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has identified a potential new mechanism for treating depression. 

The study, conducted by researchers at the Icahn School of Medicine at Mount Sinai, used the drug ezogabine to open the KCNQ2/3 potassium channels in participants’ brains. The results showed significant improvements in 

 Because anhedonia is associated with poor response to antidepressant medication, worse overall outcomes, and increased suicide risk, this finding is especially important. 

“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients,” said the paper’s lead author, James Murrough, MD, PhD, associate professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai. “Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment.”

The study included 45 participants with high levels of anhedonia and divided them into 

 The treatment lasted 5 weeks, with clinical measures of depression and anhedonia taken at weekly visits. Although the study did not meet its primary endpoint at the 5-week mark, it found that participants on ezogabine had increased reward anticipation and large improvements on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), compared with the placebo.

The United States Food and Drug Administration approved ezogabine in 2011 as an anticonvulsant for epilepsy, but this is the first study to test it as a depression treatment. The drug acts on the KCQ2/3 channel, which affects brain cell function by regulating the movement of electrical charges across cell membranes.

A previous study led by co-author Ming-Hu Han, PhD, found that changes in KCNQ2/3 potassium partially determined whether mice showed 

signs of depression and anhedonia following stress

 Mice with increased KCNQ2/3 channels in their brains appeared resistant to depression. When the mice were given drugs to increase KCNQ2/3 channel activity, previously depressed mice no longer showed depressive or anhedonic behaviors.

“The fundamental insight by Dr Han’s group that a drug that essentially mimicked a mechanism of stress resilience in the brain could represent a whole new approach to the treatment of depression was very exciting to us,” said Murrough.

 The previous study by Han’s group paved the way for the current study.

“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression,” Han said of the current study.

 “We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders.”

1. Mount Sinai Health System. Researchers identify brain ion channel as new approach to treating depression. 

. March 1, 2021. Accessed April 7, 2021. 

https://www.newswise.com/articles/researchers-identify-brain-ion-channel-as-new-approach-to-treating-depression?sc=dwhr&xy=5013482

2. Costi S, Morris LS, Kirkwood KA, et al. Impact of the KCNQ2/3 channel opener ezogabine on reward circuit activity and clinical symptoms in depression: results from a randomized controlled trial. 

3. Friedman AK, Juarez B, Ku SM, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. 

Opening certain potassium channels in the brain reduces depressive symptoms and anhedonia. 

Is There a New Mechanism for Treating Depression?

The way to treat anxiety in bipolar disorder is to treat the bipolar disorder. Anxiety is a synonym for distress, and nearly all mental disorders cause distress, except perhaps the classic, euphoric manias that lift the patient into a carefree state of bliss.

Some mood episodes are more anxiety-provoking than others, and at the top of the list are mixed states. Although anxiety does not appear in the criteria for mixed states, it is often created when 

 The International Society for Bipolar Disorders has even calculated the exact proportions for this troubling recipe. It takes only 1 manic symptom during a depression, or 2 depressive symptoms during a mania, to spark anxiety.

Mixed states tend to respond better to anticonvulsants and atypical antipsychotics than to lithium, which may be why anxiety predicts resistance to lithium in 

 There are, however, 2 exceptions to this rule: suicide and panic disorder. Both mixed states and anxiety raise the risk of suicide in bipolar disorder, and lithium 

 This preventative effect is independent of lithium’s mood benefits, so it is worth considering lithium in patients who are suicidal, even when it has a lower chance of reducing the core symptoms.

Although the classic lithium-responsive patient tends to have pure manias and hypomanias and no anxiety disorder comorbidities, a recent study identified panic disorder as a 

 Although anxiety is low in pure mania and hypomania, these patients are on high alert for threat, which is the essence of panic disorder. One study found that they had more phobias of panic sensations than patients in 

The next step in treating mixed states is to reduce antidepressants and anything else that contributes to manic symptoms (eg, drugs of abuse, steroids, and irregular circadian rhythms). Most patients who are in a mixed state have been on an antidepressant for a long time, and it can be difficult to tell if the drug is exacerbating the mixed presentation. Given these uncertainties, it is best to taper slowly, 

 Rapid discontinuation can trigger mania and other mood symptoms. The work is much like tapering a benzodiazepine. If the symptoms worsen, raise back the dose and slow down the taper.

