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COVID-19 has caused a surprising change in vaping and other substance usage in young adults aged 18 to 25. According to a recent 

 by Mayo Clinic during the pandemic, 44% of young adults decreased vaping, while 27.9% increased their use. Nearly 70% increased their alcohol consumption, while 47.3% decreased tobacco product use. Of those who used marijuana, 39.2% increased use, while 36% decreased use.

“Substance use is highest in the young adult age group, so we wanted to target this population,” Pravesh Sharma, MD, a psychiatrist at Mayo Clinic Health System in Eau Claire, WI, and the study’s lead author, said to the press. “We would like to understand why they vape and what their attitudes were regarding the potentially harmful nature of vaping.”

Before the pandemic, Mayo Clinic researchers were studying the potential harm of vaping to the respiratory system. With the onset of COVID-19, however, the survey shifted course. Rather than solely assessing the factors influencing vaping, the new, adjusted survey investigated young adults’ use of other common substances, such as alcohol, marijuana, and tobacco; and asked questions to better understand the effects of daily stresses during a public health crisis.

“As COVID-19 came on the scene, it was primarily thought to have severe respiratory implications,” said Sharma. “Since we were about to launch a study examining the factors associated with vaping use, which can lead to lung injury, it made sense to revise our questionnaire slightly to address the broader question of the use of vaping and other common substances during a respiratory disease pandemic.”

The survey was sent out in April to approximately 6119 young adults who had been seen in Midwestern Mayo Clinics within 4.2 months before the pandemic. Its release followed the stay-at-home orders and social distancing mandates issued by state and local governments.

Of 1018 respondents, more than half reported vaping, using marijuana, using tobacco, or drinking alcohol during the COVID-19 pandemic. (The authors note that the study’s limitations include a reliance on self-reporting and a 16.6% response rate.)

“We did see some reduction in inhaled substances, which could mean that young adults were reacting to the news coverage of COVID-19’s respiratory effects,” said Sharma.

An interesting, unintended discovery was also made: the more lonely, depressed, or anxious the survey respondents felt, the more likely they were to add or substitute another substance. Perhaps, as Sharma suggested, this was due to an attempt to cope with limited social interactions and strain.

“During the time of this pandemic, screening for substance use, loneliness, anxiety and depression is crucial,” Sharma stated. “Just asking, ‘How are you holding up during this difficult time’ goes a long way.”

1. Sharma P, Ebbert JO, Rosedahl JK, Philpot LM. Changes in substance use among young adults during a respiratory disease pandemic. 

2. Mayo Clinic. Changes in vaping, other substance use, another side effect of COVID-19. News release. November 19, 2020. 

https://www.newswise.com/coronavirus/changes-in-vaping-other-substance-use-another-side-effect-of-covid-19/?article_id=742048&sc=dwhr&xy=5013482

How has the COVID-19 pandemic affected the way young adults use substances like vaping, alcohol, and marijuana? 

A Shift in the Air: Changes in Young Adults’ Vaping and Substance Use During COVID-19

The association between smoking cigarettes and the risk of developing serious and potentially fatal health problems (most notably cardiovascular diseases, pulmonary diseases, and cancer), has long been accepted fact. However, an additional health problem that may also be associated with smoking has often been overlooked: pain.

Two recent papers indicate a strong association between smoking and pain.

 Among the review’s important findings is that those who suffer from chronic pain are substantially more likely to smoke than are those who do not suffer from chronic pain. Although smoking rates continue to decline in the latter group, this does not appear to be occurring in those with pain.

Cigarette smoking has been cited as a risk factor for a wide variety of painful conditions, including back pain, headache, and diabetic peripheral neuropathy. Smoking appears to be associated with both the development and severity of pain.

 specifically studied the most likely locations of pain among individuals who smoke. The study examined data from a 2003-2004 National Health and Nutrition Examination Survey which contained data from comprehensive bodily pain questionnaires in addition to questions on other health issues, including tobacco use.

 The study compared 1054 participants in the survey who smoked tobacco to 1316 who did not.

Those who smoked were found to be more likely to suffer chronic pain. Although the likelihood of pain was increased throughout the body, the study found that spine pain, and especially low back pain, had the strongest association with smoking. The second strongest association was between headaches and smoking. Smoking was also associated with both trunk pain, which included the chest and abdomen, and limb pain. (All statistical associations drawn from 

This is an interesting and perhaps an unexpected finding. Because of the association between smoking and cardiovascular and cerebrovascular problems, it is easy to see why headaches would be fairly common among individuals who smoke. However, it might be reasonably expected that pain in the trunk and limbs would be more common than pain in the spine. The authors suggest that vascular factors may play a greater role in back pain than is often thought.

