory pain resulting from chemically-induced pleurisy, a condition involving inflammation of the two thin layers of tissue separating the lungs from the chest wall that causes characteristic, exquisite, sharp chest pain made worse by breathing. A more recent study by the same authors (Oliviera 2016) found that oral α-terpineol significantly decreased pain in a mouse model of fibromyalgia. The analgesic effect was reversed by naloxone and ondansetron, indicating that α-terpineol probably also works by binding to opioid and serotonin receptors.

 

A third study (Soleimani 2019) reported that α-terpineol reduced neuropathic (nerve-related) pain, which is notoriously difficult to treat, by suppressing inflammatory cells and reducing levels of painful inflammatory chemicals in the spinal cords of rats. The analgesic effect of α- terpineol was comparable to that of gabapentin, a standard neuropathic pain drug with many potential adverse side effects.

 

Finally, inhalation of lavender (Lavandula angustifolia, active ingredient: linalool) by morbidly obese surgical patients undergoing gastric banding procedures improved post operative pain control and significantly decreased morphine usage compared to placebo (Kim 2007). Similar to CBN, linalool has demonstrated a remarkable ability to alleviate pain and promote healing of burns without scarring (Gattefosse 1993), and the local anaesthetic effects are reported to equal those of procaine (trade name: Novocain) and menthol (an active ingredient in Bengay and Icy Hot; Re 2000, Ghelardini 1999). The analgesic effects of linalool have been linked to interaction at the adenosine A2A (Peana 2006) and glutamate receptors (Batista 2008).

 

Breathing

THC is a bronchodilator showing benefit in treating asthma (Tashkin 1973, Tashkin 1974, Tashkin 1977). THC and CBD demonstrate further potential therapeutic effects by reducing airway inflammation and enhancing the destruction of lung cancer cells (Hausted 2014, Shang 2016).

 

Most importantly however, the body’s endocannabinoid receptors are found in low concentrations in the respiratory centers of the brainstem, accounting for the remarkably low toxicity of cannabis compared to other recreational and pharmaceutical drugs (Herkenham 1990, Nguyen 2010, Lachenmeier 2015). Cannabis will not stop breathing nor gravely disrupt normal heart function. The lethal amount of THC in humans has been calculated at greater than 4000 mg (Gable 1993) — a dose that could not be realistically achieved following oral consumption, smoking or vaporizing cannabis (Arnold 2018). For example, to consume 4000 mg of THC one would have to smoke about 60 pounds of high potency cannabis in one setting, which is physically impossible. This is why cannabis has never killed anyone.

 

Nausea & Vomiting

Nausea and vomiting are often difficult to control even with the use of pharmacologic agents such as ondansetron. THC and CBD (Parker 2002) produce anti-nausea effects by binding to the CB1 and serotonin receptors respectively (Pacher 2006). They have been found to be effective in treating both acute and anticipatory nausea — the latter being notoriously difficult to treat, and for which no FDA-approved medications are currently available. Additionally, CBDA (Rock 2016) and THCA (Rock 2013) have both been demonstrated to be effective, more potent than CBD and THC, and non-psychoactive (Rock 2016, Bolognini 2013, Rock 2020), again making them excellent options for daytime use.

 

Constipation & Diarrhea

The endocannabinoid system has been identified throughout the gastrointestinal tract and is an integral part of the brain-gut axis (Sharkey 2016) thereby mediating various physiological bowel activities including motility, inflammation, healing, and fibrosis (Camilleri 2018, Hasenoehrl 2016). Because the purpose of the endocannabinoid system is to promote balance, cannabis can uniquely treat both the constipation that accompanies opioid use as well as the diarrhea that characterizes opioid withdrawal syndrome. Cannabis has been shown to

 

alleviate both constipation or diarrhea associated with irritable bowel syndrome, a presumptive clinical endocannabinoid deficiency syndrome (Russo 2016). THC also positively alters the gut microbiome (Kelly 2015, Zhu 2014) which impacts these disorders as well. Multiple receptor signaling pathways are certainly involved, including acetylcholine, estrogen, prostaglandin, and purine receptors (Huang 2018), which are targeted by cannabis compounds such as CBD.

 

Anxiety & Depression (common sides effect of opioid addiction and withdrawal)

It has been proposed (Hill 2005) that an endocannabinoid deficiency may underlie some of the symptoms of melancholic depression, and that supplementation of the endocannabinoid system with phytocannabinoids from the plant may ultimately be a novel form of pharmacotherapy for treatment-resistant depression. Studies have shown that pharmacological and genetic blockade of the cannabinoid CB 1 receptor induce a state that is analogous to melancholic depression, including symptoms such as reduced food intake, heightened anxiety, increased arousal, wakefulness, deficits in extinction of aversive memories, supersensitivity to stress and suicidal thoughts.

 

The similarities between melancholic depression and an endocannabinoid deficiency are quite interesting in light of findings (Haj-Dahmane 2014, Dinan 2005) that the body’s endocannabinoid activity in serotonergic neurons associated with depression and anxiety is down-regulated by chronic stress and possibly increased by some antidepressants. Research

(Abush 2013, Ganon-Elazar 2012, Ganon-Elazar 2009, Ramot 2012) is showing that cannabinoid administration can prevent as well as normalize problems associated with depression and anxiety, such as reduced brain plasticity, cognitive deficits in learning and memory, and elevated stress hormone levels. Chronic cannabinoid exposure was also shown (Bortolato 2007, Macri 2004) to enhance stress coping responses and to exert long-term antidepressant effects.

 

Some of the strongest evidence of the role the cannabinoid CB1 receptor plays in depression, anxiety and other problems associated with opioid addiction came from clinical trials (Moreira 2009) conducted in the development of a French weight loss medication called rimonabant (trade name: Acomplia), which was approved for use in much of the world in 2006, though not in the US. Rimonabant effectively helped people lose weight (Després 2005) by antagonizing cannabinoid CB1 receptors in the brain, where they stimulate appetite, and peripherally in adipose tissue (fat cells) where activation of CB1 receptors induces lipogenesis and fat storage

 

(Silvestri 2013). Unfortunately, by blocking the CB1 receptor in the brain, rimonabant caused depression and anxiety in 10% of patients and suicidal thoughts in 1%, leading to its removal from the market in 2008. Other adverse side effects, such as pain, nausea and vomiting, diarrhea and sleep problems confirm the role of the cannabinoid CB1 receptor and therapeutic mechanism of THC in those physiological systems involved in opioid withdrawal as well.

 

What is particularly fascinating and timely regarding rimonabant is that a group of French physicians and scientists are advocating (Briand-Mésange 2020) for the return of rimonabant to treat COVID-19 in the sickest patients admitted to the ICU, who are obese in an effort to prevent severe complications and death. A recent study (Simonnet 2020), identified obesity as a powerful independent risk factor for severe COVID-19 due to its adverse effects on lung physiology, induction of hazardous comorbidities such as diabetes and hypertension, but perhaps most importantly because the inflammatory state accompanying obesity may represent a ticking time bomb contributing to the life-threatening cytokine storm (Guzik 2020) observed in COVID-19 and characterized by acute respiratory distress syndrome and multiorgan failure. CB1 blockade, similar to that of rimonabant, was shown to reduce pulmonary inflammation in at least two different preclinical models (Johnson 2015, Cinar 2017).

 

THC produces anxiolytic (anti-anxiety) and mood elevating effects by binding to the CB1 receptor. CB1 receptors are particularly dense in the areas of the brain associated with anxiety: the amygdala, hippocampus, and prefrontal cortex. Caution in using THC is important however, because cannabinoids that bind to CB1, like THC, are known to be “biphasic”, meaning that low doses of THC (e.g. < 5 mg) increase serotonin and have potent antidepressant and anxiolytic effects, whereas high doses decrease serotonin and worsen depression and anxiety and can even cause panic attacks and paranoia (Rey 2012, Bambico 2007).

 

CBD exerts its anxiolytic and antidepressant effects by binding to dopamine and serotonin receptors in the hippocampus and prefrontal cortex of the brain (Zanelati 2010). As mentioned above, CBD also has an indirect effect on CB1 receptors by inhibiting the breakdown of the endocannabinoid anandamide made by our bodies. Accumulating increased amounts of anandamide available to bind to CB1 receptors in the brain produces mildly uplifting effects similar to therapeutic low doses of THC.

 

CBD is considered the best choice for anxiety (Liu 2015) and works particularly well during the day due to its nonintoxicating nature. Combinations of CBD and THC can also be an excellent option, because they are synergistic, meaning they help each other work better together.

Additionally, CBD impacts the way in which THC binds to the cannabinoid receptors tempering the effects of THC, including its psychoactivity. The strongest research evidence (Bambico 2008, Hillar 2014, Micale 2013, Zanelati 2010) supporting the use of cannabinoids to treat depression comes from rodent models, which demonstrate that THC and CBD consistently give the same results as common antidepressants with fewer adverse side effects.

 

The minor cannabinoid CBG (cannabigerol) also shows promise and deserves further study. CBG, like CBD, owes its antidepressant effects (Musty 2006) most likely to its ability to strongly bind to a serotonin receptor (Cascio 2010). An extract of another minor cannabinoid, CBC (cannabichromene), displayed pronounced antidepressant effects in rodent models (Deyo 2003).

 

Terpenoids can also positively affect anxiety and depression. Linalool contributes to the calming, sedating and uplifting effects of cannabis by modulating glutamate and GABA neurotransmitter systems (Nunes 2010). In two randomized, double-blind (Araj-Khodaei 2020), placebo-controlled (Akhondzadeh 2003) human clinical trials linalool was found to significantly improve mild to moderate depression. In the more recent study (Araj-Khodaei 2020), the mood elevating effect of linalool was similar to that of the SSRI antidepressant fluoxetine (trade name: Prozac) with a quicker onset and fewer adverse side effects.

 

Limonene is commonly known as the antidepressant terpene but can also relieve anxiety exerting these effects by binding to serotonin and glutamate NMDA receptors respectively (López 2017). In a compelling human clinical trial (Komori 1995), 12 hospitalized depressed patients were exposed to citrus fragrance in the ambient air. This olfactory administration of limonene resulted in an ability to markedly reduce doses of antidepressants and successfully discontinue these medications in 9 of 12 patients. Abnormal depression in neuroendocrine hormone levels and immune function associated with psychiatric disorders normalized, and limonene was stated to be more effective than antidepressants. Anxiolytic and sedative effects have also been demonstrated (Buchbauer 1991, Buchbauer 1993) with α-terpineol.

 

Sleep

The endocannabinoid system has been shown to play a key role in the modulation of the sleep- wake cycle in rats (Mendez-Diaz 2013, Pava 2014), and this is felt to be true in humans as well. While THC can initially be stimulating, its metabolites acting on the CB1 receptor are more sedative. To allow time for this metabolism and to avoid known impairments in slow-wave sleep and dreaming (Monti 2021), I recommended that cannabis be taken 3-4 hours before bed. If nightmares are a problem, as in cases of PTSD, take cannabis about 1 hour before bed.

Vaporization can be a reasonable option for medication delivery when one’s primary problem is in falling asleep, though vaping on waking in the middle of the night can also be appropriate as long as it occurs more than 2 hours before wake up time. Start with a single 2 second inhalation, which will contain about 2 mg of THC depending on potency, is around the threshold at which most people will start to feel the dose. The effects are almost immediate, with THC levels measurable in the blood within 5 seconds of inhalation. There is no need to inhale deeply or hold the cannabis vapors in the lungs longer than 3 seconds, as prolonged exposure may be potentially harmful over time. To more fully appreciate the effects of that amount of cannabis and to more precisely titrate the dose the medication, wait 5-10 minutes before taking another puff if needed.