In bipolar disorder, anxiety is a non-specific symptom with 

, including mood episodes, stress, and comorbid anxiety disorders. With so many different causes, can any mood stabilizer truly be said to be anxiolytic? Probably not, but we do have a few trials that may point the way when selecting a mood stabilizer for a patient with significant anxiety.

Among the anticonvulsants, valproate and lamotrigine improved anxiety in small controlled trials of 

 Valproate’s evidence here is more robust, and this medication also improved anxiety in patients who do not have bipolar disorder, perhaps because of its benzodiazepine-like 

 Lamotrigine may also treat obsessive compulsive disorder through glutamatergic effects, based on a small placebo controlled and several uncontrolled studies.

The atypical antipsychotics can also improve anxiety. Quetiapine and olanzapine reduced anxiety in large, randomized, placebo-controlled trials of patients with bipolar depression and non-specific anxiety (both were secondary analyses). The effect sizes were large enough to make them noticeable to the casual observer (

0.35 for olanzapine and 0.56 for quetiapine

 Quetiapine had similar anxiolytic effects in the 300 mg and 600 mg doses, and olanzapine had similar anxiolytic effects as monotherapy or when paired with fluoxetine.

These anxiolytic properties do not seem to extend to other atypical antipsychotics. Ziprasidone and risperidone both failed in placebo-controlled trials of bipolar disorder with anxiety, and risperidone actually worsened anxiety in a study of bipolar with comorbid panic disorder.

The unanswered question here is whether these medications were targeting anxiety directly or treating mild mixed states. Most of the patients had 1 to 2 manic symptoms along with their depression, judging from their average Young Mania Rating Scale of 5, and anxiety was higher as the 

 On the other hand, quetiapine has a large effect size in generalized anxiety disorder (GAD), suggesting 

 Quetiapine came close to FDA approval in GAD, but was held back because the FDA did not think this disorder was severe enough to warrant all the risks of an antipsychotic. That lesson applies to bipolar disorder as well. Quetiapine may be very effective for anxiety, but it should not be used in mild cases.

Anxiety may not offer a direct path to pharmacotherapy in bipolar disorder, but it does tell us something about the care of the patient. These patients are at greater risk for treatment dropout, adverse effects of medications, substance abuse, and suicide. Supportive psychotherapy, fast-acting treatment, and an extra phone call to make sure they are tolerating any new medication go a long way in these cases.

is the Mood Disorders Section Editor for 

 and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently 

The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis.

2. Swann AC, Secunda SK, Katz MM, et al. 

Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome.

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment.

4. Nunes A, Ardau R, Berghöfer A, et al. 

Prediction of lithium response using clinical data.

5. Simon NM, Otto MW, Fischmann D, et al. 

Panic disorder and bipolar disorder: anxiety sensitivity as a potential mediator of panic during manic states.

Treating anxiety by discontinuing antidepressants: a case series.

Treating nonspecific anxiety and anxiety disorders in patients with bipolar disorder: A review.

Divalproex in the treatment of bipolar depression: a placebo-controlled study.

9. Sheehan DV, Harnett-Sheehan K, Hidalgo RB, et al. 

Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient.

10. Bach DR, Korn CW, Vunder J, Bantel A. 

Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.

Valproate (depakine-chrono) in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study.

12. Bruno A, Micò U, Pandolfo G, et al. 

Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study

. J Psychopharmacol. 2012;26(11):1456-1462.

13. Lydiard RB, Culpepper L, Schiöler H, et al. 

Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies.

14. Tohen M, Calabrese J, Vieta E, et al. 

Effect of comorbid anxiety on treatment response in bipolar depression.

15. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. 

Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis.

Some mood episodes are more anxiety-provoking than others, and at the top of the list are mixed states.

How to Treat Anxiety in Bipolar Disorder

 (COVID-19) crisis continues, we hear more and more about the current—and projected—mental health fallout from illness, lockdown, job loss, forced relocation, loneliness, loss of friends and family, and death. Data about the direct neuropsychiatric sequelae of COVID-19 infection in addition to the indirect social or economic consequences are also mounting. Yet we do not hear about individuals with social anxiety disorder, or individuals on the high end of autism spectrum disorder (ASD), who are also socially anxious and relieved to be working from home.