Whether e-cigarettes, which are becoming more popular, are any less associated with pain than traditional cigarettes remains an unanswered question.

From personal experience treating patients with chronic pain who also smoke, I know that helping them with smoking cessation attempts can be challenging. Although most patients are often well aware of the risks associated with smoking, their pain and its impact on their lives may make it more difficult for them to quit. Their pain may make them feel restricted, and their ability to participate in previously enjoyable activities is limited. Smoking is one of the few such activities in which they can still indulge. They may also feel that smoking helps them cope with the pain.

There is evidence indicating that nicotine may have some analgesic effects, but abstaining from smoking may cause individuals to suffer hyperalgesia, a 

 Thus, those who smoke may receive temporary relief from tobacco use, and their pain may get worse when they try to stop.

Additionally, depression and anxiety are frequent comorbidities among those with chronic pain, and their presence can also contribute to the challenge of getting patients to 

Ultimately, all evidence points to the importance of convincing patients with chronic pain who also smoke that tobacco is not helpful. Indeed, tobacco may be significantly exacerbating their pain and adding to their misery.

The multitude of challenges can understandably make it difficult to convince patients with chronic pain to stop using tobacco. Unfortunately, there are only a limited number of studies that have sought to investigate the 

Although no single optimal treatment has yet been identified, it appears that while nicotine replacement therapy can be useful, the interventions that are most successful are those that address both the pain and the smoking using 

 In this way, treating tobacco use disorder and comorbid chronic pain is similar to the treatment of pain and iatrogenic opioid use disorder, where there must be management of both problems together in order to be successful in treating either.

Of course, this raises the important issue of who treats pain and how it is treated. 

(For more information on psychiatry and pain, see the November Special Report.)

For the most part, the management of chronic pain has been under the aegis of anesthesiology, followed by physiatry and neurology, with psychiatry far down the list. However, the order of these specialties would be reversed if we asked which is best able to aid in smoking cessation. One doubts that there are many anesthesiologists, physiatrists, or neurologists who have expertise in treating patients with nicotine addiction.

As a result, it is difficult for patients with chronic pain who smoke to find health care professionals qualified to treat both issues. If it appears to patients that smoking and pain are 2 separate problems that require different medical specialties to treat them, it may make it more difficult to convince them that the issues are actually entangled. Nonetheless, the evidence suggests that managing 1 issue may aid in managing the other.

1. LaRowe LR, Ditre JW. Pain, nicotine, and tobacco smoking: current state of the science. 

2. Smuck M, Schneider BJ, Ehsanian R, et al. Smoking is associated with pain in all body regions, with greatest influence on spinal pain. 

3. Ditre JW, Zale EL, LaRowe LR, et al. Nicotine deprivation increases pain intensity, neurogenic inflammation, and mechanical hyperalgesia among daily tobacco smokers. 

4. Nakajima M, Al'Absi M. Nicotine withdrawal and stress-induced changes in pain sensitivity: a cross-sectional investigation between abstinent smokers and nonsmokers. 

5. Zale EL, Maisto SA, Ditre JW. Anxiety and depression in bidirectional relations between pain and smoking: implications for smoking cessation. 

6. Ditre JW, Zale EL, LaRowe LR. A reciprocal model of pain and substance use: transdiagnostic considerations, clinical implications, and future directions. 

7. Hooten WM, LaRowe LR, Ditre JW, et al. Effects of a brief pain and smoking cessation intervention in adults with chronic pain: a randomized controlled trial. 

Two recent papers look at the subtle and surprising links between smoking and pain in different parts of the body. 

Pain and Smoking: Is There an Association?

 is a retired oncologist and the author of the book

A Spiritual Pathway to Recovery from Addiction, A Physician's Journey of Discovery

Addiction occurs among doctors at the same rate as the general population. Dr Linville Meadows shares his own story with addiction recovery and rehabilitation. 

A Doctor Impaired

 and Senior Vice President at Appriss Health. She is a physician and healthcare services researcher, trained in Critical Care and Emergency Medicine, and faculty at Johns Hopkins University School of Medicine.

The reported increase in opioid related overdoses, likely fed by the disturbances of COVID-19, necessitates a need for more widely-accessible Naloxone, an emergency life-saving treatment. 

