Psychiatrists and other behavioral health professionals need to better understand the relationship between cannabis and mental disorders so that they can respond to increasing medical and recreational marijuana use among their patients. More than half of states now allow for medical use, and 8 states and the District of Columbia have legalized adult personal or recreational use.

 

 

Knowledge about herbal cannabis, the endocannabinoid system, and cannabinoid pharmacology is rapidly expanding. However, compared with the literature on non-medical cannabis use, the scientific literature on therapeutic use of cannabis is underdeveloped, as noted in a recent systematic review of medical cannabis and mental health.1 Although herbal cannabis has a long history of medicinal use, its federal prohibition under the Controlled Substances Act of 1970 with Drug Enforcement Administration Schedule I status has focused the federally supported cannabis research agenda for half a century on the potential harms rather than on the historically acknowledged therapeutic benefits of this complex plant.

 

Medicinal potential of cannabis

 

For the sake of this discussion, herbal cannabis refers to plant material derived from the flowering tops of Cannabis indica, sativa, or ruderalis biotypes. Indica, sativa, and indica-sativa hybrid strains are commonly available on the medicinal cannabis market.

Herbal cannabis is biochemically rich in a variety of compounds, both psychoactive and non-psychoactive. It has been reported that there are 483 compounds unique to marijuana, including more than 60 cannabinoids and some 140 terpenes. The phytocannabinoid that produces much of the psychoactive effect is delta-9-tetrahydrocannabinol (THC). However, there is increasing interest in another constituent, cannabidiol ( CBD), which is not considered psychoactive but appears to have therapeutic value for a wide variety of conditions, either alone or in combination with THC.

 

Although federal policy has disallowed access to cannabis even for medicinal use since the passage of the Controlled Substances Act, THC was approved in a synthetically manufactured formulation in 1985 as an oral medication indicated for nausea and vomiting associated with chemotherapy. Originally a Schedule II medication, molecular THC was later reclassified under Schedule III, which indicates lower abuse potential. From the late 1970s into the early 1990s, a few patients gained access to herbal cannabis through the federal Investigational New Drug program, but no new patients were enrolled after 1992.

 

It is ironic that currently in the US the non-psychoactive compound CBD is generally accessible for medicinal use only in the form of federally prohibited herbal cannabis products available under state medical marijuana laws. Grant and colleagues2 have summarized succinctly a point made by many others: “Based on evidence currently available the Schedule 1 classification is not tenable; it is not accurate that cannabis has no medical value, or that information on safety is lacking.” Interestingly, the US government has held a patent on substituted CBD derivatives as antioxidants and neuroprotectants for nearly 2 decades.

 

Perceived benefits of medical cannabis

 

 

Regardless of the legal status of cannabis, many patients with psychiatric disorders use cannabis and report improvement in their symptoms. Patients use cannabis for symptoms of PTSD, anxiety disorders, depression, ADHD, bipolar disorder, chronic pain, insomnia, opiate dependence, and even schizophrenia. In addition, patients use cannabis for neurological conditions such as the spasticity of multiple sclerosis, agitation in dementia, and specific seizure disorders that are unresponsive to standard therapies. Patients also use cannabis to reduce the nausea and anorexia of cancer chemotherapies and to improve their mood and outlook—frequently with their oncologist’s approval.

With the advent of state medical cannabis laws beginning with California in 1996, medical cannabis has become commercially available in many states as herbal material that may be smoked or vaporized, as well as consumed in a wide variety of other preparations (Table). In addition to the various formulations available through state-based programs, pharmaceutical-grade whole herbal cannabis extracts have been under development during the past 2 decades. The first product to gain approval for medical use was Sativex, a whole herbal extract standardized to a THC: CBD ratio of 1:1 and administered as a sublingual spray. Sativex was approved in Canada for use in multiple sclerosis in 2005 and chronic cancer pain in 2006, and has been approved for medical use in at least 2 dozen countries, although it is not FDA approved. More recently, a liquid formulation of pure plant-derived CBD (Epidiolex) has been undergoing trials as an anticonvulsant for seizures refractory to other available treatments.