Free from the social pressures of the job site, many of these individuals report feeling less distress overall. They are not necessarily free from anxiety altogether; their anxiety focuses on fears of being forced to return to offices when the epidemic ends. They are perturbed by the prospect of sacrificing the social obligation-free sanctuary that they have serendipitously and unexpectedly enjoyed during this strange time.

 taken of a group of workers; it found 80% wanted to continue to work remotely at least part of the time after the pandemic. Individuals with social anxiety disorder presumably comprise some small part of the 80%, yet it is unlikely that all 80% of the WSJ sample want to work remotely for the same reasons as the patients I am discussing. The article, “Is a Home Office Actually More Productive? Some Workers Think So,” detailed the motivations of generic employees, focusing on financial and family drivers of their choice of workplace, but does not break down data by personality type or DSM diagnosis.

Before commenting on experiences relayed to me by the aforementioned subgroup of my patients, let us first look at the better publicized psychiatric fallout from the COVID-19 crisis. Centers for Disease Control and Prevention (CDC) 

 from late June 2020 state that 40% of the American population were facing COVID-related depression, anxiety, stress-related disorders, or substance use.

high-risk groups, noting that financial stressors, including epidemic-related job loss, along with limited savings to cushion the blow, increased an individual’s risk for mental health sequelae.

 about increasing drug and alcohol use are equally grim from a medical and mental health point of view, given that liquor sales skyrocketed during lockdown, as per several articles in the WSJ.

 Anonymous liquor store owners have said that demands for their stock during the epidemic rivals sales seen only during weeks between Christmas and New Year’s.

We can estimate the long-term mental and medical impact of alcohol overuse, even though many medical consequences of alcohol overuse do not surface for 20 years. The potentially lethal cardiovascular, oncological, as well as gastrointestinal consequences are not as obvious or immediate as motor vehicle accident-related deaths or fatal subdural bleeds from slip-and-fall accidents that occur while intoxicated. Yet those later sequelae are just as deadly in the long run, so much so that 

 is twice that of the better-publicized opioid-related mortality,with alcohol claiming over 95,000 lives per year,

 compared with 46,800 annual opioid overdoses.

Opiate overdoses have already exploded. If we extrapolate from data related to September 11, 2001, when 

 in Manhattan remained high long after posttraumatic stress disorder symptoms subsided,

 we can anticipate (but not guarantee) similar consequences from this epidemic.

Alarmist claims about projected increases in suicide hit the press, having borrowed data from CDC websites and embellished it with artistic license not appropriate to scientific studies. Some of the most ominous predictions have been refuted; after reading the fine print, we can see that these highly publicized numbers about suicide pertain to individuals who were contemplating suicide rather than to completed suicides. In response to those data, some British medical journals 

 readers that “supposition, however, is no replacement for evidence,” and that “the literature on the effect of COVID-19 on suicide should be interpreted with caution.”

Although reports of increased suicidal ideation since the start of the COVID-19 crisis were striking enough to enter the CDC logs, we must recall that suicidal ideation is not the same as attempted suicide, and that attempted suicide is not identical to completed suicide.

In addition, a New York City Health Department 

 “Mental Health in New York City: Impact of COVID-19 on Mental Health in New York City,” published in September 2020 and emailed widely in January 2021, offered even more 

 It dissected the data, breaking it down by race and ethnicity, and ferreted even more risk factors for anxiety and depression. It focused on the greater New York area, where most of my patients reside. Similar to the 

data, the 3 top drivers of psychological distress included “feeling cut off or distant from people,” “job loss or reduced hours,” and “overwhelming or above-average financial stress.” Interestingly, many individuals on the spectrum specifically prefer to be “distant from people,” although individuals with pure social anxiety disorder often lament their limitations in partaking in such social activities.

What do these data tell us about the socially phobic individuals who report less stress during the lockdown, but experience more stress when contemplating the possibility of a return to onsite work? Let me point out that although the data showed that 40% of the American population endorsed symptoms of depression, anxiety, or trauma during the shelter-in-place mandates and work-from-home policies, this is not the same as saying that 100% of the population is suffering similarly.

My clinical experience indicates that some individuals are benefiting from limits on social interactions; they prefer the work-at-home policies and appreciate convenient excuses to avoid after-work get-togethers and sit-down holiday dinners.

Admittedly, I cannot offer elegant statistics to rival numbers garnered from formal population-based quantitative studies. All I can share are anecdotal reports gleaned from my large private psychiatric practice, originally based in New York City, but now relocated offsite to upstate New York. Yet those anecdotal reports are impressive. Gainfully employed but socially phobic patients and those on the high end of the autism spectrum (who also tend to be debilitated by social anxiety) are doing better than baseline now that they are freed from the pressures of office politics, enforced personal interactions, and water cooler–style conversations.