 

I never recommend smoking cannabis because combustion creates about 1500 new compounds, some of which are noxious and linked to pulmonary disease and cancer in tobacco smokers (Moir 2008). Second-hand cannabis smoke exposes others to these same toxic chemicals, some of which actually occur in higher concentrations in cannabis smoke (Padilla 2015), and bystanders can easily become intoxicated by the THC. Detectable levels of cannabis metabolites have been found in children exposed to second-hand cannabis smoke (Wilson 2017, Cone 2015). Also, smoking burns through potentially important cannabinoids and terpenes, so they never get from the plant to the patient (Pomahacova 2009). Furthermore, smoking is inefficient, destroying up to 70% of cannabis THC through pyrolysis (Dussy 2005) with additional losses via sidestream smoke leading to a bioavailability of only 10–27% (Heustis 1992), increasing the cost of the medication borne by the patient. Finally, smoking is indiscreet and can be socially unacceptable because of the strong aroma.

 

The effects of orally administered cannabis last about twice as long as vaping — usually 5-8 hours, and the onset of action in the majority of patients is 30-90 minutes (Backes 2017).

However, a study (Leweke 2008) of oral cannabis showed a very wide variety of patient

 

responses in the rate of absorption, physical effects and efficiency of metabolism. Oral ingestion has been suggested (Backes 2017) as a way to improve the soporific (sleep inducing) and analgesic effects of THC. The primary risk of oral cannabis consumption is overmedication, which can cause patients to experience frightening levels of psychoactivity and anxiety. Too much THC is no fun for anyone, so it is imperative to “start low and go slow”. Begin by taking no more than 2.5-5 mg of THC and waiting at least 90 minutes before taking more if a higher dose is necessary.

 

CBD is regarded as wake-promoting. However, it addresses the two most prominent secondary causes of insomnia by helping to relieve anxiety and pain, making it easier for many people to relax, fall asleep and stay asleep. THC can also help treat anxiety and pain, and it has been suggested that the ability of cannabis to improve sleep may have less to do with its hypnotic effects, and more to do with reducing the symptoms derailing good sleep (Russo 2011).

 

The strongest data on the effects of cannabis on sleep come from multiple Phase I-III studies (Russo 2007) involving over 2000 human subjects and over 1000 patient years of exposure to the pharmaceutical, purified oromucosal spray called nabiximols (trade name: Sativex), mentioned above in the section on Pain. Nabiximols is derived from the cannabis plant and has a balanced CBD:THC ratio of 1:1. Nabiximols demonstrated marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathy, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the beneficial effects of nabiximols for pain or sleep was reported.

 

A non-pharmaceutical whole plant cannabis preparation different from nabiximols but also containing a CBD:THC ratio of 1:1 was also shown to be effective in improving sleep and was well tolerated, likely in part due to CBD’s synergistic and moderating effects on THC (Suraey 2020). Cannabis is often more effective than pharmaceutical sedative-hypnotics and produces little or no residual sedation the next morning, unless the dose is too high. The safety profile of cannabis is superior to that of prescription medications, with much less potential for dependence or withdrawal. Cannabis does not cause rebound insomnia or anxiety when discontinued, and in contrast to other sleep medications, there is no risk of fatal overdose.

 

The minor cannabinoid CBN (cannabinol) has also been advocated for treating insomnia. CBN binds to the endocannabinoid CB1 and CB2 receptors (Pertwee 2008, Marcu 2016), and some studies (Musty 1976, Karniol 1975, Yoshida 1995, Usami 1998, Takahashi 1975) have shown CBN to be the most sedative of the cannabinoids. An advantage of CBN is that it can help make people feel sleepy without intoxication. It produces significantly greater hypnotic effects when combined with THC (Musty 1976) and possibly CBD, with which it is commonly paired in 3:1 ratio in tinctures available by mail order via the internet.

 

Multiple terpenoids have demonstrated sedating effects and three have been specifically recommended to help with sleep (Russo 2011). β-Myrcene is known to be strongly sedating when combined with THC and can facilitate sleep. In a study of mice, exposure to β-myrcene was shown to improve the time required to fall asleep and duration of sleep (Gurgel do Vale 2002). Inhalation of linalool was found to be sedating and to improve sleep in other murine (mouse) models (Buchbauer 1991, Linck 2009). It has been proposed (Nunes 2010) that the sedating and anxiolytic properties of linalool are likely due to modulation of glutamate and GABA neurotransmitter systems. α-Terpineol has also been associated (Buchbauer 1993, Buchbauer 1991) with sedation and improved sleep.

 

Cannabis Impact on Addiction

Reward & Craving

Stimulation of the endocannabinoid system promotes release of dopamine in reward areas of the brain, such as the nucleus accumbens, by mediating aspects of reinforced behavior, including motivation, incentive salience (craving), and cost-benefit calculations. However, research (Wenzel 2018) suggests that endogenous opioid signaling underlies hedonic (pleasurable) aspects of reward, demonstrating that the endocannabinoid and endogenous opioid systems interact to support reward by augmenting dopamine release.

 

Prior to human clinical trials demonstrating the ability of CBD to suppress craving mentioned below in the list of ways cannabis can be a solution 4. OPIOID CRISIS: Cannabis Eases Opioid Cessation, similar results were seen in a study (Ren 2009) of rats capable of self-administering intravenous heroin. When these heroin addicted rats were given CBD, heroin-seeking behavior (craving) triggered by exposure to a heroin-specific stimulus cue were observed to be attenuated. CBD had a significant protracted effect after 24 hours and even 2 weeks following administration. The

 

behavioral effects were paralleled by alterations in the glutamatergic and endocannabinoid systems observed in the nucleus accumbens area of the brain associated with stimulus cue- induced heroin seeking that were normalized by CBD treatment. No physical side effects were noted.

 

In a more recent “anti-relapse” study (Gonzalez-Cuevas 2018), alcoholic rats received transdermal CBD applied to their skin daily for 7 days. CBD attenuated cue-induced and stress- induced drug seeking (craving) without producing tolerance, sedative effects, or interference with normally motivated behavior. Following treatment, relapse remained lower for about 5 months even though plasma and brain CBD levels were detectable for only 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity, both of which are intimately related to relapse. The results support the potential of CBD to prevent relapse along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment.

 

Linalool has also been mentioned above for its beneficial effects combating pain, anxiety, depression and sleep problems, which commonly impede recovery from opioid withdrawal and addiction. Potentially even more helpful, a preclinical study (Pourtaqi 2017) showed that linalool may directly help fight addiction by reducing the rewarding effects of morphine and opioid craving.

 

Likewise, more important than just treating pain and inflammation, evidence suggests that ß-caryophyllene may actually help people kick the habit. In a human clinical trial (Rose 1994), 48 cigarette smokers inhaled vapors from an essential oil of black pepper, a mint-menthol mixture or placebo. Black pepper reduced nicotine craving significantly, presumably due to the fact that black pepper is rich in ß-caryophyllene. ß-Caryophyllene strongly binds to the endocannabinoid CB2 receptor and represents a newly discovered putative mechanism of action in addiction treatment (Russo 2011).

 

CB2 receptors are present in neurons responsive to dopamine, the pleasure chemical associated with the brain’s reward system. CB2 receptors are concentrated in areas of the brain associated with addiction, such as the nucleus accumbens and ventral trigeminal area. This was demonstrated in a study of cocaine-addicted rats (Xi 2010), who were given a synthetic research

 

chemical analogous to ß-caryophyllene that activates the CB2 receptor. When this ß- caryophyllene-like substance was administered either by IV catheter into the bloodstream of the rats, inhaled through their little rat noses or by microinjection directly into the addiction areas of the rat brain, it inhibited dopamine release and cocaine self-administration by the rats. ß- Caryophyllene present in cannabis, as a high-potency CB2 receptor activator (Gertsch 2008), should produce similar anti-addiction effects, and has the advantage of being non-toxic and non- psychoactive.

 

Tolerance

Different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. THC is known to be rewarding, and produce tolerance (D’Souza 2008, Hart 2001, Jones 1981, Ramaekers 2009) and addiction. Animal research (Pistis et al. 2004) suggests that tolerance to the effects of THC may lead to cross-tolerance for other drugs including morphine, cocaine, and amphetamine, though cross-tolerance to alcohol in humans has been disproven (Ramaekers 2011).

 

CBD by contrast, is non-intoxicating and appears to have low reinforcing properties with negligible potential for abuse and addiction, and to actually inhibit drug-seeking behavior (Hurd 2015). The physiological explanation for this is similar to that of opioids, as mentioned above. Prolonged use of THC downregulates the endocannabinoid system by reducing production of endocannabinoids and cannabinoid receptors (González 2005). The body decides that if a lot of phytocannabinoids supplied from outside the body are binding to its cannabinoid receptors, it doesn’t need to invest in the system. This causes cannabis users to rely on increasing amounts of cannabis to mimic the actions of the down-regulated endocannabinoid system, leading to tolerance, increased risk of abuse and addiction. CBD is not plagued by these risks and does not hinder the endocannabinoid system, because CBD associates with many other receptor systems in the body and has limited interaction with cannabinoid receptors. Studies (Hayakawa 2007, Hayakawa 2010) indicate that tolerance can develop after repeated exposure to THC — but not CBD. In fact, CBD may produce reverse tolerance, meaning that over time less CBD is required to produce the desired effects.

 

A patient with an extremely high tolerance to the effects of cannabis may be able to withstand a dose of THC 100 times higher than a novice patient. A simple solution to this problem has been

 

elucidated by recent brain scan studies (D’Souza 2016) indicating that tolerance to the effects of cannabis as measured by CB1 receptor availability, previously shown (Hirvonen 2012) to require 28 days of abstinence for complete recovery, may be mostly reversed after just 2 days. This finding is important, because it demonstrates an easy method for patients who have developed tolerance to cannabis to dial back the amount they may need to produce a therapeutic effect, and decreasing the risks of adverse side effects, drug interactions and cannabis addiction, in addition to lowering the cost born by the patient due to medical cannabis not being covered by health insurance.

 

In studies of various animal models (Peana 2004, Peana 2006), linalool was found to play a major role in the reduction of tolerance and addiction induced by morphine probably due to several mechanisms including NMDA receptor inhibition, effects on nitrous oxide signaling and adenosine receptor stimulation.

 

Similar to linalool and ß-caryophyllene, the most exciting property of α-terpineol is that it may also help prevent a person using opioid pain relievers from developing an opioid addiction in the first place. Several mechanisms have been suggested to be involved in the development of tolerance and addiction to opioids (Kandel 2013). Findings from a recent study in mice (Parvardeh 2016) indicate that α-terpineol prevents the development of morphine- induced addiction and tolerance, and suggests these positive effects are due, at least in part, to α- terpineol’s ability to inhibit the overproduction of nitric oxide. Elevated levels of nitric oxide have been shown (Abdel-Zaher 2013, Vaupel 1997, Abdel-Zaher 2006, Abdel-Zaher 2010) to contribute to the development of morphine dependence and tolerance. Oxidative stress also appears to be involved in the development of dependence on and tolerance to opioids (Ozek 2003, Abdel-Zaher 2013), and evidence (El-Ghorab 2007, Bicas 2011) indicates that α-terpineol functions as a potent antioxidant. Finally, a third potential mechanism is that the preventive effects of the medicinal plant Stachys byzantina on morphine-induced dependence and tolerance (Hosseinzadeh 2008) likely arise from the neuroprotective effects of α-terpineol, a primary active constituent of S. byzantina (Mostafavi 2013).