Naloxone and Combatting the Rising Opioid Fatalities 

Substance use disorder (SUD), including opioid use disorder (OUD), 

 a significant proportion of the American population—20.3 million (7.4%) of Americans aged 12 years or older had a SUD in the past year.

 Of these, 2 million people had an OUD from heroin and/or misuse of prescription pain relievers.Although medication-assisted treatment (MAT) with methadone, buprenorphine, or naltrexone for OUD is the most efficacious, evidenced-based treatment that is recommended by the National Institute of Health, 

Substance Abuse and Mental Health Services Administration 

(SAMHSA), and the World Health Organization, only 11% of patients with an OUD are prescribed approved treatment.

Limited access to MAT has been cited as a substantial barrier for patients with OUD; inequities across ethnic and sociodemographic groups speak to the health disparities evident in society. The provision of appropriate treatment and lack thereof are even more troublesome when considering the vulnerable populations that bear the disproportionate burden of SUDs and OUDs—namely, those involved with the corrections system and those with serious mental illness (SMI). It is no secret that a significant 

 of the criminal justice population has an SUD.

Between 62% and 86% of individuals arrested test positive for recent drug use,3 and 64% to 76% of arrestees meet diagnostic criteria for SUD. More than half of individuals with a prescription OUD or heroin use in the past year report contact with the criminal justice system.

 Similarly, in terms of mental illness, 9.2 million Americans over 18 years old, or 3.7% of American adults, had co-occurring SUD and any mental illness in 2018.

In line with the goal of reducing recidivism, a proportion of the criminal justice population is often diverted to drug courts. According to SAMHSA, there are currently 2700 operational drug courts in the United States.

 These courts adjudicate cases involving substance-involved offenders, or individuals who were arrested for a drug-related offense and/or are eligible to enter a drug court program. Typically, an offender is followed by a drug court for 12 to 18 months. The National Drug Court Institute reports that more than 116,000 criminal offenders were served by a drug court program in 2009.

 Additionally, most individuals with SUD do not receive treatment while they are incarcerated, or they are forced to withdraw from treatment they were receiving before incarceration (

Ethical considerations around MAT in caring for these patients are apparent through lenses of health care as a source of harm, paternalism, and violation of rights; through a refusal to provide access to appropriate care; or through the intersection of medicine and epidemiology. These considerations include issues around access to MAT and the context in which consent to MAT is obtained from those to whom it is offered.

MAT is an approved treatment for OUD by the US Food and Drug Administration. The underlying pharmacology of drugs used in MAT and their physiological effects on individuals are well understood. MAT is known to assist in diminishing cravings, and some agents can alleviate the withdrawal symptoms associated with OUD. However, many drug courts and prison facilities do not afford provisions for MAT for incarcerated individuals.

In the absence of MAT, individuals with OUD are forced to undergo detoxification with full exposure to the negative physiological and psychological withdrawal symptoms that they could easily avoid with MAT, including nausea, vomiting, diarrhea, agitation, anxiety, and suicidality.

 This lack of access to approved and indicated therapy for a disease process could be construed as a punitive measure and borderline cruel and unusual punishment. In fact, detoxification in the absence of MAT is less efficacious than MAT and harmful to human health.

Surveys of drug courts and the US prison systems do find practical reasons for not providing MAT, namely, the cost and lack of access to local providers. However, there are courts that do not permit MAT because of a lack of knowledge and stigma around OUD. Many drug court teams are uncertain about the underlying physiological mechanisms of opioid receptor agonists used in MAT and their efficacy in treating OUD. Some report they believe that patients with OUD use MAT to get high and not for treatment of OUD.4 Further, others think that MAT use for OUD is essentially replacing one addictive substance with another.

The false narrative that MAT reinforces addiction or replaces an illicit substance (heroin) has a negative impact on individuals.

 Additionally, the intersection of medicine and epidemiology is evident when those with SUDs/OUDs who do not have access to MAT turn to unsafe practices, such as the use of unclean needles to inject impure heroin or heroin laced with synthetic fentanyl. This, in turn, leads to increased morbidity and mortality as well as to public health issues of increased transmission of infectious diseases.

The other side of the coin: being processed by a drug court and given the option of either incarceration or MAT. Asking an individual with a mentally incapacitating illness to consent to treatment brings in to question autonomy and validity of consent. Informed consent, by definition, should be voluntary and free of coercion.