In many instances, such individuals experienced an unexpected sense of relief, as well as a sense of accomplishment, after seeing that they could meet their work responsibilities even better without expending extra mental energy ruminating about social interactions, wondering if they said the right thing, and worrying about being forced to speak up in meetings. Having witnessed how much easier their lives can be without the usual social stresses, they identify a different source of anxiety: fear of forced return to the workplace.

Before proceeding, I must point out that the patients to whom I refer are actively and gainfully employed—and so they do not fall into the high-risk categories identified by the 

article. They did not experience the stressors, such as job loss or lack of savings, that predispose individuals to COVID-19–related psychological distress. Because they were working before the pandemic, they likely accrued savings that further buffer them from the financial stressors listed in the 

Recall that socially phobic individuals are unlikely to speak out for themselves. For them, confrontations with their boss or coworkers are even worse than water-cooler conversations.

And that is where we as psychiatrists can help. Selective serotonin reuptake inhibitors (SSRIs) and supportive therapy go only so far in ameliorating their symptoms and relieving their distress. Advocating for changing their external environment—while we change their internal environment through psychotropic medications and psychotherapy—can offer them so much more relief.

 accommodations that may allow them to continue to work from home even after the epidemic ends (with some caveats). Familiarizing ourselves with the Department of Labor website (

) will enable us to educate our patients and to direct them to standardized sources without offering legal advice that exceeds our clinical training or purview.

At a time when so many psychiatrists are concerned with climate change and its impact on mental health, should we not also concern ourselves with adapting workplaces to meet the needs of our patients? We can advocate for change, simply by following the laws that are already in place for such purposes.

 is an assistant clinical professor of psychiatry and behavioral sciences at Icahn School of Medicine at Mount Sinai, New York, NY.

1. Stamm S. Is a home office actually more productive? Some workers think so. 

https://www.wsj.com/articles/is-a-home-office-actually-more-productive-some-workers-think-so-11609563632

2. Centers for Disease Control and Prevention. Coronavirus disease 2019. Accessed February 10, 2021. 

https://www.cdc.gov/coronavirus/2019-ncov/index.html

3. Ettman CK, Abdalla SM, Cohen GH, et al. Prevalence of depression symptoms in US adults before and during the COVID-19 pandemic. 

4. Chaudhuri S. Coronavirus closed the bars. America stocked the liquor cabinet. 

https://www.wsj.com/articles/coronavirus-closed-the-bars-america-stocked-the-liquor-cabinet-11586511001

5. Jakab S. The WHO are a bunch of party poopers. 

https://www.wsj.com/articles/the-who-are-a-bunch-of-party-poopers-11587046692

6. Chaudhuri S. Online beer sales soar at brewers of Budweiser, Miller Lite. 

https://www.wsj.com/articles/online-beer-sales-drinking-at-home-boosts-budweiser-brewer-11603968729

7. Centers for Disease Control and Prevention. Deaths from excessive alcohol use in the US. Accessed February 15, 2021. 

https://www.cdc.gov/ALCOHOL/FEATURES/EXCESSIVE-ALCOHOL-DEATHS.HTML

8. Centers for Disease Control and Prevention. Drug overdose deaths. Accessed February 15, 2021. 

https://www.cdc.gov/drugoverdose/data/statedeaths.html

9.Packer S. Tele-teatime during the quarantine. 

https://www.psychiatrictimes.com/view/tele-teatime-during-quarantine

Trends in suicide during the covid-19 pandemic

. 2020;371:m4352. doi:10.1136/bmj.m4352.

11. New York City. Mental health in New York City: Impact of COVID-19 on mental health in New York City. September 2020. 

https://www1.nyc.gov/assets/doh/downloads/pdf/covid/covid-19-mental-health-impacts-hop.pdf

Patients who are report social phobia are unlikely to speak out for themselves. For them, confrontations with their boss or coworkers are even worse than water-cooler conversations. That is where psychiatrists can help.