 

Addiction

Cannabis use disorder is the medical term for what is essentially an addiction to THC, because THC is the primary compound in the cannabis plant that produces reinforcing, hedonic

 

(pleasurable) effects, reward and tolerance. Cannabis addiction rates are usually quoted as developing in about 9% of cannabis users (Lopez-Quintero 2011, Degenhardt 2013). This statistic may be a significant overestimation though, because anyone entering a court-ordered recovery program for a cannabis-related offense is automatically classified as having a cannabis use disorder regardless of whether they meet strict diagnostic criteria (Patel 2021) described in the Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-V). The overall cannabis addiction rate may actually be half the quoted number and under 5% (EMCDD 2015, Degenhardt 2013, Lemahieu 2020), though the rate is certainly higher in groups such as daily and high dose cannabis consumers (Volkow 2014). Regardless, the addiction rate for cannabis is much lower than that of other addictive drugs, such as tobacco at 68%, alcohol at 23%, cocaine at 21% (Lopez-Quintero 2011), heroin at 66% (SAMHSA 2017) and even coffee at up to 30%

(Hughes 1998).

 

Cannabis withdrawal syndrome is a criterion for cannabis use disorder and is defined in the DSM-V by the presence of symptoms such as irritability, anxiety, depression, decreased appetite and sleep difficulty, and physician signs such as abdominal pain, tremor, fever and headache.

Cannabis withdrawal is described as typically mild to moderately intense (Bonnet 2017), and not routine — about 12% of frequent cannabis users develop withdrawal (Livne 2019). Though less prevalent than has been claimed by many, cannabis addiction is real, and for this and other reasons, some people should not use THC — even if it may help them in some way.

Fortunately, the risk of developing cannabis addiction and withdrawal can be minimized by using low doses of THC (e.g. < 5-10 mg), or avoiding THC altogether in favor of effective, non- intoxicating alternative cannabinoids and terpenoids.

 

With that foundation, we are now ready to discuss the five evidence-based ways in which cannabis can help solve the opioid crisis.

 

1.     OPIOID CRISIS: Used Together with Cannabis, Opioids are Safer & More Effective

 

In a randomized, double-blind, crossover study (Roberts 2006) of an experimental model of thermal pain applied to the skin of healthy human volunteers, low doses of morphine and THC did not relieve the pain when used independently. However, the same low doses of each compound used in combination produced a significant synergistic analgesic effect. Similar

 

results were seen in another gold standard double-blind, placebo-controlled study (Cooper 2018) in which healthy volunteers were given low, subtherapeutic doses of oxycodone and THC. Pain relief was assessed by measuring how long participants could keep their hands in a bath of near freezing cold water. Neither the oxycodone nor the THC produced any analgesic effect when used on their own, but when used together, the same low doses showed significant improvement in their pain threshold and tolerance. The authors concluded “Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy”.

 

In a related study (Cox 2007) of low doses of morphine and THC in an arthritic rat model of mechanical and chronic inflammatory pain, a positive synergistic analgesic interaction was seen with the combination, but not when each medication was used independently. The combination was also noted to produce less opioid tolerance which would lead to less addiction.

 

Cannabis use with opioids can improve the depth and duration of pain relief and decrease opioid use, because the two medications when used together are synergistic and can effectively relieve pain despite each component being used at a lower dose (Babalonis 2020). Lower opioid doses are less likely to lead to opioid side effects, overdose and addiction. This further supports the view that combining cannabinoid and opioid receptor agonists for treating pain does not increase, and might decrease, the abuse liability of each individual drug (Li 2012). Human studies have also shown that cannabis use is not associated with increased opioid misuse (Azagba 2019) nor an increased risk of developing a prescription opioid addiction (Segura 2019).

 

The “opioid-sparing effect” of cannabinoids has been well described with extensive evidence showing synergy between cannabis and opioids that results in decreased opioid dose requirements (Abrams 2011, Nielsen 2017). CB1 receptors are 10 times more concentrated than opioid receptors in the brain, and cannabinoid receptors co-localize with opioid receptors on neurons in many regions involved in pain circuitry. This results in synergistic augmentation of the analgesic opioid effects and decreased opioid dose requirements (Abrams 2011, McGenney 2013, Bushlin 2010, Parolaro 2010, Welch 1992, Pugh 1996, Smith 1998, Cichewicz 2005,

Cichewicz 1999, Cichewicz 2004, Cichewicz 2003, Smith 2007). The binding of compounds to cannabinoid receptors stimulates the release of endogenous opioids, and chronic THC use promotes expression of endogenous opioid genes in structures involved in pain perception (Abrams 2011, Bushlin 2010, Russo 2008, Manzanares 1998).

 

 

A large meta-analysis (Nielsen 2017) showed that 17 of 19 preclinical studies evaluated provide good evidence of synergistic effects from opioid and cannabinoid co-administration, and that the median effective dose (ED50, the dose at which an effect is seen in at least half of the subjects) of morphine administered with THC is 3.6 times lower than the ED50 of morphine alone. The ED50 for codeine administered with THC was 9.5 times lower than the ED50 of codeine alone.

 

In an Italian hospital pain therapy unit clinical trial (Poli 2018) involving 328 patients with various chronic pain conditions for whom traditional pharmaceutical analgesics had been inadequate or intolerable, patients were given an oral dose of THC 5 mg daily, which was increased to 10 mg daily in most patients, for a total of 12 months, in addition to their standard pharmacological therapy. This low to moderate dose of THC was associated with a significant decrease in pain intensity, pain disability, and symptoms of anxiety and depression. Just under 10% of patients suspended therapy due to side effects, which consisted mainly of sleepiness and confusion.

 

The use of CBD alone has also been shown to be effective in enhancing the analgesic potential of opioids. In a study of 94 chronic pain patients who had been stable on opioids for at least 2 years, the patients added 2 soft gels containing 15 mg of hemp-derived CBD each to their usual daily pain relievers. By the 8 week follow up, 53% of patients had reduced or discontinued their opioid medications, despite many participants disclosing that they were hesitant to report any reduction in opioid use for fear of the potential consequences of limited prescription opioids. Additionally, several patients used fentanyl patches which rendered them unable to reduce their opioid intake, so the additional analgesic effect of the CBD was likely even greater than reported. Improved quality of life outcomes were measured on multiple indices in almost all (94%) patients. The introduction of CBD was also associated with significant improvement in sleep quality scores and scales of pain intensity and interference (Capano 2020).

 

Additional studies have shown significant improvement in pain symptoms by using CBD to augment the analgesic effects of opioids (Moeller-Bertram 2019, Iffland 2017). In animal models, CBD was shown to enhance the pain relieving effects of morphine by binding to supraspinal σ1 receptors which inhibits glutamate overactivity (Rodríguez-Muñoz 2018).

 

Furthermore, CBD was shown to be safe when used with opioids in a randomized, double-blind, placebo-controlled cross-over study of healthy volunteers, who were given oral gel caps containing a placebo, 400 mg or 800 mg of CBD prior to receiving intravenous low and high doses of fentanyl at a tertiary care medical center in New York City. The addition of CBD, even at these high doses, resulted in no significant changes in pharmacokinetics, kidney function, or multiple validated scales of mood and anxiety in addition to blood levels of the stress hormone cortisol. Vital signs remained stable throughout, and CBD did not potentiate the well-known tendency of opioids to impair heart and lung function — i.e. no respiratory depression or cardiovascular complications were observed in any subject at any point during the study (Manini 2015).

 

2.     OPIOID CRISIS: Cannabis can Replace Opioids in Treating Pain

 

Cannabis has the potential to help solve the opioid crisis in part because it can adequately and safely treat pain for many patients, making it a good substitute for opioids. People suffering from uncontrolled pain will, understandably, resume using opioids to obtain relief. Pain is the principle reason individuals report for purchasing cannabis from dispensaries nationwide (Kosiba 2019), and substituting cannabis for higher risk substances such as alcohol, illicit drugs, and prescription medications is common in surveys, suggesting a harm reduction role of their use (Lucas 2017 Int J Drug Policy, Lucas 2017 Harm Reduct J, Lucas 2016).

 

A comprehensive report by a committee of expert physicians and scientists working under the National Academy of Sciences, Engineering and Medicine published a document in 2017 entitled: The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research (NAS 2017). In the section on chronic pain, the authors systematically reviewed the published medical literature on the use of cannabis and concluded that: “There is substantial evidence that cannabis is an effective treatment for chronic pain in adults.”

 

The increasing evidence of cannabinoid efficacy in treating various types of pain has produced an excellent combined statistic known as the number needed to treat of 3.4 (Laupacis 1988), meaning a doctor need treat only 3.4 patients with cannabis in order to see a significant improvement in pain for 1 of them. This is better than aspirin or tramadol and similar to a 10 mg

 

intramuscular injection of morphine (Oxford 2007) and prompted the Canadian Pain Society to revise their consensus statement in 2014 to recommend cannabinoids for chronic neuropathic pain in particular (Moulin 2014).

 

Multiple clinical studies (Takakuwa 2020, Abuhasira 2018, Schleider 2018, Sagy 2019) have reported that the introduction of medical cannabis into patients’ treatment regimens effectively treated their pain and allowed up to 85% of patients to reduce or discontinue their use of opioids.

 

Finally, as mentioned in the discussion of Pain in the Effects of Cannabis on the Human Body section, the synergistic combination of CBD and THC, particularly in a 1:1 ratio, can effectively treat a wide variety of types of pain, even when opioids have been insufficient. Three gold standard double-blind, placebo-controlled human clinical trials of nabiximols (trade name: Sativex; Johnson 2010, Portenoy 2012, Wilsey 2013) demonstrated that combining THC and CBD improves relief of resistant pain, and that low doses of THC in combination with CBD can provide analgesia superior to that of high doses while posing a lower risk of adverse side effects, tolerance and addiction, and little to no intoxication.

 

3.    OPIOID CRISIS: Cannabis Enhances Opioid Addiction Medications

 

There are 2 main categories of medical treatment for opioid addiction: opioid agonists, and opioid antagonists. Opioid agonist maintenance treatment with less euphoric opioids that prevent craving and withdrawal, such as methadone (trade names: Methadose, and Dolophine) and buprenorphine (trade name: Subutex, or Suboxone when combined with naloxone), is a time- honored and effective approach to managing opioid dependence in some patients. However, about ½ of addicts will continue using problem opioids while in treatment, or drop out during the first 6 months (Mattick 2014, Soyka 2008). Methadone must be administered under supervision daily only at specialized opioid treatment programs routinely plagued by long waiting lists, and buprenorphine administration requires that trained healthcare providers be granted specialized certification and approval (DHHS 2004).

 

Treatment with the opioid receptor antagonist naltrexone (trade name: Vivitrol) is an alternative treatment approach. In patients who are able to initiate naltrexone, their overall effectiveness is comparable to opioid agonists with regards to treatment retention (50–70%) with lower rates of

 

ongoing opioid use (Bisaga 2014, Brooks 2010, Comer 2006, Krupitsky 2011). The challenge with naltrexone, however, is that initiation during detoxification is associated with significant withdrawal symptoms. The alternative is to wait for 7–10 days post-detoxification before administering naltrexone, but this approach results in high rates of relapse. A brief course of buprenorphine, followed by non-opioid medications can help ease withdrawal symptoms (Sigmon 2012). Unfortunately, buprenorphine can actually cause withdrawal in opioid addicts who are not experiencing any withdrawal symptoms (Wesson 2003). In some patients, withdrawal can still be severe after 3 weeks, further limiting naltrexone’s acceptability and adherence. With both of these treatment options, cannabis can ease detoxification and improve success.

