Thomas R. Kosten, MD

About 50 years ago (1968) in an early edition of Resident Physician, a progenitor of 

 Herbert Berger, MD (Chairman of the Committee on Alcoholism and Narcotic Addiction, New York State Medical Society) wrote about the “Physicians’ Retreat from Management of Addictions” and blamed physician attitudes for turning over this major medical challenge to non-medical personnel and the criminal justice system. This retreat from potential patients was not just active rejection from physicians’ offices but an omission of responsibility to counter the prevalent argument that these individuals were willfully evil rather than sick.

Berger went on to discuss the 1919 interpretation of the

-that keeping an opioid dependent patient “comfortable by maintaining his customary [opioid] use was not a prescription, within the meaning of the law . . . .” As a result, physicians became targets for arrest and imprisonment for prescribing narcotics to control withdrawal symptoms in attempt to make their patients comfortable. Had any progress been made from 1919 to 1968, when Dr Berger wrote his appeal?

Interestingly, on this very same page of the article in 1968 was an advertisement from Smith, Kline, and French Laboratories stating in bold type, “To reduce pain-narcotics” followed on the next page by the statement, “To reduce narcotics-Thorazine.”

As some of us may remember, chlorpromazine was used for opioid withdrawal in the late 1960s through the 1980s (and even into the 1990s in some settings), when going cold turkey was the option. In fact, chlorpromazine was frequently given to opioid dependent arrestees during incarceration, although they did not like its effects. It was never FDA approved for this purpose. Other off-label medications also were used for reducing opioid withdrawal symptoms, including the use of clonidine for 

. However, off-label marketing was quite common at that time and continued with a vengeance for opioids such as oxycontin for chronic pain, with the subsequent problems and fines against manufacturers that bring us to modern day.

Overall, the two components of the Smith, Kline, and French Laboratories (and other pharmaceutical) advertising campaign were problematic. First, reducing pain was generalized to any pain, including benign chronic pain such as backaches, headaches, peripheral neuropathies, fibromyalgia pain, and other chronic pain conditions that do not benefit from long-term opioids. Second, reducing opioids was not easy and could not be simply treated with essentially aversive medications such as chlorpromazine, which did not target the underlying neurobiology driving opioid withdrawal symptoms. Thus, little progress with the pharmaceutical industry was evident in 1968, but plenty of future problems were starting, which the next 50 years-from 1968 to the present-began addressing.

Progress has been more evident during these more recent 50 years, moving us further away from the 1919 decisions that made it illegal to provide medical help to people with an opioid addiction. While medical progress has been slow, it has been steady. In the 1970s, because of the discovery by Vincent Dole, MD, and Marie Nyswander, MD, and the efforts of the federal government led by Jerome Jaffee, MD, the national Drug Czar, the introduction of methadone maintenance provided a wide-spread agonist treatment. Parallel work led to two important milestones: 

 as a blocker for opioids and its evolution to an injectable long-acting formulation as well as the development of 

 as a partial agonist maintenance agent. In addition, the Data2000 legislation provided more relaxed prescribing restrictions. In addition to these maintenance approaches to treatment, aids for managing the symptoms of opioid discontinuation, such as clonidine and most recently lofexidine, also became available.

We have made significant progress in moving addiction into the medical treatment area and away from the social stigma that led to widespread incarceration of those with substance use disorders. Current treatments show good efficacy for opioids and promising research is ongoing for alcohol and stimulants.

However, along with the more humane treatments for addiction, an opposing trend began from the pharmaceutical industry to increase sales of opioids for managing “insufficiently treated” chronic pain syndromes. This trend during the 1990s resulted in the lawsuits and ongoing settlements for damages that began in 2007.

We have arrived at a time for financial settlements with some of the pharmaceutical companies that derived substantial profits from what resulted in an epidemic of death and destruction as a result of opioid overuse and dependence. Based on recent court settlements of single state cases, negotiations for national settlements might reach $10 billion for each company.