The Other Side of the COVID-19 Crisis: The Silent, Socially Phobic Minority 

 and the Columbia University Breakthrough Session, hosts Angela Coombs, MD, and Jennifer Sotsky, MD, discuss the possibilities and promise of psilocybin to treat psychiatric disorders and in enhancing everyday experiences with 

. Landmark studies and new research about the use of hallucinogens includes potential to treat:

Posttraumatic stress disorder
Substance use disorders


Psilocybin (mushrooms) and other hallucinogens from plants and some animal life generate perceptual changes and hallucinations, altered physical sensations, strong emotional reactions, and even dissolution of self.

The question is whether these are 

 or trips and whether they can result in lasting changes in the patient. Over time, some of the brain connections may become disrupted and new circuits may become activated.

Dr Hellerstein is a professor of clinical psychiatry at Columbia University and is conducting clinical trials of psilocybin. His books include 

Heal Your Brain: How the New Neuropsychiatry Can Help You Go from Better to Well

is a board-certified psychiatrist and assistant professor in Clinical Psychiatry at Columbia University Medical Center and the New York State Psychiatric Institute. She serves as the medical director and team psychiatrist at ONTrackNY Washington Heights Community Service clinic. She completed her public psychiatry fellowship and adult psychiatry residency at Columbia University where she was a chief resident and co-organized the curriculum on racial/ethnic mental health disparities. In addition to her clinical work in the public sector, she also works in Columbia's psychiatric emergency room and has a private practice in Upper Manhattan.



is a fellow in consultation-liaison psychiatry at Columbia University Irving Medical Center with a part time private practice. She was formerly a chief resident at Columbia’s psychiatry residency program. Before medical training, she received an MS in Narrative Medicine, an interdisciplinary field that studies illness through a humanities lens. She is co-author of 

Conquering Lyme Disease: Science Bridges the Great Divide

 and has interests in medical education, psychotherapy, and medical humanities.



Columbia University Department of Psychiatry

 for allowing us to present the Breakthrough Session podcast with experts in the field of psychiatry.


Research on psilocybin, LSD, and other hallucinogens as psychiatric treatments are in their renaissance, transitioning from banned and illegal to potentially useful in changing life for the better in some patients. More in this podcast.

David Hellerstein, MD: Psychedelic Treatments for Psychiatric Disorders



In this installment of PsychPearls and the Columbia University Breakthrough Session, hosts Angela Coombs, MD, and Jennifer Sotsky, MD, discuss anxiety with 

Anxiety as cultural phenomenon vs individual illness

Help-seeking as a sign of strength and self-knowledge


Dr Albano is professor of medical psychology (in Psychiatry) at Columbia University and director of the 

Columbia University Clinic for Anxiety and Related Disorders

 (CUCARD). She is a clinical psychologist and board-certified in clinical child and adolescent psychology. In addition to serving as director of CUCARD, she also conducts research and trains residents, fellows, and psychology postdoctoral fellows and interns. Her research is focused on the development and testing of psychosocial treatments for anxiety and mood disorders, and in understanding the impact of these disorders on the developing youth. Dr Albano devotes her career to the study and treatment of anxiety and mood disorders in children, adolescents, and young adults. She is an expert diagnostician and cognitive-behavioral therapist. Dr. Albano co-developed a cognitive behavioral treatment program for adolescents with social phobia. She has published more than 90 articles and chapters and is the coauthor of several cognitive behavioral treatment manuals, including 

Anxiety Disorders Interview Schedule (ADIS-IV) Child and Parent Interview Schedules.

is a board-certified psychiatrist and assistant professor in Clinical Psychiatry at Columbia University Medical Center and the New York State Psychiatric Institute. She serves as the medical director and team psychiatrist at ONTrackNY Washington Heights Community Service clinic. She completed her public psychiatry fellowship and adult psychiatry residency at Columbia University where she was a chief resident and co-organized the curriculum on racial/ethnic mental health disparities. In addition to her clinical work in the public sector, she also works in Columbia's psychiatric emergency room and has a private practice in Upper Manhattan. 

 is a fellow in consultation-liaison psychiatry at Columbia University Irving Medical Center with a part time private practice. She was formerly a chief resident at Columbia’s psychiatry residency program. Before medical training, she received an MS in Narrative Medicine, an interdisciplinary field that studies illness through a humanities lens. She is co-author of 

Thanks to Columbia University Department of Psychiatry for allowing us to present the Breakthrough Session podcast with experts in the field of psychiatry.



A discussion with professor of medical psychology and director of the Columbia University Clinic for Anxiety and Related Disorders.