 

A prospective human cohort study (Socias 2018) of opioid addicts initiating methadone or buprenorphine/naloxone-based opioid agonist treatment reported that the group using cannabis daily was associated with over 20% greater odds of retention in treatment compared with the group consuming cannabis less frequently and the non-cannabis group.

 

A randomized, double-blind, placebo-controlled human trial (Bisaga 2015) found that dronabinol (trade name: Marinol), a synthetic form of THC, reduced the severity of opiate withdrawal

during inpatient detoxification and naltrexone induction. The of addicts who smoked cannabis regularly during the outpatient phase had significantly less insomnia and anxiety and were more likely to complete the 8-week naltrexone trial.

 

Another randomized controlled human trial (Raby 2009) of opioid addicts admitted for inpatient detoxification and naltrexone induction found that intermittent cannabis users showed superior retention in naltrexone treatment compared to abstinent or heavy users.

 

Finally, a human study (Church 2001) of opiate addicts who received a 6-month course of outpatient treatment with naltrexone and cognitive-behavioral therapy reported that the use of non-opiate drugs (including cannabis) is common during treatment and that patients who used intermittently had superior outcomes compared to both abstinent and heavy use groups as measured by opiate-positive urines, days retained in treatment, and proportion of naltrexone doses taken. The authors concluded the data may support a “harm reduction” approach as opposed to a strict abstinence-oriented approach.

 

 

Additional studies (Seivewright 2003, Weizman 2004, Nava 2007) report that cannabis use does not negatively affect methadone treatment outcomes, nor does it lead to heroin resumption.

 

  1.     OPIOID CRISIS: Cannabis Eases Opioid Cessation

 

Unfortunately, medically assisted treatment is often simply not available, which explains why in the United States fewer than 25 percent of opioid addicts receive any form of treatment (DHHS 2004). Kicking the habit is daunting but not impossible, and evidence suggests cannabis can help. In a study (Noble 2002) of 114 heroin addicts attending a methadone maintenance clinic in London, a majority (58%) reported previously attempting to detoxify themselves from opiates without medical assistance an average of 3.6 times each. Most of these patients (61%) reported attempting self-detoxification with the help of non-standard treatment drugs: primarily diazepam in 43%, alcohol in 25%, and cannabis in 22% of the cases, resulting in moderate short-term success in abstaining from heroin for at least 24 hours in 41% of addicts.

 

Opioid addiction is not only difficult to overcome in the short term but is a classically chronically relapsing condition — validating the recovery axiom, “once an addict, always an addict”. The risk of relapse persists for multiple reasons including craving induced by drug cues, susceptibility to stress, elevated anxiety, and impaired impulse control. Promising clinical human research suggests that CBD may specifically address relapse-related issues safely and free from intoxication and the ominous risks of sedation, respiratory suppression and death in overdose associated with commonly used alternatives, such as the opioid agonists methadone and buprenorphine, benzodiazepines such as diazepam and alcohol.

 

In a powerful randomized, double-blind, placebo-controlled human trial (Hurd 2019), high dose oral CBD (400 mg and 800 mg of Epidiolex, the pharmaceutical form of purified CBD isolated from cannabis approved by the FDA in 2018 for the treatment of complex resistant seizures in children) was given to newly abstinent heroin addicts. Hurd and colleagues reported that CBD was associated with reduced craving and anxiety induced by drug cues as measured by standard, validated assessments, vital signs and salivary levels of the stress hormone cortisol. Surprisingly, although CBD was administered for only 3 days, these positive effects lasted for at least 7 days.

 

This is important because withdrawal is over within 7 days for many addicts. This protracted effect of CBD would have significant clinical implications, especially for patient populations in which daily medication adherence may be challenging. Furthermore, even these high doses of CBD produced no serious adverse effects or impact on cognition (i.e. thinking).

Addicts taking CBD remain sober, fully functional and able to actively participate in all aspects of abstinence-based recovery programs. Longer courses of CBD treatment should be studied in patients still in withdrawal after 7 days.

 

In a previous smaller randomized, double-blind, placebo-controlled human clinical trial by the same authors (Hurd 2015), opioid-dependent subjects who had been abstinent for at least a week were given a single dose of CBD or placebo. Cue-induced craving test sessions, opioid-related and neutral video cues were presented initially 1 hour after the single CBD/placebo administration, 24 hours, and 7 days later. The results showed that a single administration of CBD consistently attenuated cue-induced craving for 7 days. Interestingly, as in other studies, CBD resulted in reduced anxiety measures, suggesting again that the ability of CBD to reduce negative states in opioid addicts, may contribute to reduced craving and likelihood of relapse.

 

5.    OPIOID CRISIS: Cannabis Treats Other Problems Encountered When Stopping Opioids

 

When addicts face the horrors of opioid withdrawal knowing their suffering will stop instantly if they resume using opioids — they will start using again. A powerful way in which cannabis helps maintain sobriety is by treating or preventing the problems that occur when one quits.

Many of the most prominent and miserable features of opioid withdrawal can be alleviated with the medical use of cannabis, such as refractory pain, nausea and vomiting, diarrhea, anxiety, depression and poor sleep. Clinical research has shown cannabis to be as effective as and safer many standard pharmaceutical medications including opioids for pain (Oxford 2007, Manzanarez 2006), metoclopramide (trade name: Reglan) and ondansetron (trade name: Zofran) for nausea and vomiting (Tramer 2001, Zikos 2020), senna (trade names: Ex-Lax, Senokot) for constipation (Zhong 2019), paroxetine (trade name: Paxil) for anxiety (Nordahl 2016, Masataka 2019), commonly used antidepressants (Bambico 2008, Hillard 2014, Micale 2013, Zancloti 2010), and diazepam (trade name: Valium) for sleep (Hartley 2019). A review of the medical

 

literature is available in the National Academy of Sciences report (NAS 2017). A link to the free download page is included in the References section.

 

SUMMARY: 10 steps for using cannabis to get off opioids

The following recommendations are based on the scientific evidence presented above, my clinical experience with opioid addicted patients, and a validated protocol developed by leading cannabis physician, Dr. Dustin Sulak. A published study (Takakuwa 2020) surveying 525 patients using prescription opioids for chronic pain at 3 of Dr. Sulak’s affiliated medical cannabis clinics found that the therapeutic use of cannabis allowed 40% of patients to stop using opioids completely and another 45% to reduce their opioid dose. The introduction of medical cannabis was associated with reductions in pain of 40-100% in about half of patients and enhanced function of the affected area in 80%, leading to improved quality of life reported by 87% of patients. Additional resources for those addicted to opioids are available at Dr. Sulak’s website: https://healer.com/category/cannabis-and-opioids/

 

  1.   As a baseline, use a sublingual cannabis tincture with a balanced CBD:THC ratio of 1:1. This is usually broadly effective and well tolerated, with a rapid onset (5-15 minutes) and longer duration of effect (4-6 hours). Incorporation of other cannabinoids, such as THCA, CBDA, CBG, CBC and CBN, and terpenes, such as ß-caryophyllene, linalool, β- myrcene, limonene and α-terpineol can help but complicate treatment. I recommend consulting an experienced cannabis clinician to formulate a personalized treatment regimen and adjust dosing to best meet your specific needs.

 

  1.   Optimal dosing can be challenging. For example, I recommend that older adults and patients who have never been exposed to cannabis or tend to be sensitive to medications start with a low dose of 1 mg of both CBD and THC in a tincture held under the tongue for about 1 minute, 3 to 4 times daily or with each dose of an opioid drug. This dose is non-psychoactive but can be effective for some patients.

 

  1.   To find your optimal dose, increase the amount of CBD and THC by 1 mg everyday as needed until you see improvement, such as pain relief or decreased anxiety. The optimal THC dose for most patients is typically between 2 and 15 mg, though a few may require

 

higher doses.

 

 

  1.   If a dose stops working (tolerance) or produces adverse side effects, such as lightheadedness or confusion, you have likely overshot your optimal dose. Pausing your use of THC for as little as 2 days, in a “tolerance break”, can help make your optimal dose effective again. See Tolerance & Addiction in the section on Cannabis Impact on Addiction.

 

  1.   For immediate relief of breakthrough pain or craving, vaporize cannabis flowers rather than oils in order to make use of cannabinoids and terpenes that can be lost in the extraction process. Take one puff every 5 to 10 minutes as needed.

 

  1.   Discuss your plan to use cannabis to help you decrease or stop using opioids with your healthcare provider. Providing them with this article may be helpful. Note: The CDC recommends against testing for THC in patients prescribed opioids for chronic pain (Dowell 2016).

 

  1.   In my experience, once most patients begin using cannabis, they can gradually decrease their opioid use ultimately by at least 50%, and many can stop using opioids completely, as in Rico’s case and studies described above. However, tapering opioids should be done under the direction of a healthcare provider.

 

  1.   Consult an experienced medical cannabis clinician to guide your use of cannabis in order to make the process as smooth as possible and maximize your likelihood of success. I am happy to help and can be reached through my website: www.DrDanCannabis.com

 

  1.   If you are sensitive to THC, use a tincture with a higher CBD:THC ratio of 4:1 or greater to decrease unwanted effects. For sleep, use a combination of CBN and THC, or CBN:CBD in a 1:3 ratio. See Sleep in the section on Cannabis Effects on the Human Body.

 

NOTE: Only use cannabis purchased from a licensed dispensary that is tested by an independent laboratory for harmful contaminants.

 

  1. Cannabis is most effective when used as part of a comprehensive recovery program that includes counseling, support groups, meditation, exercise, non-opioid medications, etc.