 

 

Health effects of cannabis: the recent National Academy review and beyond

The National Academy of Sciences, Engineering, and Medicine recently issued a report using weight-of-evidence categories in reviewing and evaluating the overall scientific literature that supports therapeutic and other health effects of cannabis or cannabinoids.3 The report concluded that there are several clinical problems for which there is conclusive or substantial evidence that cannabis or cannabinoids are effective—chronic pain, chemotherapy-induced nausea and vomiting, and patient-reported multiple sclerosis spasticity symptoms.

 

The report also concluded that there is moderate evidence that cannabis or cannabinoids are effective for improving short-term sleep outcomes in individuals with sleep disturbances associated with a variety of conditions. While none of those conditions is regarded as a psychiatric disorder, they all can be associated with other psychiatric symptoms (beyond sleep disturbance) and are all encountered by psychiatrists as comorbid conditions in clinical practice: obstructive sleep apnea, fibromyalgia, chronic pain, and multiple sclerosis. Sleep disturbances are also ubiquitous in the nosological schemes of psychiatry, notably in PTSD where nightmares are a factor.

 

At the community level, psychiatrists often advise against cannabis use, while some may recommend or approve it as an adjunctive therapeutic for patients with specific diagnostic entities and/or target symptoms. Patient reports that cannabis may relieve some of their symptoms are corroborated by a growing body of clinical literature that is as yet underdeveloped from a research perspective.1 For other patients, the expression of a psychotic disorder may have been preceded by long-term cannabis use and/or cannabis use may be seen as an ongoing factor that exacerbates symptoms of mental illness.

The National Academy report concluded that there is substantial evidence of a statistical association between cannabis use and the development of schizophrenia or other psychoses, and that the risk is highest among the most frequent users. The increased risk is a weak effect, and the causal implications of the association unclear. Although cannabis use may lead to exacerbation of psychosis in some patients, the possibility remains that patient use for symptom relief may account in part for the statistical association.

 

Schizophrenia, CBD, and THC

 

Molecular CBD has been shown to treat symptoms of schizophrenia under controlled clinical trial conditions, with results comparable to those of treatment with an approved antipsychotic medication, and with a favorable adverse-effect profile.4 Other studies support the view that CBD may have therapeutic potential as an antipsychotic and may counter or offset psychotomimetic effects of THC. Differences between THC and CBD notwithstanding, in a small case series, 6 patients with schizophrenia and a history of symptom relief with cannabis use were treated with the addition of low-dose prescription THC to regimens that included clozapine in some cases or multiple antipsychotics in 1 patient.5 Four of the 6 patients showed improvement with the addition of THC to their regimen, and in 3 of the 4 patients a specific antipsychotic effect was evident. As with the anxiogenic potential of THC, dosage may be important in the relationship between THC and psychosis.

 

Cannabis and cognition

 

The National Academy report also acknowledged that there is moderate evidence of a statistical association between cannabis use and better cognitive performance among individuals with psychotic disorders and a history of cannabis use. It has been speculated that this could represent a less cognitively vulnerable subgroup of patients who would not have developed psychosis in the absence of exposure to cannabis, but this is not known. More generally, there is moderate evidence of a statistical association between acute cannabis use and impairment in the cognitive domains of learning, memory, and attention. However, results have been mixed on the question of longer-term and residual cognitive impairment. A recent report indicates neuropsychological decline in persistent long-term users with cannabis use disorders, although an earlier meta-analysis found no

residual impairment.6,7 Evidence of impaired academic achievement and educational outcomes was judged to be limited according to the National Academy report. Again, with cognitive functioning as with the risk of psychosis, dosage may be an important factor, since the findings of impairment relate primarily to heavy long-term use and even more specifically to those patients with cannabis use disorders.

 

Cannabis, cannabinoids, and dementia

 

Although the National Academy report did not find evidence of therapeutic effects of cannabis or cannabinoids for symptoms associated with dementia, several interesting findings in this area are worth mentioning. Basic scientific evidence suggests that cannabinoids may suppress neuronal excitotoxicity and neuroinflammation and be potentially beneficial in targeting plaque formation in Alzheimer disease.8 However, the only clinical applications of cannabinoids in patients with dementia have involved targeting behavioral disturbances including agitation, food refusal, and irritability in small open studies with reported success.