Anne Marie Albano, PhD: A Conversation on the Spectrum of Anxiety

A new question must be added to the list that mental health clinicians ask their older patients while taking a history, regardless of age: “Have you used any cannabis products recently?”

I learned this lesson during a follow-up appointment with an 82-year-old man with Alzheimer disease. He reported some rather abrupt cognitive decline, and I asked him and his wife about recent medical changes without finding any clear precipitant. Finally, his wife sheepishly confessed that their son had sent them a grab bag of cannabis-derived products that the patient was taking. The family was desperate for anything to help his cognitive decline and they had heard that cannabis was a miracle cure for Alzheimer disease and many other conditions. Unfortunately, the patient received no benefit but did experience some mild, noticeable adverse effects. Without my probing, I never would have known. The next patient I asked explicitly about using cannabis products responded in an equally explicit manner: “No I haven’t,” he said, “but can you get me some?” It was clear that the age of cannabis had arrived.

Older individuals with psychiatric disorders are increasingly using cannabis, largely in the form of prescribed medical marijuana and cannabidiol (CBD). This trend has been driven by several factors: reduced stigma, lifted restrictions on possession and sale by most states, and the enormous proliferation of articles and ads that tout supposed benefits of 

 for many conditions that afflict the elderly, including chronic pain, peripheral neuropathy, stress, anxiety, depression, insomnia, headaches, and the adverse effects of chemotherapy.

 As a result, medical marijuana use by individuals 65 or older has increased more than 8-fold in recent years, from less than 0.5% in 2006 to 4.2% in 2018

). In a survey of 345 adults in Colorado, 16% had used medical marijuana since legalization, with half the users being 75 or older.

 CBD has seen a particularly enormous surge in interest and availability after it was exempted from federal regulations in the 2018 US Farm Bill. Since then, it is estimated that 6.4% of adults aged 45 to 55 and 3.7% of those 55 or older have used CBD at least once.

Although the cannabis sativa plant contains hundreds of chemicals known as cannabinoids, the 2 main active chemicals are Δ-٩-tetrahydrocannabinol (THC) and CBD. THC has both psychotropic and euphoric properties and confers the high associated with marijuana, while CBD is noneuphoric because it does not activate the cannabinoid 1 receptor like THC does. The same plants that produce THC also produce CBD. Both THC and CBD come in a variety of forms; they can be smoked, vaped, eaten, ingested as liquids, used as oils, and applied via creams and cosmetics.

The psychotropic effects of both THC and CBD are mainly because of their interaction with endogenous cannabinoid receptors in the brain, as well as activation of a variety of other cannabinoid and noncannabinoid receptors (ie, serotonergic, glutaminergic, µ-opioid, and α1-adrenergic) in the central nervous system and on immunologic cells. Based on their known and theorized properties, marijuana and CBD have been proposed as remedies to modulate symptoms of stress, insomnia, pain, inflammation, and cognitive impairment, particularly in older individuals. As a result, there are many unsubstantiated claims that THC and/or CBD can treat Alzheimer disease, Parkinson disease, schizophrenia, and anxiety and mood disorders.

Several small case series have suggested a tentative basis for some of these claims. For example, a study looked at the use of an oral spray containing THC and CBD for peripheral nerve pain and found that it was well tolerated and showed a trend toward improvement in pain and sleep.

 Medical marijuana use has been associated with some improvement in both movements and neuropsychiatric symptoms in individuals with Parkinson disease.

 One small case series found improvement in behavioral and psychological symptoms of dementia from cannabis oil containing THC.

 A related randomized control trial of 50 individuals with dementia and associated neuropsychiatric symptoms did not see any benefit from THC, but did find it was well tolerated and with no appreciable effect on memory.

 Despite these limited data, agitation associated with dementia is a qualifying condition for medical marijuana in several states.

Gruber and colleagues studied a sample of middle-aged individuals using medical marijuana over 3 months and found improvements in 

 and reductions in depression, insomnia, and impulsivity.

 They also saw a reduction in the use of benzodiazepines and opioids as well as a normalization of brain activation waves to states seen in normal controls. It is not clear, however, if these neurocognitive results were the direct result of the medical marijuana or an indirect benefit of decreases in pain, anxiety, and 

Although there are many other in vivo, in vitro, and animal studies of THC and CBD, it is clear that evidence is limited, and there are few randomized controlled trials to support most of their theorized clinical benefits. In addition, these studies are based on a variety of cannabis products from multiple sources and with variable contents.