References

  • Abdelfatah R, et al. Looking back at jazz singer Billie Holiday’s influence on American music. National Public Radio 2019. Last accessed March 6, 2021: https://www.npr.org/2019/08/22/753493982/looking-back-at-jazz-singer-billie-holidays-influence-on-american- music
  • Abrams D, et al. Cannabis in cancer care. Clin Pharmacol Ther 2015; 97(6):575-586.
  • Abrams D, et al. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 2011; 90(6):844-851.
  •  Abuhasira R, et al. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. Eur J Intern Med 2018; 49:44-50.
  • Ahmad Z, et al. Comparison of fatal recreational drug overdoses between celebrities and non-celebrities. STEM Fellowship Journal 2020; 6(1):1-7e.
  • Akhondzadeh S, et al. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression: A double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27(1):123-127.
  •  Anslinger H. Organized protection against organized predatory crime—Peddling of narcotic drugs. J Crim L & Criminology 1933; 24(3):636-654.
  •  Araj-Khodaei M, et al. A double-blind, randomized pilot study for comparison of Melissa officinalis L. and Lavandula angustifolia Mill. with fluoxetine for the treatment of depression. BMC Complement Med Ther 2020; 20:207.
  •  Arnold J, et al. WHO Expert committee on drug dependence pre-review: Δ-9-tetrahydrocannabinol, Section 3: Toxicology. World Health Organization 2018. Last accessed March 6, 2021: https://www.who.int/medicines/access/controlled-substances/Section3-thc-Toxicology.pdf?ua=1
  • Azagba S, et al. Trends in opioid misuse among marijuana users and non-users in the U.S. from 2007-2017. Int J Environ Res Public Health 2019; 16(22):4585.
  •  Babalonis S, et al. Therapeutic potential of opioid/cannabinoid combinations in humans: Review of the evidence. Eur Neuropsychopharmacol 2020;36:206-216.
  •  Bachhuber M, et al. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010.
  • JAMA Intern Med 2014; 174(10):1668-1673.
  • Backes M. Cannabis pharmacy: The practical guide to medical marijuana. New York: Black Dog & Leventhal Publishers 2017. 320 pages.
  • Bambico F, et al. The cannabinoid CB1 receptor and the endocannabinoid anandamide: Possible antidepressant targets. Expert Opin Ther Targets 2008; 12(11):1347-1366.
  • Banta-Green C, et al. Opioid use behaviors, mental health and pain—development of a typology of chronic pain patients. Drug Alcohol Depend 2009; 104(1-2):34-42.
  • Barnes J. The medical and surgical history of the Civil War, Vol 4. Wilmington, NC: Broadfoot Publishing Company 1992.
  • Baron E. Medicinal properties of cannabinoids, terpenes, and flavonoids in cannabis, and benefits in migraine, headache, and pain: An update on current evidence and cannabis science. Headache 2018; 58(7):1139-1186.
  • Barrett M, et al. Isolation from Cannabis sativa L. of cannflavin—a novel inhibitor of prostaglandin production.
  • Biochemical Pharmacology 1985; 34(11):2019-2024.
  • Batista P, et al. Evidence for the involvement of ionotropic glutamatergic receptors on the antinociceptive effect of (-)-linalool in mice. Neurosci Lett 2008; 440(3):299-303.
  • Berenbaum M. What is synergy? Pharmacol Rev 1989; 41(2):93-141.
  • Bird S, et al. Scotland’s National Naloxone Programme. Lancet 2019; 393(10169):316-318.
  • Bisaga A, et al. The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone. Drug Alcohol Depend 2015; 154:38-45.
  • Bisaga A, et al. A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence. J Subst Abuse Treat 2014; 46(5):546-552.
  • Bisogno T, et al. Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001; 134(4):845-852.
  • Bolognini D, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 2013; 168(6):1456-1470. 
  • Bonnet U, et al. The cannabis withdrawal syndrome: current insights. Subst Abuse Rehabil 2017; 8:9-37.
  • Bortolato M, et al. Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry 2007; 62(10):1103-1110.
  • Boscarino J, et al. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. Addiction 2010; 105(10):1776-1782.
  • Bradford A, et al. Association between US state medical cannabis laws and opioid prescribing in the Medicare Part D population. JAMA Intern Med 2018; 178(5):667-672.
  • Briand-Mésange F, et al. Possible role of adipose tissue and endocannabinoid system in COVID-19 pathogenesis: Can rimonabant return? Obesity 2020; 28(9):1580-1581.
  • Brooks A, et al. Long-acting injectable versus oral naltrexone maintenance therapy with psychosocial intervention for heroin dependence: A quasi-experiment. J Clin Psychiatry 2010; 71(10):1371-1378.
  • Buchbauer G, et al. Fragrance compounds and essential oils with sedative effects upon inhalation. J Pharm Sci 1993; 82(6):660-664.
  • Buchbauer G, et al. Aromatherapy: evidence for sedative effects of the essential oil of lavender after inhalation. Z Naturforsch C J Biosci 1991; 46(11-12):1067-1072.
  • Bushak L. Civilization’s painkiller: A brief history of opioids. Newsweek 2016. Last accessed March 6, 2021: https://www.newsweek.com/civilization-painkiller-brief-history-opioid-486164
  • Bushlin I, et al. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol 2010; 10(1):80-86. 
  • Cao M, et al. Effects of chronic opioid use on sleep and wake. Sleep Med Clin 2018; 13(2):271-281.
  • Camilleri M. Cannabinoids and gastrointestinal motility: Pharmacology, clinical effects, and potential therapeutics in humans. Neurogastroenterol Motil 2018; 30:e13370. 
  • Capano A, et al. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: A prospective cohort study. Postgraduate Medicine 2020; 132(1):56-61.
  • Cascio M, et al. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 2010; 159(1):129-141.
  • (CDC 2020 Heroin) Centers for Disease Control and Prevention. CDC website: Opioid overdose, Opioid basics, Heroin 2020. Last accessed March 6, 2021:
  • https://www.cdc.gov/drugoverdose/opioids/heroin.html 
  • (CDC 2020 COVID) Centers for Disease Control and Prevention. Overdose deaths accelerating during COVID-19, Expanded prevention efforts needed. Press release 2020. Last accessed March 6, 2021: https://www.cdc.gov/media/releases/2020/p1218-overdose-deaths-covid-19.html 
  • Chou R, et al. Opioid treatments for chronic pain. Comparative effectiveness review No. 229. AHRQ Publication No. 20-EHC011. Agency for Healthcare Research and Quality 2020. Last accessed March 6, 2021: https://www.ncbi.nlm.nih.gov/books/NBK556253/pdf/Bookshelf_NBK556253.pdf
  • Chou R, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel.
  • J Pain 2009; 10(2):113-130.
  • Chowdhuri S, et al. Sleep disordered breathing caused by chronic opioid use: Diverse manifestations and their management. Sleep Med Clin 2017; 12(4):573-586.
  • Church S, et al. Concurrent substance use and outcome in combined behavioral and naltrexone (trade name: Vivitrol) therapy for opiate dependence. J Drug Alcohol Abuse 2001; 27(3):441-452.
  • Cicero T, et al. The changing face of heroin use in the United States: A retrospective analysis of the past 50 years.
  • JAMA Psychiatry 2014; 71(7):821-826.
  • Cichewicz D, et al. Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal Δ 9- tetrahydrocannabinol. Eur J Pharmacol 2005; 525(1-3):74-82.
  • Cichewicz D. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci 2004; 74(11):1317-1324.
  • Cichewicz D, et al. Antinociceptive synergy between Δ 9-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther 2003; 304(3):1010-1015.
  • Cichewicz D, et al. Enhancement mu opioid antinociception by oral Δ 9-tetrahydrocannabinol: Dose-response analysis and receptor identification. J Pharmacol Exp Ther 1999; 289:859-867.
  • Cinar R, et al. Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis. JCI Insight 2017; 2(8):e92281.
  • Clayton R, et al. Reflections on 40 years of drug abuse research: Changes in the epidemiology of drug abuse.
  • Journal of Drug Issues 2009; 39(1):41-55.
  • Clendinning J. Observations on the medicinal properties of the Cannabis sativa of India. Med Chir Trans 1843; 26:188-210.
  • Comelli F, et al. Beneficial effects of a Cannabis sativa extract treatment on diabetes-induced neuropathy and oxidative stress. Phytother Res 2009; 23(12):1678-1684.
  • Comelli F, et al. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytother Res 2008; 22(8):1017-1024.
  • Comer S, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: A randomized, placebo-controlled trial. Arch Gen Psychiatry 2006; 63(2):210-218.
  • Cone E, et al. Nonsmoker exposure to secondhand cannabis smoke. III. Oral fluid and blood drug concentrations and corresponding subjective effects. J Anal Toxicol 2015; 39(7):497–509.
  • Cooper Z, et al. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability.
  • Neuropsychopharmacology 2018; 43(10):2046–2055.
  • Costa B, et al. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol 2007; 556(1-3):75-83.
  • Cox M, et al. Synergy between Δ 9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol 2007; 567(1-2):125-130.
  • Crothers T. Morphinism and narcomanias from other drugs: Their etiology, treatment, and medicolegal relations. Philadelphia: W. B. Saunders 1902. 351 pages.
  • D’Souza D, et al. Rapid changes in CB1 receptor availability in cannabis dependent males after abstinence from cannabis. Biol Psychiatry Cogn Neurosci Neuroimaging 2016; 1(1):60-67.
  • D’Souza D, et al. Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology 2008; 33(10):2505-2516.
  • Daubresse M, et al. Ambulatory diagnosis and treatment of nonmalignant pain in the United States, 2000-2010. Med Care 2013; 51(10):870–878.
  • Davis W, et al. Neurobehavioral actions of cannabichromene and interactions with Δ 9-tetrahydrocannabinol. Gen Pharmacol 1983; 14(2):247-252.
  • (DEA Fentanyl 2020) Drug Enforcement Administration. Drug Fact Sheet: Fentanyl 2020. U.S. Department of Justice. Last accessed March 6, 2021:
  • https://www.dea.gov/sites/default/files/2020-06/Fentanyl-2020_0.pdf
  • (DEA 2019 NDTA) 2019 National Drug Threat Assessment . Drug Enforcement Administration Strategic Intelligence Section, U.S. Department of Justice. Last accessed March 6, 2021: https://www.dea.gov/sites/default/ files/2020-01/2019-NDTA-final-01-14-2020_Low_Web-DIR-007-20_2019.pdf
  • Degenhardt L, et al. The global epidemiology and contribution of cannabis use and dependence to the global burden of disease: Results from the GBD 2010 study. PLoS One 2013; 8(10):e76635.
  • De Petrocellis L, et al. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 2008; 325(3):1007-1015.
  • Després J, et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353(20):2121-2134.
  • Deyo R, et al. A cannabichromene (CBC) extract alters behavioral despair on the mouse tail suspension test of depression. Proceedings 2003 Symposium on the Cannabinoids. International Cannabinoid Research Society: Cornwall, ON, p. 146.
  • (DHHS 2004) Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004.
  • Dhaliwal A, et al. Physiology, opioid receptor. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2020.
  • Dhawan K, et al. Reversal of morphine tolerance and dependence by Passiflora incarnata – A traditional medicine to combat morphine addiction. Pharmaceutical Biology 2002; 40(8):576-580.
  • Dietrich A, et al. Endocannabinoids and exercise. British Journal of Sports Medicine 2004; 38(5):536-541.
  • Dinan T. Stress: the shared common component in major mental illnesses. Eur Psychiatry 2005; 20(Suppl 3):S326-328.
  • Dowell D, et al. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA 2016; 315(15):1624-1645.
  • Dückelmann A, et al. When and how should peritoneal endometriosis be operated on in order to improve fertility rates and symptoms? The experience and outcomes of nearly 100 cases. Arch Gynecol Obstet 2021. Online ahead of print.