In Ohio and in a recent Oklahoma case, the judge stated that one company “engaged in false and misleading marketing of both their drugs and opioids generally, and the law makes clear that such conduct is more than enough to serve as the act or omission necessary to establish the first element of Oklahoma’s public nuisance law.”

Having such massive infusions of funding into public coffers can bring great benefits to treatment of substance use disorders, damage 

, and new treatment discoveries. However, we need to look back at the Master Settlement Agreement (MSA) from the tobacco lawsuits that were settled 20 years ago in 1998.What happened with those billions of dollars? States collected an estimated $27.3 billion from the MSA and taxes in fiscal year 2019, yet today no state funds tobacco prevention at the level recommended by the 

Centers for Disease Control and Prevention

 (CDC). Overall, states spend less than 3% of MSA funds on programs that would help prevent smoking in youth and help smoking cessation. Twenty-nine states and the District of Columbia spend less than 20% of the CDC recommendation. On the other hand, Alaska and California spend more than 70% of the CDC recommended funding-$655 million annually-on prevention and cessation programs. In contrast, tobacco companies spend more than $14 to market tobacco products for every $1 the states spend to reduce tobacco use.

Because there are new challenges in reducing tobacco and nicotine use since the agreement, the MSA funds could have been better directed to detecting and addressing future threats than to the many other conditions unrelated to health care for which they were used. Among the new challenges is e-cigarette use by youths, which has skyrocketed to epidemic levels; the CDC and FDA show that from 2017 to 2018 e-cigarette use increased by 78% among high school students (to 20.8%) and by 48% among middle school students (to 4.9%).

The associated morbidity and mortality attributed to vaping with e-cigarettes has been startling and led to dramatically quick actions by Federal government standards, but with no benefit from the MSA funds. Similarly, the legalization of cannabis and its widespread smoking and vaping in many parts of the US has brought with it many health burdens in psychiatric and medical comorbidity, which have not been addressed with any portion of the MSA funds.

This lack of vision and missed opportunities associated with MSA funds should not be repeated with the accumulating opioid epidemic settlement funds. The obvious parallel for opioids with comorbid abuse of other DEA scheduled medications such as stimulants and sedatives strongly argues that these opioid settlement funds need essential investments in prevention, treatment, and research into related types of addictive substances and their delivery systems. However, such an investment is not likely to happen without substantial effort from the medical community.

To jump start these future opioid settlement funds, the federal government currently has allocated funding for the Helping to End Addiction Long-term (HEAL) initiative for the ongoing epidemic of deaths, which are now primarily from fentanyl. These HEAL funds are very welcome in the field and should provide some significant help for our patients, but these funding sources are not sustained and even their re-authorization in Congress will only carry for another year. Thus, the upcoming challenge will not be in the courts, but in the state legislatures, which are likely to get a substantial influx of financial resources for sustained periods from the opioid settlements.

These funds can help address the current opioid epidemic, but perhaps more importantly, these sustained funds need to be directed toward the rapidly growing epidemic of stimulants, particularly methamphetamine. While the fatalities associated with this opioid epidemic have indeed shifted to an illicit market of heroin and fentanyl and away from the original challenges with marketed commercial opioids, fentanyl is not only mixed with opioids, it is also being mixed with stimulants and causing increased mortality among drug users.

 are also fueled by pharmaceutical companies who market stimulants for adults and children with attention-deficit/hyperativity disorder; however, many adults are getting stimulants for such off-label uses as depression, anxiety, and improved concentration. College campuses are awash in illicit stimulant use, and many young adults are becoming addicted to stimulants. Moreover, there is now the added risk of illicit fentanyl adulteration and overdose.

The financial resources that are clearly on their way to states and communities from both pharmaceutical company settlements and the more immediate federal HEAL grants need appropriate planning for wise spending-not wasting these resources by missing the mark for which they were intended.

So, have we made progress since that article was published in 1968 or are we on a two-steps forward, one backward pattern? Let us hope a future psychiatrist will be able to write a more positive article.

 is Jay H. Waggoner Endowed Chair, Co-Founder, Institute for Clinical and Translational Research, and Professor of Psychiatry, Neuroscience, Pharmacology, and Immunology, Baylor College of Medicine, Houston, TX.