 

A recent single-photon emission computed tomography study of patients with cannabis use disorders found decreased cerebral blood flow in a number of regions including the hippocampus. The investigators speculated that individuals with cannabis use disorders may be at increased risk for Alzheimer disease based on previous findings relating that risk to decreased hippocampal blood flow.9 Further studies will be necessary to investigate the potential therapeutic applications of cannabinoids in dementia, and whether excessive long-term cannabis use is a potential risk factor.

 

Cannabis and PTSD

 

Evidence that cannabis or cannabinoids are effective for improving symptoms of PTSD is considered limited by the National Academy report, but clinical reports and case series excluded under its research quality criteria are more positive for the benefits of cannabis for PTSD symptoms. A growing number of states have included PTSD as one of the acceptable indications for recommending or approving medicinal use of cannabis. Clinicians who have written large numbers of medical cannabis recommendations have documented that a sizeable minority have been for psychiatric indications, with PTSD being perhaps the most common.10

 

Greer and colleagues11 reported on 80 patients with PTSD who were approved for medicinal use of cannabis through the New Mexico Medical Cannabis program. As a retrospective assessment, the study’s methodology limits the scientific conclusions that can be drawn. However, the authors reported decreases of 75% overall and separately in each of the 3 respective (DSM-IV) symptom clusters: re-experiencing, hyperarousal, and avoidance, as measured by current versus retrospective baseline Clinician Administered PTSD Scale (CAPS) scores, with and without cannabis use, respectively. The study was not included in the National Academy report, but it was reviewed by Walsh and colleagues,1 who noted that most studies on the therapeutic use of cannabis by persons with mental health conditions are not of methodologically high quality.

 

The beneficial effects of cannabinoid medicines for PTSD are consistent with what is known about the psychobiology of PTSD and the emerging research on the endocannabinoid system.12 Components of the endocannabinoid system include cannabinoid (CB1 and CB2) receptors; endogenous ligands anandamide, 2-arachidonoylglycerol (2-AG), and others; and enzymes that regulate endocannabinoid ligand production. Endocannabinoid signaling occurs in retrograde fashion, with postsynaptic release of ligands that bind to presynaptic cannabinoid receptors and inhibit presynaptic neurotransmitter release. This contrasts with the classic monoaminergic neurotransmitter systems that have shaped much of our thinking in psychopharmacology, and represents a potential alternative strategy for psychopharmacologic intervention (Figure).

 

CB1 receptors are widespread throughout the brain. Based on animal and human studies, the endocannabinoid system appears to be involved in the extinction of aversive memories, and both THC and CBD have been shown individually in separate studies to facilitate extinction of the conditioned fear response.13,14 Recent neuroimaging studies have found increased CB1 receptor availability in multiple brain regions in PTSD, including the amygdala-hippocampal-cortico-striatal circuit implicated in its pathophysiology.15

The National Academy report also found limited evidence of an association between cannabis use and increased severity of symptoms among individuals with PTSD, but the cause-and-effect relationships are unclear. Individuals with more severely symptomatic PTSD may be more likely to self-medicate with cannabis. The possibility of symptom exacerbation with cannabis use must be weighed against reported therapeutic benefit in individual cases. Other psychiatric diagnoses for which the National Academy report found limited evidence for effectiveness include Tourette syndrome and social anxiety disorders.

 

Cannabis and opioids

 

The National Academy report did not find evidence to support or refute the conclusion that cannabis or cannabinoids are effective in achieving abstinence from addictive substances. However, one study of molecular THC to decrease opioid withdrawal during acute detoxification and increase treatment retention with naltrexone found that patients who elected to continue smoking marijuana were more likely to complete treatment.16

On the issue of whether cannabis access might impact opioid use and related problems, other recent studies have found decreased mortality17 due to opioid narcotic overdoses and reductions in hospitalizations18 related to opioid dependence and opioid overdose in states that have passed medical cannabis laws. Another recently published analysis of data on 44,000 illicit opioid users who completed the National Survey on Drug Use and Health from 2007 to 2013 found that marijuana use was associated with a 55% reduced risk of past year opioid abuse.19

 

Knowledge gaps: risks and benefits of cannabis for psychiatric patients

 

Much of the foregoing discussion has focused on the 2 compounds in herbal cannabis that have received the most research attention and have also been of greatest clinical interest: THC and CBD. There are, however, numerous other compounds that are unique to cannabis. The concentrations of these compounds vary widely among the genetically different strains of cannabis and the conditions under which the plant is grown. At this point, we have insufficient research on cannabis and its constituent cannabinoids and terpenes to fully understand its potential to help or harm psychiatric patients and therefore guide clinical practice.

