What is Harm Reduction?
By Hawaiian Ethos Medical Director, Stacey Marie Kerr MD
In the purest sense, harm reduction strategies are efforts to reduce the effects of any harm that comes our way, whether that harm comes from natural causes, such as the inevitable break-down and need for repair of organic matter, or from external causes such as injury, disease, or well-intentioned medical treatments.
Examples of harm reduction include conscious avoidance of known sources of disease or injury, needle exchange programs, or replacing heroin with methadone or buprenorphine. While avoidance may be the most effective method of harm reduction, total avoidance of all possible harm is realistically impossible.
This article will address the use of cannabinoids as harm reduction agents useful in the body’s own inherent methods of repair, in the management of dependence, addiction, and in the risk of overdose with harmful, sometimes lethal, medications.
Cannabis has been used as medicine for many thousands of years, but only recently has science been able to study its use and possible mechanisms as a therapeutic agent. The endocannabinoid system (ECS) consists of membrane receptors, neurotransmitters, and enzymes to generate and degrade those neurotransmitters. It was not until 1967 that the phytocannabinoid THC was synthesized for research purposes, and in 1990 THC receptors were identified in the brain. Two primary types of receptors have been studied: CB1 receptors and CB2 receptors. The finding of these receptors led to a search for the body’s own activating endogenous ligands, and in 1992 the endocannabinoid, anandamide, was identified binding to CB1 receptors. This would be the first of several endocannabinoids that we can now study. Learning about the endocannabinoid system, its components, and their mechanisms of action is still in early stages but the potential is significant. These are powerful new tools available to health care if we learn to appropriately utilize them.
The endocannabinoid system is a modulating system continually working to regulate the body to maintain a healthy state. Most neurotransmitters are synthesized on the presynaptic membrane and affect receptors postsynaptically. But the ECS is unique in that the cannabinoids are synthesized on the postsynaptic membrane and act in a retrograde fashion to regulate the release of neurotransmitters at the presynaptic membrane. This retrograde system is constantly working for homeostasis, regulating and repairing all body systems including the cardiovascular, endocrine, immune, nervous, musculo-skeletal and reproductive systems (Melamede, 2005). Thus, it may be identified as part of the inherent evolutionary harm reduction program built into all living vertebrates. Can this inherent function be extended to the use of phytocannabinoids for the purposes of harm reduction from external sources?
Addiction and Substitution
Physical addiction to drugs is a disease causing uncontrollable cravings and an inability to control drug use. These cravings are triggered by changes in the brain’s mesolimbic reward system that are difficult to reverse. Different substances affect this reward system with different receptor interactions.
For opioids, it all begins when opioid receptors in the brain are stimulated by drugs that satisfy a need or fulfill a desire. The mesolimbic reward system responds quickly and dopamine is released, producing a strong sensation of pleasure. Dopamine acts as a motivator, controlling energy and excitement about new ideas, so when there is more dopamine available we feel wonderful. If we stimulate this reward system repeatedly, the dopamine receptor cells are down-regulated and no longer able to provide pleasure without external stimulus. Thus the addictive behavior seems to be the only way to satisfy overwhelming cravings. In those without addiction, the prefrontal cortex helps overcome urges to get pleasure from unsafe substances, but this feedback mechanism is compromised in addicted individuals.
Alcohol also binds to receptors in the brain’s reward system. It inhibits excitatory neurons and stimulates inhibitory neurons, most notably at the GABA receptors. Alcohol can be so pleasantly calming because GABA is the brain’s primary inhibitory neurotransmitter, linked with relaxation and anti-anxiety effects. So when alcohol increases GABA release, the brain becomes much calmer and quieter.
Cannabis releases dopamine in the reward system, but it does this indirectly. Dopaminergic neurons may or may not have CB1 receptors, but GABAergic neurons do. Dopamine is usually inhibited by GABA, but when cannabis binds to the CB1 receptors on GABA neurons, it removes inhibition of dopamine and dopamine is then released into the reward system. (Oleson EB, 2012)
All of these substances interact with the reward system in our brain. If avoidance of inappropriately rewarding substances is the first goal of harm reduction, how can exposure to cannabis help with obtaining and maintaining abstinence in problems of addiction?