  • Dunn K, et al. Frequency and correlates of sleep disturbance in methadone and buprenorphine-maintained patients.
  • Addict Behav 2018; 76:8-14.
  • Dussy F, et al. Isolation of Δ 9-THCA-A from hemp and analytical aspects concerning the determination of Δ 9- THC in cannabis products. Forensic Sci Int 2005; 149(1):3-10.
  • (EMCDDA 2015) European Monitoring Centre for Drugs and Drug Addiction. 2015 European Drug Report: Trends and Developments. Lisbon: EMCDDA 2015.
  • Evans F. Cannabinoids: The separation of central from peripheral effects on a structural basis. Planta Med 1991; 57(S 1):S60-S67.
  • Fattori V, et al. Capsaicin: Current understanding of its mechanisms and therapy of pain and other pre-clinical and clinical uses. Molecules 2016; 21(7):844. 
  • Fine P, et al. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med J 2013; 4(4):e0022. 
  • Fleming M, et al. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain 2007; 8(7):573-582.
  • Formukong E, et al. Inhibition of A23187–induced release of leukotriene B4 in mouse whole blood Ex vivo and human polymorphonuclear cells in vitro by the cannabinoid analgesic cannabidiol. Phytother Res 1991; 5(6):258-261.
  • Formukong E, et al. Analgesic and antiinflammatory activity of constituents of Cannabis sativa L. Inflammation 1988; 12(4):361-371.
  • FRONTLINE. The Opium Kings 1998. PBS. Last accessed March 6, 2021: https://www.pbs.org/wgbh/pages/frontline/shows/heroin/etc/history.html
  • Fuss J, et al. A runner’s high depends on cannabinoid receptors in mice. PNAS 2015; 112:(42)13105-13108. 
  • Gable, R. Toward a comparative overview of dependence potential and acute toxicity of psychoactive substances used nonmedically. Am J Drug Alcohol Abuse 1993; 19(3):263-281.
  • Galaj E, et al. β-Caryophyllene inhibits cocaine addiction-related behavior by activation of PPARα and PPARγ: Repurposing a FDA-approved food additive for cocaine use disorder. Neuropsychopharmacology 2021; 46(4):860-870.
  • Galaj E, et al. Potential of cannabinoid receptor ligands as treatment for substance use disorders. CNS Drugs 2019; 33(10):1001-1030.
  • Gallily R, et al. Overcoming the bell-shaped dose-response of cannabidiol by using cannabis extract by using
  • Cannabis extract enriched in cannabidiol. Pharmacology & Pharmacy 2015; 6(2):75-85.
  • Ganon-Elazar E, et al. Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress. Neuropsychopharmacology 2012; 37(2):456-466.
  • Ganon-Elazar E, et al. Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance. J Neurosci 2009; 29(36):11078-11088.
  • Gattefossé R, et al. Gattefossé’s aromatherapy. Saffron Walden: C.W. Daniel 1993; 180 pages.
  • Ghelardini C, et al. Local anaesthetic activity of the essential oil of Lavandula angustifolia. Planta Med 1999; 65(8):700-703. 
  • Gladden R, et al. Fentanyl law enforcement submissions and increases in synthetic opioid-involved overdose deaths
  • —27 states, 2013-2014. MMWR Morb Mortal Wkly Rep 2016; 65(33):837-843.
  • González S, et al. Cannabinoid tolerance and dependence: a review of studies in laboratory animals. Pharmacol Biochem Behav 2005; 81(2):300-318.
  • Gonzalez-Cuevas G, et al. Unique treatment potential of cannabidiol for the prevention of relapse to drug use: Preclinical proof of principle. Neuropsychopharmacology 2018; 43(10):2036-2045.
  • Gorman J. “A perk of our evolution: Pleasure in pain of chilies”. New York Times (20 September 2010). 
  • Grant B, et al. Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry 2017; 74(9):911–923.
  • Gurgel do Vale T, et al. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown. Phytomedicine 2002; 9(8):709-714.
  • Guzik T, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020; 116(10):1666-1687.
  • Haj-Dahmane S, et al. Chronic stress impairs α1-adrenoceptor-induced endocannabinoid-dependent synaptic plasticity in the dorsal raphe nucleus. Journal of Neuroscience 2014; 34 (44) 14560-14570
  • Hampson A, et al. Cannabidiol and (-) Δ 9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 1998; 95(14):8268-8273. 
  • Hari J. “The Hunting of Billie Holiday”. Politico Magazine 2015. Last accessed March 6, 2021: https://www.politico.com/magazine/story/2015/01/drug-war-the-hunting-of-billie-holiday-114298/
  • Hart C, et al. Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology 2001; 25(5):757-65.
  • Hartley M. The ‘sleepy’ cannabinoid CBN might not actually be sedating. Leafly 2019. Last accessed March 6, 2021:
  • https://www.leafly.com/news/health/is-cbn-cannabinoid-sedating
  • Hasenoehrl C, et al. The gastrointestinal tract—A central organ of cannabinoid signaling in health and disease.
  • Neurogastroenterol Motil 2016; 28:1765–1780.
  • Haustein M, et al. Cannabinoids increase lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. Biochem Pharmacol 2014; 92(2):312-325.
  • Hayakawa K, et al. Therapeutic potential of non-psychotropic cannabidiol in ischemic stroke. Pharmaceuticals (Basel) 2010; 3(7):2197-2212.
  • Hayakawa K, et al. Repeated treatment with cannabidiol but not Δ 9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 2007; 52(4):1079-1087.
  • He Y, et al. β-Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents. Br J Pharmacol 2020; 177(9):2058-2072.
  • Herkenham M, et al. Cannabinoid receptor localization in brain. Proceedings of the National Academy of Sciences
  • 1990; 87(5):1932-1936.
  •  Hill M, et al. Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression?
  • Behav Pharmacol 2005; 16(5-6):333–352.
  • Hillard C, et al. Endocannabinoid signaling in the etiology and treatment of major depressive illness. Curr Pharm Des 2014; 20(23):3795-3811.
  • Hine B, et al. Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats. Res Commun Chem Pathol Pharmacol 1975; 12(1):185-188.
  • Hirvonen J, et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 2012; 17(6):642-649.
  • Hosseinzadeh H, et al. Effects of Stachys byzantina C. Koch aerial parts aqueous extract on morphine dependence and tolerance in mice. Pharmacologyonline 2008; 2:614-617.
  • Huang T, et al. Uncovering the mechanisms of Chinese herbal medicine (MaZiRenWan) for functional constipation by focused network pharmacology approach. Front Pharmacol 2018; 9:270.
  • Huestis M, et al. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol 1992; 16(5):276-282.
  • Hurd Y, et al. Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: A double-blind randomized placebo-controlled trial. Am J Psychiatry 2019; 176(11):911-922.
  • Hurd Y, et al. Early phase in the development of cannabidiol as a treatment for addiction: Opioid relapse takes initial center stage. Neurotherapeutics 2015; 12(4):807-815.
  • Iffland K, et al. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis Cannabinoid Res 2017; 2(1):139-154.
  • Inciardi J. The War on Drugs: Heroin, cocaine, crime, and public policy. Palo Alto: Mayfield Publishing Company 1986. p. 231. 
  • Jiang D, et al. [Advances in research of pharmacological effects and formulation studies of linalool]. Zhongguo Zhong Yao Za Zhi 2015; 40(18):3530-3533. 
  • Johnson A, et al. The intracerebroventricular injection of rimonabant inhibits systemic lipopolysaccharide-induced lung inflammation. J Neuroimmunol 2015; 286:16-24.
  •  Johnson J, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 2010; 39(2):167-179.
  • Jones C. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers — United States, 2002-2004 and 2008-2010. Drug Alcohol Depend 2013; 132(1-2):95-100.
  • Jones R, et al. Clinical relevance of cannabis tolerance and dependence. J Clin Pharmacol 1981; 21(S1):143S-152S. Karniol I, et al. Effects of Δ 9-tetrahydrocannabinol and cannabinol in man. Pharmacology 1975; 13(5):502-512.
  • Kelly C, et al. Update on fecal microbiota transplantation 2015: Indications, methodologies, mechanisms, and outlook. Gastroenterology 2015; 149:223–237.
  • Kim J, et al. Treatment with lavender aromatherapy in the post-anesthesia care unit reduces opioid requirements of morbidly obese patients undergoing laparoscopic adjustable gastric banding. Obes Surg 2007; 17(7):920-925.
  • Klauke A, et al. The cannabinoid CB2 receptor-selective phytocannabinoid β–caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. European Neuropsychopharmacology 2014; 24(4):608-620.
  • Knopf A. CBD may help prevent relapse in abstinent heroin addicts. Alcohol Drug Abuse Weekly 2019; 31(22):3-4.
  • Komori T, et al. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation
  • 1995; 2(3):174-180.
  • Kosiba J, et al. Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: Systematic review and meta-analysis. Soc Sci Med 2019; 233:181-192.
  • Kossen J. Cannabis and depression. Leafly 2016; Last accessed March 6, 2021: https://www.leafly.com/news/health/cannabis-and-depression
  • Kotwal, A. Innovation, diffusion and safety of a medical technology: A review of the literature on injection practice.
  • Social Science & Medicine 2005; 60(5):1133–1147.
  • Krupitsky E, et al. Injectable extended-release naltrexone for opioid dependence: A double-blind, placebo- controlled, multicentre randomised trial. Lancet 2011; 377(9776):1506-1513.
  • Lachenmeier D, et al. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Sci Rep 2015; 5:8126.
  • Lemahieu J, et al. The World Drug Report 2020. (United Nations publication, Sales No. E.20.XI.6). 
  • Li J, et al. Interactions between Δ 9-tetrahydrocannabinol and heroin: Self-administration in rhesus monkeys. Behav Pharmacol 2012; 23(8):754–761.
  • Linck V, et al. Inhaled linalool-induced sedation in mice. Phytomedicine 2009; 16:(4)303-307. 
  • Lipari R, et al. Key substance use and mental health indicators in the United States: Results from the 2018 National Survey on Drug Use and Health. Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration 2019. Last accessed March 6, 2021: https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHNationalFindingsReport2018/ NSDUHNationalFindingsReport2018.pdf
  • Liu B, et al. GPR55: From orphan to metabolic regulator? Pharmacol Ther 2015; 145:35-42.
  • Livne O, et al. DSM-5 cannabis withdrawal syndrome: Demographic and clinical correlates in U.S. adults. Drug Alcohol Depend 2019; 195:170-177. 
  • López V, et al. Exploring pharmacological mechanisms of lavender (Lavandula angustifolia) essential oil on central nervous system targets. Front Pharmacol 2017; 8:280.
  •  Lopez-Quintero C, et al. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 2011; 115(1-2):120-130.
  • Lucas P, et al. Medical cannabis access, use, and substitution for prescription opioids and other substances: A survey of authorized medical cannabis patients. Int J Drug Policy 2017; 42:30-35. 
  • Lucas P. Rationale for cannabis-based interventions in the opioid overdose crisis. Harm Reduct J 2017; 14(1):58.
  • Lucas P, et al. Substituting cannabis for prescription drugs, alcohol and other substances among medical cannabis patients: The impact of contextual factors. Drug Alcohol Rev 2016; 35(3):326-333. 
  • Lutz P, et al. Opioid receptors: Distinct roles in mood disorders. Trends Neurosci 2013; 36(3):195-206. 
  • McDonagh M, et al. Nonopioid pharmacologic treatments for chronic pain. Comparative effectiveness review No. 228
  • AHRQ Publication No. 20-EHC010. Agency for Healthcare Research and Quality 2020. Last accessed March 6, 2021:
  • https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/nonopioid-chronic-pain.pdf McGeeney B. Cannabinoids and hallucinogens for headache. Headache 2013; 53(3):447-458.
  • McHugh D, et al. N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci 2010; 11:44.
  • McPartland J, et al. Care and feeding of the endocannabinoid system: A systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS ONE 2014; 9(3):1-21.