 

Many states with medical cannabis dispensaries have “counselors” who help guide patients to find the strain of cannabis most likely to benefit the patient’s symptoms. While such guidance is an imprecise proposition and there is substantial subjectivity in whether a given variety of cannabis will reduce symptoms, there are some generalities that guide dispensary counselors in their decisions about cannabis strain selection.

 

Most medical cannabis is from the Cannabis sativa plant, the Cannabis indica plant, or a hybrid variety derived from cross-breeding the two. Broadly speaking, the conventional wisdom is that marijuana and its extracts from Cannabis indica tend to be more sedating and produce more muscle relaxation than those from Cannabis sativa varieties, and patients with anxiety, insomnia, and chronic pain are frequently steered toward those strains. However, named strain variations are not the only source of self-selection of specific varieties of cannabis by patients. Many medical dispensaries offer laboratory analyses of the major cannabinoid concentrations in the cannabis they sell. As with the products mentioned above, the primary cannabinoid compounds of interest have been THC and CBD, but there are others of potential interest.

 

The medical cannabis patient and the practicing psychiatrist

 

Psychiatric patients may use medical cannabis to ameliorate their symptoms, either while in active psychiatric treatment or as a “more natural” alternative. If they are in active psychiatric treatment, they may be receiving additional pharmacotherapy. The astute clinician would want to know the details of the patient’s cannabis use; be alert for adverse effects and potential drug interactions; openly discuss the strengths and weaknesses of cannabis use in psychiatric treatment; and follow the emerging literature on its potential effect on psychopathology, treatment outcomes, and long-term prognosis.

Patients may feel stigmatized not only by their mental disorder, but also by their cannabis use, and may be reluctant to discuss it with their provider for fear of being denied treatment or labeled a substance abuser in need of rehab. Open discussions between psychiatrist and patient about the patient’s cannabis use can potentially be beneficial, especially if the psychiatrist is receptive to learning about the perceived benefits of using cannabis.

 

Physician advice on reducing smoking and alcohol consumption has a real impact on patient behavior. Perhaps an open and stigma-free discussion about the frequency of cannabis use and the dosing and composition of cannabis might reduce the subsequent risk for a cannabis use disorder or a psychotic break. Actual therapeutic benefit from cannabis use for any given patient might help to minimize total psychotropic medication burden, decrease reliance on opioid analgesics, and/or decrease or eliminate alcohol use. The challenge for modern psychiatry is to recognize the widespread use of cannabis in our society, to advocate for research that fills in our knowledge gaps, to recognize that there are both risks and benefits for psychiatric patients, and to acknowledge that patients need to discuss their cannabis use with their psychiatrists without shame or fear.

 

 

 

MORE ABOUT Christopher G. Fichtner, MD

 

Dr. Fichtner is a Clinical Professor of Psychiatry at the University of California, Riverside School of Medicine, and a staff psychiatrist with the Riverside University Health System—Behavioral Health. He received his medical degree from The University of Chicago Pritzker School of Medicine (1987). Dr. Fichtner is a diplomate of the American Board of Psychiatry and Neurology and a Fellow of the American Psychiatric Association, with specialty certification in administrative psychiatry. In addition, he is a Fellow of the American Association for Physician Leadership and a past President of the American Association of Psychiatric Administrators. His work in federal (VA), state, and county public mental health systems included a stint as Illinois State Mental Health Director (2003 to 2005), which shaped his views on drug policy.

 

In 2010, Well Mind Books published Cannabinomics: The Marijuana Policy Tipping Point, in which he argued that impending large-scale policy change was evident in 3 converging policy trajectories: growing consumer demand for medicinal cannabis access (medical marijuana); increasing recognition of drug war failure, especially as it relates to widespread cannabis use (public health); and the increasingly apparent economic potential of a socially integrated cannabis industry (legalization).