 It should be obtained from someone with the capacity to make a decision after they have an understanding of the risks and benefits of available options. Consent under the threat of incarceration, or while incapacitated, is not informed consent and compromises individual 

Many individuals with OUDs/SUDs choose Narcotics Anonymous, peer support, drug-free toxification, or treatment modalities other than MAT.3 Assuming a binary disposition, MAT versus drug-free detoxification is overly punitive and a violation of voluntariness and self-determination of these individuals.

Patients with SUDs/OUDs often contend with unfavorable correctional system interactions as well as SMI, and they predominantly comprise minorities from low-income or limited educational backgrounds and with reduced social support. They are a vulnerable population whom society has largely marginalized.2 Their rights are threatened, and they are afforded subpar and borderline unethical care. The underlying reasons behind this unsettling phenomenon is a lack of health literacy around MAT and stigma associated with OUD in nonclinical settings.

An ethical framework is needed, as well as best practice guidelines highlighting the efficacy of and science behind MAT specifically directed at the correctional system. 

Addressing limitations in knowledge base and highlighting shortcomings in protecting the rights of incarcerated individuals are both essential, in partnership with all stakeholders (including incarcerated patients, rights groups, judges, the correctional system, and medical bodies).

is a fourth-year medical student at Central Michigan University College of Medicine, Saginaw, MI. 

Central Michigan University College of Medicine.

 Key Substance Use and Mental Health Indicators in the United States: Results From the 2018 National Survey on Drug Use and Health. 

(HHS Publication No. PEP19‑5068, NSDUH Series H‑54). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. 2019. Accessed September 10, 2020. 

https://store.samhsa.gov/product/key-substance-use-and-mental-health-indicators-in-the-united-states-results-from-the-2018-national-survey-on-Drug-Use-and-Health/PEP19-5068

2. Winkelman TN, Chang VW, Binswanger IA. Health, 

Polysubstance Use, and Criminal Justice Involvement Among Adults With Varying Levels of Opioid Use

Medication-assisted treatment for opioid use disorders in correctional settings: An ethics review

4. Matusow H, Dickman SL, Rich JD et al. Medication assisted treatment in US drug courts: Results from a nationwide survey of availability, barriers and attitudes. 

5. Substance Abuse and Mental Health Services Administration. Adult Drug Courts and Medication-Assisted Treatment for Opioid Dependence. 

 2014;8(1). Accessed September 10, 2020. 

https://store.samhsa.gov/product/Adult-Drug-Courts-and-Medication-Assisted-Treatment-for-Opioid-Dependence/sma14-4852

When is coercive methadone therapy justified?

. New York: Oxford University Press; 2019.

This article was originally published on August 17, 2020, and has since been updated. -Ed

A significant proportion of incarcerated individuals struggle with with addiction. So what is being done about it? 

The Case for Medication-Assisted Treatment: An Ethical Priority

How can clinicians help patients struggling with addiction, especially during this time when uncovering past traumas might feel impractical? 

interviews child and adolescent and addiction psychiatrist, John Calvin Chatlos, MD. Dr Chatlos is affiliated with Rutgers-Robert Wood Johnson Medical School, in New Brunswick, NJ, and medical director of the Wei Ji Point Ambulatory Withdrawal Management program and the Specialized Addiction Treatment Services outpatient program.

Navigating Addiction Treatment in the Face of Difficulties

Thomas Kosten, MD, and Carla B. Marienfeld, MD, tackled the topic of concurrent 

 and opiate use in patients in a Medical Crossfire® at Annual Psychiatric Times® World CME Conference™. The simple answer to the question, both agreed, is “no,” but they also agreed there are no easy solutions.

To better understand the issues at hand, 

, director of the Division of Alcohol and Addiction Psychiatry and founding co-director at the Institute for Clinical & Translational Research at 

Editorial Board, examined the US Food and Drug Administration’s (FDA) warnings over the past few years.

In 2016, he reported the FDA published “

New Safety Measures Announced for Opioid Analgesics, Prescription Opioid Cough Products, and Benzodiazepines

” noting that it is “requiring class-wide changes to drug labeling, including patient information, to help inform health care providers and patients of the serious risks associated with the combined use of certain opioid medications and a class of central nervous system (CNS) depressant drugs called benzodiazepines.”

FDA shared additional almost contradictory guidance

Opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS). The combined use of these drugs increases the risk of serious side effects; however, the harm caused by untreated opioid addiction can outweigh these risks. Careful medication management by health care professionals can reduce these risks. We are requiring this information to be added to the buprenorphine and methadone drug labels along with detailed recommendations for minimizing the use of medication-assisted treatment (MAT) drugs and benzodiazepines together.