  •  Macrì S, et al. Single episode of maternal deprivation and adult depressive profile in mice: Interaction with cannabinoid exposure during adolescence. Behav Brain Res 2004; 154(1):231-238.
  • Malfait A, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 2000; 97(17):9561-9566.
  • Manchikanti L, et al. Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician 2008; 11(2 Suppl):S63-88. 
  • Manini A, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med 2015; 9(3):204-210. 
  • Manzanares J, et al. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol 2006; 4(3):239-257. 
  • Manzanares J, et al. Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain. Brain Res Mol Brain Res 1998; 55(1):126-132.
  • Marcu J. An overview of major and minor phytocannabinoids. In: Preedy V, ed. Neuropathology of Drug Addictions and Substance Misuse, Volume 1: Foundations of Understanding, Tobacco, Alcohol, Cannabinoids and Opioids.
  • London: Academic Press; 2016:672-678.
  •  (Martin 2017 JAMA Psych) Martins S, et al. Changes in US lifetime heroin use and heroin use disorder: Prevalence from the 2001-2002 to 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry 2017; 74(5):445-455.
  • (Martin 2017 Addict Behav) Martins S, et al. Prescription opioid use disorder and heroin use among 12-34 year-olds in the United States from 2002 to 2014. Addict Behav 2017; 65:236-241. 
  • Masataka N. Anxiolytic effects of repeated cannabidiol treatment in teenagers with social anxiety disorders. Front Psychol 2019;10:2466. 
  • Mattick R, et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.
  • Cochrane Database Syst Rev 2014; (2):CD002207.
  • Mehmedic Z, et al. Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci 2010; 55(5):1209-1217.
  • Meldrum M. The ongoing opioid prescription epidemic: Historical context. Am J Public Health 2016; 106(8):1365– 1366.
  • Méndez-Díaz M, et al. Entopeduncular nucleus endocannabinoid system modulates sleep-waking cycle and mood in rats. Pharmacol Biochem Behav 2013; 107:29-35.
  •  Mercadante S, et al. Hyperalgesia and opioid switching. Am J Hosp Palliat Care 2005; 22(4):291-294. 
  • Mercadante S, et al. Burst ketamine to reverse opioid tolerance in cancer pain. J Pain Symptom Manage 2003; 25(4):302-305.
  • Micale V, et al. Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther
  • 2013; 138(1):18-37. 
  • Mlost J, et al. Cannabidiol for pain treatment: Focus on pharmacology and mechanism of action. Int J Mol Sci 2020; 21(22):8870.
  • Moeller-Bertram T, et al. Can CBD reduce the use of pain medication? Lessons from a survey in a pain clinic environment. The Journal of Pain 2019; 20(4 Supplement):S64.
  • Moir D, et al. A comparison of mainstream and side-stream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chem Res Toxicol 2008; 21(2):494–502.
  • Monti J, et al. Cannabinoids and Sleep. Advances in Experimental Medicine and Biology [Internet]. Springer International Publishing 2021; Last accessed March 22, 2021 at: https://www.google.com/books/edition/Cannabinoids_and_Sleep/XboZEAAAQBAJ? hl=en&gbpv=1&dq=Cannabinoids+and+Sleep+Molecular,
  • +Functional+and+Clinical+Aspects+2019+monti&pg=PR12&printsec=frontcover 
  • Mostafavi H, et al. Chemical composition of essential oil of Stachys byzantina from North-West Iran. Journal of Essential Oil Bearing Plants 2013; 16(3):334–337. 
  • Moulin D, et al. Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society. Pain Res Manag 2014; 19(6):328-335. 
  • Musty R, et al. A cannabigerol extract alters behavioral despair in an animal model of depression. Proceedings of the Symposium on the Cannabinoids. Int Cannabinoid Res Soc 2006;32.
  • Musty R, et al. Interactions of Δ-9-tetrahydrocannabinol and cannabinol in man. In: Braude MC, Szara S, eds. The Pharmacology of Marihuana [sic], Vol 2. New York: Raven Press 1976:559-563.
  • Nahas G, et al. Effects and interactions of natural cannabinoids on the isolated heart. Proc Soc Exp Biol Med 1985; 180(2):312-316.
  • (NAS 2017) National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press 2017. Last accessed March 6, 2021:
  • http://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state
  • Nava F, et al. Chronic cannabis use does not affect the normalization of hypothalamic-pituitary-adrenal (HPA) axis induced by methadone in heroin addicts. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31(5):1089-1094.
  • Newton D. Marijuana: A reference handbook, 2nd edition. ABC-CLIO 2017. p. 183. ISBN 978-1440850516.
  •  Nguyen P, et al. Statistical parametric mapping reveals ligand and region-specific activation of G-proteins by CB1 receptors and non-CB1 sites in the 3D reconstructed mouse brain. Neuroimage 2010; 52(4):1243-1251.
  • Noble A, et al. Self-detoxification attempts among methadone maintenance patients: What methods and what success? Addict Behav 2002; 27(4):575-584. 
  • Nordahl H, et al. Paroxetine, cognitive therapy or their combination in the treatment of social anxiety disorder with and without avoidant personality disorder: A randomized clinical trial. Psychother Psychosom 2016; 85(6):346-356.
  • Nunes D, et al. Psychopharmacology of essential oils. In: Baser KHC, Buchbauer G, editors. Handbook of Essential Oils: Science, Technology, and Applications. Boca Raton, FL: CRC Press 2010; pp 297-314.
  • (NYAM 1944) New York Academy of Medicine for the Mayor’s Committee on Marihuana [sic], the City of New York. The Laguardia Committee Report: The Marihuana Problem in the City of New York. 1944, New York USA.
  •  (O’Donnell 2017 Trends) O’Donnell J, et al. Trends in deaths involving heroin and synthetic opioids excluding methadone, and law enforcement drug product reports, by census region—United States, 2006–2015. MMWR Morb Mortal Wkly Rep 2017; 66(34):897–903.
  •  (O’Donnell 2017 Fentanyl) O’Donnell J, et al. Deaths involving fentanyl, fentanyl analogs, and U-47700—10 states, July–December 2016. MMWR Morb Mortal Wkly Rep 2017; 66(34):1197–1202.
  •  Oliviera M, et al. α-Terpineol, a monoterpene alcohol, complexed with β-cyclodextrin exerts antihyperalgesic effect in animal model for fibromyalgia aided with docking study. Chem Biol Interact 2016; 254:54-62. 
  • Oliviera M, et al. α-Terpineol reduces mechanical hypernociception and inflammatory response. Basic & Clinical Pharmacology & Toxicology 2012; 111(2):120–125.
  •  Onderdonk M. Pain management: 9 Celebrities who died from painkiller ODs. Everyday Health 2019; Last accessed March 12, 2021: https://www.everydayhealth.com/pain-management-pictures/six-celebrities-who-have-died-from- painkiller-ods.aspx
  • Oxford league table of analgesic efficacy. Bandolier Journal 2007. Last accessed March 6, 2021: http://www.bandolier.org.uk/booth/painpag/Acutrev/Analgesics/Leagtab.html
  • Pacher P, et al. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58(3):389-462. 
  • Padilla M, et al. Allowing cigarette or marijuana smoking in the home and car: Prevalence and correlates in a young adult sample. Health Educ Res 2015; 30(1):179–191.
  • Parker K, et al. 2005 ASCO Annual Meeting Proceedings. J Clin Oncol 2006; 24:8526.
  • Parker L, et al. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport 2002; 13(5):567-570. 
  • Parolaro D, et al. Cellular mechanisms underlying the interaction between cannabinoid and opioid systems. Curr Drug Targets 2010; 11(4):393-405.
  • Parvardeh S, et al. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: Role of nitric oxide. Iran J Basic Med Sci 2016; 19(2):201-208.
  • Patel J, et al. Cannabis use disorder. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.
  • Paulozzi L, et al. Vital signs: Overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep 2011; 60(43):1487-1492. 
  • Pava M, et al. Endocannabinoid modulation of cortical up-states and NREM sleep. PLoS One 2014; 9(2):e88672.
  • Peana A, et al. (-)-Linalool inhibits in vitro NO formation: Probable involvement in the antinociceptive activity of this monoterpene compound. Life Sci 2006; 78(7):719-723.
  • Peana A, et al. Profile of spinal and supra-spinal antinociception of (-)-linalool. Eur J Pharmacol 2004; 485(1-3):165-174.
  • Pertwee R. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ 9- Tetrahydrocannabinol, cannabidiol and Δ 9-tetrahydrocannabivarin. Br J Pharmacol 2008; 153(2):199-215.
  • Pino C, et al. Prescription of opioids for acute pain in opioid naïve patients. UpToDate 2021. Last accessed March 6, 2021:
  • https://www.uptodate.com/contents/prescription-of-opioids-for-acute-pain-in-opioid-naive-patients#H2911413240
  • Pistis M, et al. Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biol Psychiatry 2004; 56(2):86-94.
  • Poli P, et al. Medical cannabis in patients with chronic pain: Effect on pain relief, pain disability, and psychological aspects. A prospective non-randomized single arm clinical trial. Clin Ter 2018; 169(3):e102-e107.
  • Pollio A. The name of cannabis: A short guide for nonbotanists. Cannabis and Cannabinoid Research 2016; 1(1):234–238.
  • Pomahacova B, et al. Cannabis smoke condensate III: the cannabinoid content of vaporised Cannabis sativa. Inhal Toxicol 2009; 21(13):1108-1112.
  •  Portenoy R, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial. J Pain 2012; 13(5):438-449.
  • Pourtaqi N, et al. Effect of linalool on the acquisition and reinstatement of morphine-induced conditioned place preference in mice. Avicenna J Phytomed 2017; 7(3):242–249.
  • Powell D, et al. Do medical marijuana laws reduce addictions and deaths related to pain killers? J Health Econ
  • 2018; 58:29-42.
  • Pud D, et al. Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend 2006; 82(3):218-223. 
  • Pugh G, et al. The role of endogenous opioids in enhancing the antinociception produced by the combination of Δ 9- tetrahydrocannabinol and morphine in the spinal cord. J Pharmacol Exp Ther 1996; 279(2):608-616. 
  • Qin N, et al. TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 2008; 28(24):6231-6238.
  • Raby W, et al. Intermittent marijuana use is associated with improved retention in naltrexone treatment for opiate- dependence. Am J Addict 2009; 18(4):301-308.
  • Rahn E, et al. Cannabinoids as pharmacotherapies for neuropathic pain: From the bench to the bedside.
  • Neurotherapeutics 2009; 6(4):713-737.
  • Raichlen D, et al. Wired to run: Exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high’. J Exp Biol 2012; 215(Pt 8):1331-1336. 
  • Raji M, et al. Association between cannabis laws and opioid prescriptions among privately insured adults in the US.
  • Prev Med 2019; 125:62-68.
  • Ramaekers J, et al. Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users. Psychopharmacology (Berl) 2011; 214(2): 391–401.
  • Ramaekers J, et al. Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J Psychopharmacol 2009; 23(3):266-277.
  • Ramot A, et al. Cannabinoid receptors activation and glucocorticoid receptors deactivation in the amygdala prevent the stress-induced enhancement of a negative learning experience. Neurobiol Learn Mem 2012; 97(4):393-401.
  • Re L, et al. Linalool modifies the nicotinic receptor-ion channel kinetics at the mouse neuromuscular junction.
  • Pharmacol Res 2000; 42(2):177-182. 
  • Ren Y, et al. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci 2009; 29(47):14764-14769. 
  • Rey A, et al. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 2012; 37(12):2624–2634.
  •  Reynolds J. On the therapeutical uses and toxic effects of Cannabis indica. The Lancet 1890; 135(3473):637-638. Reynolds J. On some of the therapeutical uses of Indian hemp. Archives of Medicine 1868; 2:154-160.
  • Roberts J, et al. Synergistic affective analgesic interaction between Δ-9-tetrahydrocannabinol and morphine. Eur J Pharmacol 2006; 530(1-2):54-58.