Currently we have several commonly used medications to help addicts. Methadone has been used for many years, binding to the same receptors as morphine and other opiates. It is a long-acting opiate, so it produces minimal tolerance and does not create the craving and compulsivity of short-acting opiates. Still, methadone is addictive and relapse rates are high in those who discontinue use. Naltrexone monopolizes and blocks the receptors in the brain so addictive opioids can no longer stimulate the reward system. Naloxone strips the opiates from the receptors, effectively bringing patients back from overdose crises. Buprenorphine has biphasic actions: at low doses, it acts like methadone, and at high doses it behaves like naltrexone in blocking receptors. Combining those last two, we have Suboxone, a combination of buprenorphine and naloxone, which is also highly addictive. All these treatment modalities have a significant risk of addiction or relapse. But they are what is currently being used with best intention in addiction medicine. (Kosten TR, 2002)
Since they all affect the reward center in the brain, what makes cannabis different from methadone, naltrexone, buprenorphine, naloxone, or Suboxone? Clinically we are seeing that it can help. Indeed, it is reported that intermittent cannabis use is associated with improved retention in Naltrexone treatment for opiate dependence. (These findings did not hold true for those using cannabis regularly.) (Raby WN, 2009)
This observed effect may have something to do with the indirect action of cannabinoids in the reward system. While naltrexone is blocking receptors from opiates, cannabinoids can be supporting the release of dopamine through CB1 receptors on GABA neurons, thus compensating for a painful complete deficit of dopamine caused by the naltrexone. Some of the other effects of cannabis may also be helpful in increasing tolerability of naltrexone: appetite stimulation, antiemetic, antispasmodic, and analgesic effects – many that help relieve physical discomforts that go with opioid withdrawal.
Substitution has been noted to be helpful with addiction disorders. If the substitution is with an agent that is perceived as safer, with less potential for addiction, and if it’s effective at treating symptoms of withdrawal, easier to access, with a higher level of societal acceptance, then the substitution may increase treatment success. In 2009 a review of 92 medical cannabis patients who reported using cannabis as a substitute for alcohol was published in the Harm Reduction Journal. All participants reported cannabis substitution for alcohol as either very effective (50%) or effective (50%). 40% used cannabis as a substitute for alcohol, 26% used it to replace illicit drugs, and 65.8% used it to replace prescription drugs. Those using it as a substitute for prescription drugs reported that cannabis had fewer side effects and better symptom management. (Reiman, 2009)
Cannabis has already made a difference in reducing harm from opioid overdose. A study published in JAMA in 2014 analyzed death certificate data from 1999 to 2010 and found that “States with medical cannabis laws had lower mean opioid analgesic overdose mortality rates compared with states without such laws.” This was true even when they excluded intentional, suicidal overdoses. They also noted that cannabis use can cause “modest reductions in opioid withdrawal symptoms for some patients.” (Bachhuber, 2014)
It may not make sense to substitute one addiction for another, so the question must be asked: Is cannabis itself addictive? Are we simply trading one harm for another? This has been debated for years with passion on both sides of the question.
Most agree on the accepted diagnosis of Cannabis Use Disorder. This is a recognized subset of substance abuse disorders listed in the DSM 5. (305.20 for mild or 304.30 for moderate or severe)
The definition of Cannabis Use Disorder includes the following:
1. Use of cannabis for at least a one year period, with the presence of at least two of the following symptoms, accompanied by significant impairment of functioning and distress.
2. Difficulty containing use of cannabis- the drug is used in larger amounts and over a longer period than intended.
3. Repeated failed efforts to discontinue or reduce the amount of cannabis that is used.
4. An inordinate amount of time is occupied acquiring, using, or recovering from the effects of cannabis.
5. Cravings or desires to use cannabis. This can include intrusive thoughts and images, and dreams about cannabis, or olfactory perceptions of the smell of cannabis, due to preoccupation with cannabis.
6. Continued use of cannabis despite adverse consequences from its use, such as criminal charges, ultimatums of abandonment from spouse/partner/friends, and poor productivity.
7. Other important activities in life, such as work, school, hygiene, and responsibility to family and friends are superseded by the desire to use cannabis.
8. Cannabis is used in contexts that are potentially dangerous, such as operating a motor vehicle.
9. Use of cannabis continues despite awareness of physical or psychological problems attributed to use, e.g. anergia, amotivation, chronic cough.
10. Withdrawal, defined as the typical withdrawal syndrome associate with cannabis, or cannabis or a similar substance is used to prevent withdrawal symptoms.