It did not end there, though, Kosten said. 

 the FDA announced it is requiring a black box warning on benzodiazepines, noting “the risks of abuse, misuse, addiction, physical dependence and withdrawal reactions to help improve their safe use.”

 In doing so, they specifically noted the concurrent use of opioid pain relievers and the risks associated with such.

To further explore the complexity of the question, Marienfeld, associate clinical professor of psychiatry at the University of California, San Diego, presented a case example. The patient, a 33-year-old man, was stable on buprenorphine/naloxone (16 mg/4 mg sublingually) and had no opioid use in the previous 3 years. To address his anxiety, he was taking 90 mg daily of duloxetine and meeting with a social worker regularly for coping strategies to psychosocial stressors. Nonetheless, the patient was experiencing panic attacks 3 to 4 times per week that came on suddenly and dissipated almost as quickly. Urine drug screens over 6 months were consistently showing low levels of alprazolam.

Staff discussed the black box warnings about combining buprenorphine and alprazolam, including the risks of overdose and dependence. Based on these discussions, it is decided to use low dose of clonazepam (0.5 mg daily) as needed to address the panic attacks (15 tablets per month) and to monitor the urine weekly. At 3 months follow-up, the urine testing had only showed clonazepam metabolites and no illicit opioids. The patient’s mood was relatively stable as before, and he reported a great reduction in panic attacks.

Based on this positive experience, is it safe to prescribe clonazepam for patients who are taking buprenorphine? Kosten said the simple answer is no. But there is a more complicated answer, he told attendees. If you are a careful clinician who is seeing the patient regularly (once or more per month) and can do regular urine testing, then you can start to think about this treatment strategy, he explained. Of course, this has become a real challenge over the last few months in the COVID environment, when most patient interactions are via telepsychiatry. Valid urine testing may be compromised, as patients may be tempted to be less honest when dealing with third party laboratory testing. To ensure valid urine test, he suggested testing for other levels to help ensure it truly was the patient’s urine. (For instance, Kosten quipped, if your male patient’s urine is positive for pregnancy, you can guess it was not their urine.)

Marienfeld agreed that some of the urine testing during COVID have been suspicious, although now that things are settling back down, there seems to be a more return to normalcy in the urine testing and results.

She further noted the question of safety is not a black-and-white answer, and she pointed to the FDA’s re-evaluation of their 2016 statement in 2017. The recognition that stable patients were being removed from effective treatments (methadone and buprenorphine) for opioid use disorder because of benzodiazepine use thereby increasing their risk of relapse to illicit opioid use. This illicit use combined with benzodiazepines is a much less safe approach and increases risks of negative outcomes, Marienfeld added. Thus, when you think about the question from a harm-reduction standpoint, it is less safe for patients to have them relapse on illicit opioids outside of treatment where monitoring is absent and thus no potential interventions to prevent negative outcomes.

Kosten and Marienfeld also discussed the issue of choosing the appropriate benzodiazepine: Would it be appropriate to simply choose the drug the patient likes or requests? Patients with a history of substance use disorder are at a higher risk for misuse, especially those with opioid use disorder, Marienfeld explained. Thus, it is important to choose agents that have slower onset of action, which are less likely to be abused. If you are going to take a risk to use a benzodiazepine, she said, clonazepam is likely a less risky option based on about onset of action and duration of effect.

In discussing the harm-reduction approach, Marienfeld also noted it is important to really look at symptoms and functioning to determine if using benzodiazepines is really reducing harm or if prescribing these agents are actually increasing harm.

Kosten agreed, and he added that “harm reduction” is often seen as a dirty word in substance abuse treatment in the United States. Yet, he said, it is the way the rest of the world looks at these situations. He further emphasized the need for clinical judgement. It is not quite like as in suicide prevention, in which the consequences are immediate, Kosten told attendees. On the other hand, it is like suicide, in that the combination of these drugs have a very legal potential.

The Annual Psychiatric Times® World CME Conference™ was held October 15 – 17. More information can be found 

. Next year’s conference is scheduled for September 30 – October 2, 2021, in San Diego.

1. US FDA. New safety measures announced for opioid analgesics, prescription opioid cough products, and benzodiazepines. August 31, 2016. Accessed October 17, 2020. 

https://www.fda.gov/drugs/information-drug-class/new-safety-measures-announced-opioid-analgesics-prescription-opioid-cough-products-and

2. US FDA. FDA Drug Safety Communication: FDA urges caution about withholding opioid addiction medications from patients taking benzodiazepines or CNS depressants: careful medication management can reduce risks. September 26, 2017. Accessed October 17, 2020. 