  • Rock E, et al. Effect of combined doses of Δ 9-tetrahydrocannabinol and cannabidiol or tetrahydrocannabinolic acid and cannabidiolic acid on acute nausea in male Sprague-Dawley rats. Psychopharmacology (Berl) 2020; 237(3):901-914. 
  • Rock E, et al. Effect of cannabidiolic acid and ∆ 9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain. Psychopharmacology (Berl) 2018; 235(11):3259-3271.
  • Rock E, et al. Effect of combined oral doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models. Psychopharmacology (Berl) 2016; 233(18):3353-3360.
  • Rock E, et al. Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in
  • Suncus murinus. Br J Pharmacol 2013; 170(3):641-648.
  • Rodríguez-Muñoz M, et al. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the σ1 receptor. Molecular Brain 2018; 11(1):51.
  • Rudd R, et al. Increases in heroin overdose deaths—28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep 2014; 63(39):849.
  • Russo E. Clinical endocannabinoid deficiency reconsidered: Current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis Cannabinoid Res 2016; 1(1):154-165.
  • Russo E. Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163(7):1344-1364.
  • Russo E. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag 2008; 4(1):245-259.
  • Russo E, et al. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers 2007; 4(8):1729-1743.
  • Russo E, et al. A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 2006; 66(2):234-246.
  • Russo E. Clinical endocannabinoid deficiency: Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett 2004;
  • 25(1-2):31-39.
  • Russo E. Handbook of psychotropic herbs: A scientific analysis of herbal remedies for psychiatric conditions. Binghamton: Haworth Press, 2001.
  • Russo E, et al. 41st Annual Meeting of the American Society of Pharmacognosy. Seattle, WA, 2000. Sagy I, et al. Safety and efficacy of medical cannabis in fibromyalgia. J Clin Med 2019; 8(6):807.
  • (SAMSA 2020) Substance Abuse and Mental Health Services Administration.. Key substance use and mental health indicators in the United States: Results from the 2019 National Survey on Drug Use and Health (HHS Publication No. PEP20-07-01-001, NSDUH Series H-55). Rockville, MD: Center for Behavioral Health Statistics and Quality. Last accessed March 6, 2021: https://www.samhsa.gov/data/sites/default/files/reports/ rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR1PDFW090120.pdf
  • (SAMHSA 2017) Substance Abuse Center for Behavioral Health Statistics and Quality. Results from the 2016 National Survey on Drug Use and Health: Detailed Tables. SAMHSA 2017. Last accessed March 6, 2021: https://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015/NSDUH- DetTabs-2015.pdf
  •  Schleider L, et al. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med 2018; 49:37-43.
  •  Scholl L, et al. Drug and opioid-involved overdose deaths—United States, 2013-2017. MMWR Morb Mortal Wkly Rep 2018; 67(5152):1419-1427.
  • Segura L, et al. Association of US medical marijuana laws with nonmedical prescription opioid use and prescription opioid use disorder. JAMA Netw Open 2019; 2(7): e197216.
  •  Seivewright N. Methadone treatment outcomes appear mainly unaffected by cannabis use. Addiction 2003; 98(3):251-252.
  • Shafer R, et al. Marihuana [sic]: A signal of misunderstanding. First Report of the National Commission on Marihuana and Drug Abuse 1972. U.S. Government Printing Office via Internet Archive digital scan. Last accessed March 6, 2021:
  • https://archive.org/details/marihuanasignalo00unit/page/n5/mode/2up
  • Shang V, et al. Δ 9-Tetrahydrocannabinol reverses TNFα-induced increase in airway epithelial cell permeability through CB 2 receptors. Biochem Pharmacol 2016; 120:63-71.
  •  Sharkey K, et al. The role of the endocannabinoid system in the brain-gut axis. Gastroenterology 2016; 151(2):252– 266. 
  • Shi Y. Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever. Drug Alcohol Depend 2017; 173:144-150.
  • Shiels M, et al. Trends in U.S. drug overdose deaths in non-Hispanic Black, Hispanic, and Non-Hispanic White persons, 2000-2015. Ann Intern Med 2018; 168(6):453-455.
  • Sigmon S, et al. Opioid detoxification and naltrexone induction strategies: recommendations for clinical practice.
  • Am J Drug Alcohol Abuse 2012; 38(3):187-199.
  • Silvestri C, et al. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders.
  • Cell Metab 2013; 17(4):475-490.
  • Simonnet A, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Obesity (Silver Spring) 2020; 28(7):1195-1199.
  • Skelly A, et al. Noninvasive nonpharmacological treatment for chronic pain: A systematic review update. Comparative Effectiveness Review No. 227. AHRQ Publication No. 20-EHC009. Agency for Healthcare Research and Quality; 2020. Last accessed March 6, 2021: https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/noninvasive-nonpharm-pain-update.pdf
  • Smith P, et al. Low dose combination of morphine and Δ 9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur J Pharmacol 2007; 571(2-3):129-137.
  • Smith F, et al. The enhancement of morphine antinociception in mice by Δ 9-tetrahydrocannabinol. Pharmacol Biochem Behav 1998; 60(2):559-566.
  • Socías M, et al. High-intensity cannabis use is associated with retention in opioid agonist treatment: A longitudinal analysis. Addiction 2018; 113(12): 2250–2258.
  • Soleimani M, et al. Analgesic effect of α-terpineol on neuropathic pain induced by chronic constriction injury in rat sciatic nerve: Involvement of spinal microglial cells and inflammatory cytokines. Iran J Basic Med Sci 2019; 22(12):1445-1451.
  • Soyka M, et al. Retention rate and substance use in methadone and buprenorphine maintenance therapy and predictors of outcome: Results from a randomized study. Int J Neuropsychopharmacol 2008; 11(5):641-653.
  • Sparling P, et al. Exercise activates the endocannabinoid system. Neuroreport 2003; 14(17):2209-2211. Stevens C. The evolution of vertebrate opioid receptors. Front Biosci 2009; 14:1247-1269.
  • Suraev A, et al. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) for chronic insomnia disorder (‘CANSLEEP’ trial): Protocol for a randomised, placebo-controlled, double-blinded, proof-of-concept trial. BMJ Open 2020; 10(5):e034421.
  • Takahashi R, et al. Pharmacologic interaction between cannabinol and Δ 9-tetrahydrocannabinol.
  • Psychopharmacologia 1975; 41(3):277-284.
  • Takakuwa K, et al. A survey on the effect that medical cannabis has on prescription opioid medication usage for the treatment of chronic pain at three medical cannabis practice sites. Cureus 2020; 12(12):e11848.
  • Tashkin D, et al. Bronchial effects of aerosolized Δ 9-tetrahydrocannabinol in healthy and asthmatic subjects. Am Rev Respir Dis 1977; 115(1):57-65.
  • Tashkin D, et al. Acute pulmonary physiologic effects of smoked marijuana and oral Δ 9-tetrahydrocannabinol in healthy young men. N Engl J Med 1973; 289(7):336-341.
  • Tashkin D, et al. Acute effects of smoked marijuana and oral Δ 9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. Am Rev Respir Dis 1974; 109(4):420-428. 
  • Teichtahl H, et al. Sleep-disordered breathing in stable methadone programme patients: A pilot study. Addiction
  • 2001; 96(3):395-403.
  • Tham M, et al. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol 2019; 176(10):1455–1469.
  • Toubia T, et al. The endogenous opioid system: Role and dysfunction caused by opioid therapy. Clin Obstet Gynecol
  • 2019; 62(1):3-10.
  • Tramer M, et al. Cannabinoids for control of chemotherapy-induced nausea and vomiting: Quantitative systematic review. BMJ 2001; 323(7303):16-21.
  • Udoh M, et al. Cannabichromene is a cannabinoid CB 2 receptor agonist. Br J Pharmacol 2019; 176(23):4537-4547.
  • United States Census Bureau. United States and world population clock. Last accessed March 6, 2021: https://www.census.gov/popclock/
  • Usami N, et al. Synthesis and pharmacological activities in mice of halogenated Δ 9-tetrahydrocannabinol derivatives. Chem Pharm Bull (Tokyo) 1998; 46(9):1462-1467.
  • Vijayalaxmi A, et al. Anti-arthritic and anti-inflammatory activity of β–caryophyllene against Freund’s complete adjuvant induced arthritis in Wistar rats. Journal of Bone Reports & Recommendations 2015; 1(2):1-10.
  • Volkow N, et al. Don’t worry, be happy: Endocannabinoids and cannabis at the intersection of stress and reward.
  • Annu Rev Pharmacol Toxicol 2017; 57:285-308.
  • Wang D, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest 2005; 128(3):1348– 1356.
  • Weizman T, et al. Cannabis abuse is not a risk factor for treatment outcome in methadone maintenance treatment: A 1-year prospective study in an Israeli clinic. Aust N Z J Psychiatry 2004; 38(1-2):42-46.
  • Welch S. Blockade of cannabinoid-induced antinociception by norbinaltorphimine, but not N,N-diallyl-tyrosine- Aib-phenylalanine-leucine, ICI 174,864 or naloxone in mice. J Pharmacol Exp Ther 1993; 265(2):633-640.
  • Welch S, et al. Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther 1992; 262(1):10-18.
  • Wen H, et al. Association of medical and adult-use marijuana laws with opioid prescribing for Medicaid enrollees.
  • JAMA Intern Med 2018; 178(5):673-679.
  • Wenzel J, et al. Endocannabinoid regulation of reward and reinforcement through interaction with dopamine and endogenous opioid signaling. Neuropsychopharmacology 2018; 43(1):103–115.
  • Wesson D, et al. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003; 35(2):253-259.
  • Wilsey B, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013; 14(2):136-148.
  • Wilson K, et al. Detecting biomarkers of secondhand marijuana smoke in young children. Pediatr Res 2017; 81(4):589–592.
  • Wilson N, et al. Drug and opioid-involved overdose deaths — United States, 2017-2018.
  • MMWR Morb Mortal Wkly Rep 2020; 69(11):290-297.
  • (WONDER 2020 Heroin) Wide-ranging online data for epidemiologic research. Atlanta, GA: CDC, National Center for Health Statistics; 2020. Available at http://wonder.cdc.gov. Citation on the CDC website Opioid overdose: Opioid Basics, Heroin 2020. Last accessed March 6, 2021: https://www.cdc.gov/drugoverdose/opioids/heroin.html
  • (WONDER 2020 Data Analysis) Wide-ranging online data for epidemiologic research. Atlanta, GA: CDC, National Center for Health Statistics; 2020. Available at http://wonder.cdc.gov. Citation on the CDC website Opioid overdose: Data, Data Analysis and Resources 2020. Last accessed March 6, 2021: https://www.cdc.gov/drugoverdose/data/ analysis.html
  • Xi Z, et al. Brain cannabinoid CB2 receptors inhibit cocaine self-administration and cocaine-enhanced extracellular dopamine in mice. Proceedings 20th Annual Symposium on the Cannabinoids 2010. International Cannabinoid Research Society: Lund, p 32.
  • Xiao L, et al. Nocturnal sleep architecture disturbances in early methadone treatment patients. Psychiatry Res 2010; 179(1):91-95.
  • Yoshida H, et al. Synthesis and pharmacological effects in mice of halogenated cannabinol derivatives. Chem Pharm Bull (Tokyo) 1995; 43(2):335-337.
  • Zanelati T, et al. Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors. Br J Pharmacol 2010; 159(1):122-128.
  • Zhong L, et al. Efficacy of MaZiRenWan, a Chinese herbal medicine, in patients with functional constipation in a randomized controlled trial. Clin Gastroenterol Hepatol 2019; 17:1303–1310.
  • Zhu L, et al. Structural changes in the gut microbiome of constipated patients. Physiol Genomics 2014; 46:679–686.
  • Zikos T, et al. Marijuana, ondansetron, and promethazine are perceived as most effective treatments for gastrointestinal nausea. Dig Dis Sci 2020; 65(11):3280-3286.
  • Zygmunt P, et al. Δ 9-Tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci 2002; 22(11):4720-4727.

By Dr. Dan (Daniel Price MD)