 The 2 exceptions include a Food and Drug Administration (FDA)-approved form of synthetic THC known as dronabinol, which is used for treating appetite and weight loss resulting from AIDS as well as nausea and vomiting from chemotherapy, and a medication containing CBD for the treatment of 2 rare childhood seizure disorders. Dronabinol has also been studied in Alzheimer disease to treat anorexia and agitation and was found to be well tolerated with variable efficacy for both conditions.

, a CBD-THC combination, has been approved for the treatment of muscle spasms associated with multiple sclerosis.

The use of medical marijuana and CBD in older adults must be approached with caution because there are several potential adverse effects. It has been well established that heavy marijuana use in both young and middle-aged adults can cause mild functional and structural brain impairments affecting attention, 

, motor coordination, verbal memory, and executive function.

 Although these effects may be more variable with lighter use in older adults, they may be amplified by preexisting brain impairment as well as by underlying pulmonary and cardiovascular conditions, especially when medical marijuana is smoked or vaped.

 One review of 184 older patients (median age, 82) who were on medical marijuana for 6 months found that approximately 80% reported some benefit for the treated symptoms, but one-third reported adverse effects, including dizziness (12%) and sleepiness and fatigue (11.2%).

 Other reported adverse effects from a national epidemiologic survey included changes in mood and cognition, psychosis, increased heart rate and blood pressure, urinary retention, and blurred vision.

 In addition, THC has been associated with impaired driving in young adults, which could also be a problem in older drivers who may be impaired at baseline.

 of CBD use found that it is generally well tolerated with few adverse effects, the most common one being diarrhea.

 Other adverse effects associated with CBD include nausea, drowsiness, fatigue, dry mouth, and mood changes. Keep in mind that CBD is an inhibitor of several cytochrome P450 enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2D6, and CYP3A4. CBD can lead to drug-drug interactions with several commonly used medication groups in older patients, including blood thinners, antibiotics, anticonvulsants, antidepressants, and antipsychotics.

What To Ask Patients, and What To Tell Them

In this new era of medical marijuana and CBD, there are several important takeaways for clinicians working with older patients. Do not assume that because a patient is elderly and has physical or cognitive limitations that they do not fit the profile of a cannabis user. To the contrary: Every older patient along with their caregivers should be queried as to their use of cannabis, whether recreationally, from mail order or friends and family, or through a prescription. To this end, every clinical history should include questions about the use of cannabis products, including the stated reasons for use, the type of marijuana or CBD being used, and observed benefits and adverse effects. Concomitant medical conditions must be reviewed for potential vulnerabilities, such as an individual with hypertension using a product that increases blood pressure or heart rate, or an individual with chronic obstructive pulmonary disease using vaping oils. Potential 

 also need to be considered, with a focus on the categories of medications discussed in the article.

Patients and their caregivers need to understand that nearly all benefit claims are largely unsubstantiated, as they lack a rigorous scientific basis. Slick articles and ads generally exaggerate potential benefits, or they refer to in vitro or animal studies and anecdotal reports, making them sound as if they constitute direct evidence of clinical effects. They also need to understand the differences between THC and CBD, along with the fact that production is largely unregulated, so products can have many different ingredients and properties. Several studies have found wide discrepancies between labels for cannabis products and their actual contents, especially when it comes to the amount of THC or CBD.

 Thus, many products that claim only to have CBD actually have varying degrees of THC present. This lack of consistency often accounts for both inconsistent clinical effects as well as adverse effect issues, and these factors lead many older adults to discontinue use of cannabis products.

Finally, keep in mind that older patients with preexisting 

 such as in Alzheimer disease might be particularly vulnerable to adverse effects such as drowsiness, dizziness, fatigue, and mood changes, which in turn can account for significant and unpredictable fluctuations in cognition and behavior. Such unpredictability (in the amount of drug being ingested over time and the ensuing effects on brain and body) is exactly the sort of variability that can be hazardous in the older patient. Compounding these risks is the fact that many individuals will use products such as CBD oil without the knowledge and supervision of a knowledgeable clinician.

The bottom line is that more rigorous scientific study using randomized controlled trials is needed to substantiate the proposed benefits of cannabis and more fully understand the range and impact of common adverse effects.

is the chief medical officer at MIND Institute at Miami Jewish Health.

1. Gruber SA, Sagar KA, Dahlgren MK, et al. 

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