 

In Cannabinomics, he intimated that marijuana policy reform would likely be associated with public health benefits—especially through naturalistic substitution of cannabis for alcohol. Examples of patient use of cannabis as an alternative to opioid analgesics also featured prominently in the book. Emerging data—cited briefly in his article with Howard Moss, MD, in this issue of Psychiatric Times—support the view that marijuana policy liberalization holds potential as a partial solution to the opioid crisis.

 

Dr. Fichtner’s media appearances in connection with his book have included interviews with Dylan Ratigan (MSNBC), Paul Eggers (First Business, PBS), Bill Moller (WGN Radio), and Brad Pomerance (Charter California Edition).

In 2016, Dr. Fichtner received the UCR School of Medicine Psychiatry Education Service Award.

 

 

Disclosures

 

 

 

 

Dr. Fichtner reports no conflicts of interest concerning the subject matter of this article. Dr. Moss reports that he owns 24 common stock shares of GW Pharmaceuticals currently valued at $2900 in his IRA. GW Pharmaceuticals is the maker of the drugs Sativex and Epideolex.

Dr. Fichtner and Dr. Moss are Clinical Professors of Psychiatry at the University of California, Riverside School of Medicine.

 

References

 

 

 

1. Walsh Z, Gonzalez R, Crosby K, et al. Medical cannabis and mental health: a guided systematic review. Clin Psychol Rev. 2017;51:15-29.

2. Grant I, Atkinson JH, Gouaux B, Wilsey B. Medical marijuana: clearing away the smoke. Open Neurol J. 2012;6:18-25.

3. Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda; Board on Population Health and Public Health Practice; Health and Medicine Division; National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. A Report of the National Academies of Sciences, Engineering, and Medicine. Washington, DC: The National Academies Press; 2017.

4. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translat Psychiatry. 2012;2:e94.

5. Schwarcz G, Karajgi B, McCarthy R. Synthetic delta-9-tetrahydrocannabinol (dronabinol) can improve the symptoms of schizophrenia. J Clin Psychopharmacol. 2009;29:255-258.

6. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. PNAS. 2012:E2657-E2664.

7. Grant I, Gonzalez R, Carey CL, et al. Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol Soc. 2003;9: 679-689.

8. Walther S, Halpern M. Cannabinoids and dementia: a review of clinical and preclinical data. Pharmaceuticals. 2010;3:2689-2708.

9. Amen DG, Darmal B, Raji CA, et al. Discriminative properties of hippocampal hypoperfusion in marijuana users compared to healthy controls: implications for marijuana administration in Alzheimer’s dementia. J Alzheimer Dis. 2017;56:261-273.

10. Gieringer D. Medical use of cannabis: experience in California. In: Grotenhermen F, Russo E, eds. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. New York: Haworth Integrative Healing Press; 2002:143-151.

11. Greer GR, Grob CS, Halberstadt AL. PTSD symptom reports of patients evaluated for the New Mexico Medical Cannabis Program. J Psychoactive Drugs. 2014;46:73-77.

12. Krumm BA. Cannabis for posttraumatic stress disorder: a neurobiological approach to treatment. Nurse Pract. 2016;41:50-54.

13. Abush H, Akirav I. Cannabinoids modulate hippocampal memory and plasticity. Hippocampus. 2010;20:1126-1138.

14. Akirav I. The role of cannabinoids in modulating emotional and non-emotional memory processes in the hippocampus. Front Behav Neurosci. 2011;5:34.

15. Neumeister A, Normandin MD, Pietrzak RH, et al. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry. 2013;18: 1034-1040.

16. Bisaga A, Sullivan MA, Glass 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.

17. Marcus A, Bachhuber MA, Saloner B, et al. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Int Med. 2014;174:1668-1673.

18. Shi Y. Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever. Drug Alcohol Depend. 2017;173:144-150.

19. Pisano VD, Putnam NP, Kramer HM, et al. The association of psychedelic use and opioid use disorders among illicit users in the United States. J Psychopharmacol. 2017. http://journals.sagepub.com/doi/abs/10.1177/0269881117691453. Accessed March 21, 2017.

 

 

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