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-urges-caution-about-withholding-opioid-addiction-medications

3. US FDA. FDA requiring labeling changes for benzodiazepines: boxed warning to be updated to include abuse, addiction and other serious risks. September 23, 2020. Accessed October 17, 2020. 

https://www.fda.gov/news-events/press-announcements/fda-requiring-labeling-changes-benzodiazepines

While there are risks for prescribing benzodiazepines and opioids concurrently, experts agree there are times when it may be an appropriate treatment decision.

Should Benzodiazepines and Opioids Be Used Concurrently?

According to a recent study, US veterans may see a reduction in their chronic pain symptoms if they reduce their unhealthy alcohol use.

 Analysis showed that reduced drinking for 1 year increased the odds of improved pain symptoms after 2 years and stopped usage of smoking, cannabis, or cocaine.

Researchers pulled data from Veterans Aging Cohort Study (VACS), focusing on approximately 1500 participants, both HIV positive and HIV negative, out of the 7000 veterans that receive care in VACS health centers. Using the VACS surveys conducted from 2003 to 2015, where veterans marked their past-year alcohol/substance use and their co-occurring symptoms or conditions, researchers analyzed the impact of decreased drinking on chronic pain, psychiatric symptoms, and alternate substance usage on veterans with regular alcohol abuse. 

The first survey indicated co-occurring symptoms or conditions were common. Almost half had moderate to severe chronic pain, and more than half had anxiety symptoms, while a third had depression. More than two-thirds reported smoking, a third reported past cannabis use, and another third reported cocaine use.

Researchers identified 2 groups after the following year’s survey: those who had reduced drinking and those who had not. They compared the 2 groups for improvement of their conditions after the following year, and found some improvement in chronic pain, but little evidence for reduction in symptoms of anxiety or depression.

As the timing of alcohol reduction relative to condition improvement was unknown and the analysis did not control for other impacting factors, it cannot be definitely concluded that reduced drinking is the cause for improvement.

More precise studies, where timing and reasons for changes in drinking habits are monitored, will need to be conducted to fully evaluate the effect of reduced drinking on chronic pain and other co-occurring conditions. Until then, the findings from this study suggest enough improvement in chronic pain symptoms for veterans to support efforts in reduced drinking.

Want more clinical tips for managing substance use in your patients? Join us at the Annual Psychiatric Times® World CME Conference October 15-17 to hear ideas and the latest clinical updates Brian Koffman, MDCM, MS Ed, Carla B. Marienfeld, MD, and Thomas Kosten, MD. Register online

https://www.gotoper.com/conferences/psychtimes/meetings/psychtimes20conference#registration

1. Caniglia E, Stevens ER, Khan M, Young KE, et al. Does reducing drinking in patients with unhealthy alcohol use improve pain interference, use of other substances, and psychiatric symptoms? October 8, 2020.

2. Research Society on Alcoholism. Reducing Drinking Among US Veterans with Unhealthy Alcohol Use Might Improve Chronic Pain Symptoms and Reduce Other Substance Use. News release. 

 October 3, 2020. Accessed October 7, 2020. 

https://www.newswise.com/articles/reducing-drinking-among-us-veterans-with-unhealthy-alcohol-use-might-improve-chronic-pain-symptoms-and-reduce-other-substance-use

Veterans with chronic pain should consider reducing alcohol usage to combat symptoms. 

Study Shows Some Reduction in Chronic Pain for Veterans After Decreased Unhealthy Alcohol Use

The association between Cannabis sativa (cannabis) and psychosis goes back at least as far as the Pen-ts’ao Ching, the world’s oldest pharmacopeia, which is attributed to the Chinese emperor Shen-Nung (circa 2700 BC). It says, “ma-fen [the fruit of cannabis] if taken in excess will produce visions of devils . . . over the long term, it makes one communicate with spirits.”

 In the West, cannabis was used as an experimental psychotomimetic in the 19th century by pioneering French psychiatrist Jacques-Joseph Moreau, and it 

 Cannabis’ acute psychotomimetic effect is transitory; however, consistent evidence indicates that the chronic and intense use of the plant, especially if started in adolescence, contributes to the occurrence of schizophrenia.

We know that cannabis contains about 100 cannabinoid compounds and that the psychotomimetic effects of the plant are induced by tetrahydrocannabinol (THC).