1. Campaign for Tobacco-Free Kids. A State-by-State Look at the 1998 Tobacco Settlement 21 Years Later. January 16, 2020.

Articles

How much progress has been made in the area of substance use disorders in the last 40 years?

Are We Making Any Progress in Treatment and Attitudes?

Judgements and settlements are starting in Oklahoma against various pharmaceutical companies for their alleged roles in that state’s 

crisis. During these judgements and negotiations with three major companies, the financial liability potentially ranged from a judgement for more than $500 million in this single state case to negotiations that might reach $10 billion for each company to resolve national claims. In this most recent Oklahoma case, the judge stated that one company “engaged in false and misleading marketing of both their drugs and opioids generally, and the law makes clear that such conduct is more than enough to serve as the act or omission necessary to establish the first element of Oklahoma’s public nuisance law.”

Several aspects of this ruling seem remarkable and perhaps contradictory. From a conventional understanding of a “public nuisance,” this bland-sounding civil offense seems relatively minor and hardly the basis for a significant financial judgement. Police officers may issue fines for a public nuisance offense, which is a ticket with a payable fine that ranges from $100 to $300. From an international perspective, the Indian Penal Code states that a public nuisance “. . . shall be punished with a fine, which may extend to two hundred rupees,” which is equivalent to about $3. Is the severity of the alleged pharmaceutical manufacture’s public nuisance offense consistent with the magnitude of the financial liability in this judgement?

Compared with the tobacco smoking settlement amounts for hundreds of billions of dollars or to the Wall Street analysts’ expectation of a fine up to $5 billion for this case in Oklahoma, this $500 million seems a relatively modest amount to pay. The importance of this initial landmark case is of course significant; however, we need to recognize that nationally more than 2000 additional court cases are still pending. Moreover, the recent Purdue offer to settle its 2000 pending opioid related lawsuits for $10 to $12 billion needs to be recognized.

Since most major pharmaceutical companies and wholesale distributors are defendants in these nationally pervasive cases, how large could the ultimate pool of funds be? If each of these 20 to 30 companies was required to pay even $500 million over 2000 lawsuits the national settlement would be about $10 billion each. The $10 billion from a single company would lead to about $6 million for each of the municipal plaintiffs, which, when multiplied by the 20 to 30 companies with pending lawsuits, would result in hundreds of billions of dollars to distribute.

What is the implication of having hundreds of billions of dollars available for addiction disorders, mental health, and other health care services? Would these be the only beneficiaries of these funds? In 2017, the White House Council of Economic Advisors estimated the national health care costs related to the opioid epidemic to be about $500 billion, but that estimate is of money already spent and does not offer a framework for spending new funds from a settlement with the pharmaceutical companies.

Furthermore, by 2017 much of the fatal and catastrophic outcomes associated with opioids were attributable to heroin and illicit fentanyl, not pharmaceutic company sources. Thus, what portion of any final settlement would health care components deserve to provide care for the estimated 11 million current and potentially future substance use disorder patients? We might learn something from the tobacco company financial settlements and their distribution across the US, when the period of being a public nuisance lasted considerably longer and had an impact on a substantially larger proportion of the population.

A look back on the benefits for addictions prevention and treatment and for health care broadly is not encouraging on this 20th anniversary of the Master Settlement Agreement (MSA), which is an accord reached in November 1998 between the state Attorneys General of 46 states, five US territories, the District of Columbia, and the five largest cigarette manufacturers in America. This MSA settlement required the tobacco industry to pay the settling states billions of dollars annually forever. Specifically, the MSA also had the original participating manufacturers agree to pay a minimum of $206 billion over the first 25 years of the agreement. Over the years, the states have collected tremendous amounts of revenue related to the MSA, but are spending little of it on tobacco prevention and cessation programs.