11. Tolerance to Cannabis, as defined by progressively larger amounts of cannabis are needed to obtain the psychoactive effect experienced when use first commenced, or, noticeably reduced effect of use of the same amount of cannabis
However, Cannabis Use Disorder is not the same as addiction. It may be indicative of psychological addiction or dependence, but what about physical addiction? While cannabis does affect the reward system and dopamine levels, most cannabis users do not exhibit symptoms of addiction such as severe cravings and withdrawal when they discontinue use. If they do quit, and feel symptoms such as irritability, sleep and appetite disturbances, are these simply symptoms that were being effectively treated while using an appropriate medicine? When they occur, these relatively mild problems usually disappear within a few days unlike those of opioid withdrawal.
The side effects of cannabis are not as dangerous as those of opiates or alcohol. It is impossible to have a fatal overdose of cannabis because it does not affect brainstem functions. Yes, it can become a problem if used irresponsibly, so at this time, we must be aware of possible use disorders. Clinicians should monitor and educate patients about appropriate use of cannabis as medicine when used for harm reduction.
Opioids and Cannabis
Hawaii, and the rest of the United States, is in the middle of an opioid epidemic. Drug overdose deaths in Hawaii increased by 83% from 2006 to 2014, more than double the national average. (Bussewitz, 2016) The US has only 5% of the world’s population but we consume 80% of the world’s opioids, and nearly 50% of people who use opioids for more than a month in the first year continue to use them for three years or longer. Dependence and abuse of pharmaceuticals is currently the fastest growing form of problematic substance use in North America. (Sulak, 2016) From 1999 to 2015, more than 183,000 people have died in the U.S. from overdoses related to prescription opiates. More people are dying from prescribed opiates than from the use of heroin. (CDC, 2016) (Rudd RA, 2016)
Even though they are the first-line treatment for chronic pain, opioids do not treat chronic pain as effectively as commonly believed. A review published in 2015 in the Annals of Internal Medicine stated, “Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain in function.” The authors also identified an increased risk of serious harm associated with long-term opioid use – risks that include overdose, fractures, heart attacks, sexual dysfunction and addiction. (Chou, 2015)
The pain is certainly real. Many patients report, “The drugs don’t take away my pain but I just don’t care as much about it.” And then they ask for more because they have built up tolerance to the current dose. Pain is a problem. If refilling prescriptions for opiates, keeping up with escalating dosing needs, and attempting to balance an increasing need for relief with the risks of side effects is not working, what can a caring physician do?
We are not yet clear about all the physiologic mechanisms in the observed decreased overdose effects in states with medical cannabis laws, but a new way of looking at treating chronic pain is beginning to be seriously considered. Avoiding overdose by using fewer and lower doses of addicting, potentially fatal medications is yet another type of harm reduction. If we begin treatment of chronic pain with cannabis, and if necessary, supplement cannabis with opioids, we may be able to avoid escalation and overdoses while treating the pain more effectively.
Cannabis and Opioids for Chronic Pain
Opiates (derivatives of opium) and cannabinoids have much in common. Both bind to receptors in the brain, many in the same locales. Both have a presence in the peripheral body. Both are present in areas of the brain that regulate addiction, reward, reinforcement and behavior. Both create similar physiologic responses that include hypothermia, sedation, hypotension, antinociception, and motor depression. The opioid receptors are dense in the brain stem but CB1 endocannabinoid receptors are not – a relevant distinction if considering the potential for fatal overdose. It has been proven that these two receptor systems have an interactive reciprocal relationship. (Robledo P, 2008)
Chronic pain comes in many forms; neuropathic, visceral, and somatic pain may all respond differently to our use of pain medications. A growing body of evidence points to the therapeutic use of cannabis in the treatment of most types of chronic pain. When used together with opiates, cannabinoids can lead to a greater cumulative pain control, can prevent the development of tolerance to and withdrawal from opiates, and even rekindle opiate analgesia after a prior dosage has become ineffective. (Cichewicz D. &., 2003) (Cichewicz D. e., 1999) (Russo, 2008a) (Cichewicz D. &., 2003) Patients simply need less opioids when they use cannabis together with their prescription of opiates.