 However, we have also known since the early 1970s that the effects of cannabis cannot be attributed solely to THC.

 Other cannabinoids, including cannabidiol (CBD), have intrinsic actions as well.

In 1982, a study of the interactions between THC and CBD in healthy volunteers provided the first evidence that CBD might have antipsychotic properties. Our group administered oral CBD concomitantly with a high dose of THC to investigate whether CBD could attenuate THC-induced anxiety. Surprisingly, in addition to alleviating anxiety, CBD 

the psychotic symptoms commonly induced by THC.

More recently, this observation was confirmed in a study with THC administrated intravenously after oral pretreatment with CBD or placebo.

 In addition to blocking the psychotic symptoms induced by THC, CBD and THC presented opposite effects relative to placebo in terms of activation of the striatum during verbal recall, as assessed by functional MRI.

The early observation that CBD reduced THC-induced psychotic symptoms led us to carry out a pioneering study to test the effects of CBD in a model commonly used to identify drugs with an antipsychotic profile in laboratory animals.

 The stereotypy induced in rats by a dopaminergic agonist was clearly reduced by CBD, without producing the catalepsy that is associated with the extrapyramidal adverse effects (AEs) of classical antipsychotic drugs. This finding suggests that CBD has an atypical antipsychotic pattern. A series of other tests with different animal models confirmed and expanded the antipsychotic profile of CBD.

The next step was to evaluate the effects of CBD in a patient with schizophrenia. The patient was a woman with chronic psychosis who experienced many AEs with traditional antipsychotics, which provided the ethical justification for this first clinical test. After 4 weeks of treatment, the patient had a marked reduction in her psychotic symptoms as assessed by standardized rating scales. This published case report stimulated the undertaking of randomized controlled clinical trials (RCTs).

To date, 3 RCTs have evaluated the therapeutic effects of CBD in patients with schizophrenia. The first one, using a double-blind procedure, included 39 patients treated with either CBD (800 mg/day; n = 20) or the atypical antipsychotic amisulpride (800 mg/day; n = 19) for 4 weeks. The 2 drugs led to similar significant reductions in both positive and negative psychotic symptoms, but fewer AEs were seen in the CBD group.

In the other 2 RCTs, CBD was administered as an adjunctive treatment for 6 weeks with placebo control; however, the results were contradictory. CBD treatment (1000 mg/day; n = 42) was associated with a significant reduction in positive symptoms from baseline to the end point compared with placebo (n = 44) in one study (

 Results from the other RCT, which used a very similar methodology but a lower CBD dose (600 mg/day; n = 20), found no significant symptomatic differences between treatments with CBD and placebo (n = 19).

 A possible explanation for the contradictory results may be the 400-mg difference in daily CBD doses.

The CBD dose-response relationship appears to have a particular feature. The anxiolytic effects of CBD, described in the early 1980s and confirmed by later animal and human studies, clearly follow this dose-response pattern.

 In 1990, CBD was tested in a range of doses in rats with the elevated plus-maze model and was found to act according to a bell-shaped dose-response curve. CBD induced an anxiolytic-like effect only at intermediate doses.

This dose-response curve was also observed in healthy volunteers subjected to anxiety via a public speaking test and by public speaking in real-world settings.

 In both situations, treatment with CBD 300 mg was associated with significant decreases in anxiety symptoms, but this effect was not observed with lower or higher doses.

The same response pattern was observed in preclinical tests using other models of induced anxiety, cognitive impairment, and schizophrenia-like behavior.

 The findings suggest that this inverted U-shaped curve response pattern may be extended to other therapeutic effects of CBD, with different effective doses and therapeutic windows for each condition.

Accordingly, data from the 3 previously mentioned CBD RCTs suggest that the dose range to reduce psychotic symptoms (probably between 800 and 1000 mg/day), but not cognitive symptoms, should be higher than that used to induce anxiolytic effects (between 200 and 400 mg/day). However, precise dose ranges for each condition or symptom are yet to be determined in future RCTs with larger samples, different clinical populations, and multiple doses.

It seems that the antipsychotic effect of CBD is not limited to patients with schizophrenia. Antipsychotic effects of CBD (150 mg to 400 mg/day) were seen in patients with Parkinson disease who, for at least 3 months, had psychotic symptoms that could not be controlled by reducing antiparkinsonian drug regimens.

 We observed a reduction in psychotic symptoms (

) in addition to a significant improvement in global functioning (as assessed with the Unified Parkinson’s Disease Rating Scale and the Clinical Global Impression Scale).