States collected an estimated $27.3 billion from the MSA and taxes in fiscal year 2019, yet today no state funds tobacco prevention at the level recommended by the Centers for Disease Control and Prevention (CDC). Overall, states spend less than 3% of MSA funds on programs to prevent kids from smoking and help smokers quit. Twenty-nine states and the District of Columbia spend less than 20% of the 

Alaska and California spend more than 70% of the CDC recommended funding-$655 million annually on prevention and cessation programs. Tobacco companies, on the other hand, spend more than $14 to market tobacco products for every $1 the states spend to reduce tobacco use.

Despite overall progress in reducing smoking rates to 14%, smoking rates are highest among people with lower income and less education, American Indians/Alaska Natives, LGBT Americans, those who are uninsured or on Medicaid, and those with mental illness. These differences are in part due to the misallocation of these MSA funds to many other conditions unrelated to health care, prevention, and biomedical research.

New challenges have also evolved in the spread of nicotine abuse and dependence among youth. Youth 

 has skyrocketed to epidemic levels; the CDC and FDA show that from 2017 to 2018 e-cigarette use increased by 78% among high school students (to 20.8%) and by 48% among middle school students (to 4.9%). The obvious parallel for opioids with the many other DEA scheduled medications such as stimulants and sedatives strongly argues that investments of these settlement funds in prevention, treatment, and research in related types of addictive substances and their delivery systems is essential. However, how likely is that to happen based on our experience with the MSA for tobacco and nicotine?

The funds are available to put into health care, particularly for the youth of America, but our state leaders are not funding these programs at levels recommended by the CDC. Thus, the upcoming challenge will not be in the courts, but in the state legislatures, which are likely to get a substantial influx of financial resources to address the current epidemic with opioids. The fatalities associated with this epidemic have indeed shifted to an illicit market of heroin and fentanyl and away from the original challenges with marketed commercial opioids. Nevertheless, financial resources are clearly on their way to states and communities, and we need appropriate planning for wisely spending-not wasting these resources by missing the mark for which they were intended.

Dr Kosten is Jay H. Waggoner Endowed Chair, Co-Founder, Institute for Clinical and Translational Research, and Professor of Psychiatry, Neuroscience, Pharmacology, and Immunology, Baylor College of Medicine, Houston, TX.

1. Campaign for Tobacco Free Kids. A State-by-State Look at the 1998 Tobacco Settlement 20 Years Later; 2018. 

https://www.tobaccofreekids.org/what-we-do/us/statereport

Judgements and settlements are starting in Oklahoma against various pharmaceutical companies for their alleged roles in that state’s opioid crisis. Who would be the beneficiaries of these funds?

The Opioid Epidemic Settlements: Who Will Benefit?

Patients on opioids for chronic pain management develop common complications that respond best to discontinuation and consideration of alternative pharmacotherapies, often in combination with behavioral interventions. A presentation at the October 2019 Psych Congress in San Diego covered these chronic opioid complications in detail. This overview addresses two medications for analgesia of chronic benign pain, both of which have substance abuse risks themselves-cannabinoids and 

are associated with complications in terms of their use, potential for abuse, and administration. Without concurrent opioids, cannabinoids’ efficacy as an analgesic is poor; and 10% of people who use tetrahydrocannabinol (THC) become addicted to it.

In addition, the cannabinoids, particularly cannabidiol (CBD), can potentiate the efficacy to, and reduce tolerance to, opioids. This brief overview focuses on CBD, because data and legal regulation have been rapidly progressing for its potential role in chronic pain management both within psychiatric and primary care settings. Furthermore, all 50 states have laws legalizing CBD with varying degrees of restrictions, and many people obtain CBD online without a medical cannabis license or physician prescription.

Although we do not know the most effective therapeutic dose of CBD for pain, some preliminary estimates are available, such as the 5mg/kg twice-daily dose of Epidiolex for treating two rare seizure disorders.

 Moreover, we can compare analgesic effects using the number of patients needed to treat (NNT) for a clinically significant therapeutic effect. Tricyclic antidepressants and opioids have the lowest NNT for treating neuropathic pain (2.6 and 2.1, respectively).