We know that vaporized cannabis in humans augments the analgesic effects of opioids without significantly altering plasma opioid levels, so the synergistic effects of cannabis are apparently not due to the inhibition of opioid metabolism. Some evidence shows that phytocannabinoids increase the release of and/or the synthesis of endogenous opioids which could account for an additive effect. (Smith, 1998) (Cichewicz D. M., 1999) (Pugh, 1994) (Kaymakcalan, 1978)
Much of the research in this field has been done with rats since cannabis is still a Schedule I drug with limited opportunity to study it in clinical situations. When rats are given morphine, their opiate receptors are understandably downregulated. But when those same rats are given morphine along with very low doses of THC, those same receptors are upregulated – the exact opposite of what we see with morphine alone. A very small dose of THC, small enough to cause no intoxicating effects, makes a very big difference in the effectiveness of morphine. (Cichewicz, Haller, & Welch, 2001)
In 2009, findings were published in the journal Neuropsychopharmacology. They worked with rats who were deprived of their mothers at birth. Deprivation creates rats that are psychologically damaged and hypersensitive to the rewarding effects of morphine and heroin. They found that if maternally deprived rats are treated with THC, they do not develop morphine dependent behavior. Deprived rats continually increased their preference for morphine, while deprived rats treated with TCH did not. The production of endogenous endorphin-like peptides in these rats’ striatum, the area of the brain that is involved in drug dependence, is restored by the THC, and diminished in rats left untreated. (Lydie J. Morel, 2009)
The nonpsychoactive phytocannabinoid cannabidiol (CBD) is also showing promise in the field of addiction. Published in the journal Alcohol and Alcoholism, a study done by a team at the Scripps Institute in California reported some encouraging results. Rats in this study were given full access to cocaine and alcohol until they were addicted, then some were treated with CBD for 7 days. During that time, CBD reduced both alcohol and cocaine seeking behavior in the treated rats. Surprisingly the effect lasted as long as 5 months after treatment was terminated. They noted that CBD also reduced anxiety, and reversed high impulsivity. Finally, they concluded that CBD may have valuable neuroregulatory actions that can restore normal brain function in areas of reward, motivation, impulsivity, stress and anxiety. All this without the psychoactive high that comes with THC. (F. Weiss, 2014)
Opiates are not the only substance abuse problem we face. Crystal methamphetamine (ICE) came to the United States in the 1980’s, coming into Hawaii from the Asian market and quickly spreading to the mainland. Hawaii is now, over thirty years later, facing a full-fledged ICE epidemic. While cannabis has yet to be proven an easy solution to this epidemic, it has been shown to prevent some of the neurotoxicity caused by meth. In 2014, research showed that THC reduces the neurotoxic effects of methamphetamines by reducing two markers of neuronal damage – the overexpression of nNOS (neuronal nitric oxide synthase) and astrocyte activation. (Castelli MP, 2014)
A growing body of evidence supports these and similar findings in humans as well as in rats but more research is needed.
The cost of the opioid epidemic is significant, not only in human lives but in the economy. In 2013 the Centers for Disease Control and Prevention estimated the total “economic burden” of prescription opioid abuse in the United States at $78.5 billion a year, and this estimate is only a fraction of the total cost of chronic pain on society, considering the expenses of health care, lost productivity, substance abuse treatment and criminal justice costs. (Florence CS, 2016)
Even more money is spent in the prohibition of cannabis. A 2005 report from the department of economics at Harvard University estimates that legalizing marijuana would save $7.7 billion per year in combined state and federal government enforcement costs. (Miron, 2005) Ccommunity-based medical cannabis dispensaries like Hawaiian Ethos can both reduce potential harms and maximize benefits of use. The community based, patient centered model is growing in legitimacy, can remove some social stigmas, and is capable of increasing access to a safe, consistent supply of laboratory tested medicine. This may indirectly lead to reduction in the use of pharmaceuticals, alcohol, and illicit substances. (Lucas, 2010) (Lucas, 2009) (Lucas, 2008) (Reiman, 2006)
Continuing research gives us some positive directions in the use of cannabis to assist in our efforts at harm reduction. We see promise in its use as an adjunct to opioids for chronic pain and as an assist to manage pharmaceutical side effects. As we continue to learn about this extensive, elegant, and pervasive receptor system we begin to see that cannabis may be a valuable ally in the fight against addiction, overdose, and other harms caused by good intentions. More work needs to be done, but the field is wide open for new approaches with cannabis that may lead to success in reducing harm to patients as we treat them for difficult problems of pain, substance abuse, and addiction.
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