This important study paved the way for a new, double-blind, placebo-controlled RCT with parallel groups of patients with Parkinson treated with 2 doses of CBD (75 mg and 300 mg/day) for 6 weeks. Patients with dementia or psychotic symptoms were excluded from the study to avoid the influence of psychotic symptoms. The results showed that CBD induced a significant improvement in nonmotor symptoms, including daily life activities and rapid eye movement sleep behavior disorder.

CBD presents multiple actions in the central nervous system that may have a crucial role in the pharmacotherapy of the motor and nonmotor effects of Parkinson disease. This cannabinoid was shown to have neuroprotective properties by enhancing the recycling of old/damaged cell components via the facilitation of autophagic action.

 Moreover, CBD exerts antioxidant activities, stimulates neurogenesis, regulates mood and sleep, improves cognition and motor activity, and restores dendritic arbor and brain-derived neurotropic factor levels in the hippocampus.

The specific pharmacological mechanisms underlying the antipsychotic action of CBD are not fully understood, as this compound seems to interfere with neurotransmitter systems in diverse ways.

 For instance, CBD inhibits the reuptake and metabolism of anandamide, which may be implicated in the antipsychotic effect of CBD, as the concentrations of this endocannabinoid in the cerebrospinal fluid of patients with schizophrenia are higher than in those of controls and are inversely correlated with psychotic symptoms. It suggests a feedback mechanism in which the anandamide increase outweighs the occurrence of psychotic symptoms. Moreover, patients with prodromal psychosis present higher anandamide levels in cerebrospinal fluid (CSF) than do controls.

 The clinical improvement produced by CBD in the patients with schizophrenia has been linked with increased CSF anandamide levels. The effects of CBD on anandamide regulation in different brain regions associated with the pathophysiology of schizophrenia could explain its antipsychotic action.8

Further mechanisms that could clarify the antipsychotic action of CBD include its ability to increase hippocampal neurogenesis and neuroprotection; its interaction with 5HT1A, GPR55, and TRPV1 receptors; and its antioxidant and anti-inflammatory effects. For instance, some second-generation antipsychotics, such as ziprasidone and aripiprazole, also activate 5-HT1A receptors, which may, at least in part (in addition to the noninvolvement of dopamine antagonism), explain the absence of extrapyramidal AEs of CBD.

Research has been conducted on CBD and its potential use for neuropsychiatric conditions such as schizophrenia, anxiety, Parkinson disease, depression, and dystonia, as well as for diseases and conditions that involve other organs and systems, such as inflammation, immune response, ischemia, diabetes, cancer, and many others. Most of this are preclinical studies in laboratory animals.

The only CBD formulation approved by the FDA is Epidiolex (GW Pharmaceuticals) to treat rare forms of epilepsy in children and adolescents; it is not currently available for use in schizophrenia. Although there are controlled good laboratory and manufacturing practices, and purified synthetic analogues for CBD exist, further safety and efficacy studies are needed.

CBD can be easily purchased throughout most of the United States, which raises concerns about the use of handcrafted, uncontrolled, cannabis-enriched CBD. However, there are well-known harmful long-term effects of THC on the developing brain, cognitive impairments associated with cannabis, and worsening of psychotic symptoms and antipsychotic response, particularly in younger patients. Therefore, well-designed RCTs with larger patient samples, using high-quality and reliable CBD, are needed to ascertain the effectiveness and safety of CBD as an antipsychotic medication and to ultimately receive FDA approval for use in schizophrenia.

is a full professor, Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Brazil. 

 is a full professor, Department of Neuroscience and Behavior, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil, and a member of the National Institute of Science and Technology for Translational Medicine, Brazilian National Council for Scientific and Technological Development, Brasília, Brazil. In addition, Dr Crippa is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence.

The authors report that they are coinventors of the patent “Fluorinated CBD compounds, compositions and uses thereof.” They are also recipients of Conselho Nacional de Desenvolvimento Científico e Tecnológico productivity fellowships. In addition, Dr Crippa has received travel support from BSPG Laboratories, Ltd, and has received a grant from the University Global Partnership Network to establish global priorities in cannabinoid research excellence.

An earlier version of this article appeared online as 

Understanding the Relationship Between Cannabidiol and Psychosis: Clinical Issues

History of cannabis as a medicine: a review

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Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects.

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The acute psychotomimetic effect of cannabis is transitory, but evidence indicates that the chronic use, especially if started in adolescence, contributes to the occurrence of schizophrenia.

Addiction & Substance Use