 This NNT means that for every single patient showing a therapeutic response to each of these agents, we need to treat 2.6 patients and 2.1 patients for tricyclics and opioids, respectively. Perhaps more simply, one of every two patients treated with opioids will have satisfactory analgesia from chronic neuropathic pain. In comparison, an oral CBD spray was found to have an NNT of 5.0, which is comparable to many routine agents used in treating neuropathic pain, including SSRIs (NNT=5.0) and gabapentin (NNT=6.4).

It is also important to look at the negative aspects of treatment. A meta-analysis of 18 double-blind, randomized controlled trials on CBD efficacy analyzed the harms associated with CBD. They found that the number needed to harm (NNH) with CBD, which ideally would be high, was instead relatively low. For CBD, the NNH ranged from 5 to 8 patients, while other analgesics have NNH values above 20.

Specific adverse events contributing to the poor value for NNH included impaired motor function (NNH=5), altered perception (NNH=7), and altered cognitive function (NNH=8). Thus, assessing the efficacy of CBD must be balanced against the potential for harm in the management of neuropathic pain.

The CBD oral solution Epidiolex is available in the US for management of refractory epilepsy, but it has been used off label for chronic pain conditions.

 GW pharmaceuticals also produce nabiximols, which is a marijuana extract currently approved in the UK to treat neuropathic pain, pain due to spasticity, overactive bladder, and other symptoms associated with multiple sclerosis. GW Pharmaceuticals is currently planning Phase 3 trials for nabiximols in the US.

 Thus, these medications are likely to become available in FDA-approved formulations at doses that have potential analgesic efficacy in the not too distant future.

The role of ketamine for chronic pain is more complex, including the setting for delivery. However, ketamine use for chronic pain could be adopted within the specialized psychiatry settings that the new REMS (Risk Evaluation and Mitigation Strategies) programs are mandating for esketamine to treat depression.

Ketamine might best be considered among the antidepressants that have consistently shown efficacy for chronic pain in conditions such as peripheral neuropathy, diabetic neuropathy, phantom limb pain, and patients with depression and pain.

 The relative efficacy of antidepressants based on NNT follows the efficacy of opioids, which has an NNT of 2.1, as previously noted. In comparison, the NNT for similar opioid alternatives are as follows: 3.6 for tricyclic antidepressants; 6.4 for serotonin- norepinephrine reuptake blockers; 7.2 for gabapentin; and 7.7 for pregabalin. However, the onset of full efficacy for opioids is rapid (and usually only a few minutes after oral ingestion), while these other medications typically take six to eight weeks for full efficacy as analgesics.

In contrast to the slow onset for these antidepressant and related agents, ketamine for chronic pain has shown surprisingly quick and long-lasting results. Ketamine has obvious acute analgesic efficacy, and sustained infusions of ketamine over one to 100 hours have produced sustained analgesia for months after these single treatments.

 Specifically, one study found substantially reduced chronic neuropathic pain after 30 minutes of ketamine infusion at 0.5 mg/kg, but this relief only lasted several hours in some patients. A second set of studies using 100-hour infusions of ketamine at 20 to 30 mg/hour or 4-hour daily infusions for 10 days relieved pain for three months, but relief started declining by four to six weeks after the acute treatments. Overall, these ketamine studies showed large effect sizes in the first week following treatment (1.2; 

<.001), but by week four, the effect sizes dropped to 0.4 (although they remained statistically significant at 

=.04). Unfortunately, these reports are five to 10 years old, and there are not more recent reports. Similarly, there are no studies using the newly available intranasal formulation of esketamine, which would make the administration easier than the previous intravenous studies.

These ketamine studies have some important caveats:

• There was no improvement in functionality with analgesia from ketamine.

• Cognition and memory impairment may be persistent with longer duration or more frequent administration; and no long-term data exist.

• Ketamine has negative inotropic effects on the heart and can produce elevated liver functions with repeated dosing.

• Less serious side effects include drowsiness and dizziness during repeated treatment (about one-quarter of patients reported these symptoms).

• Dissociation and abuse are potential psychiatric complications from even a single administration of ketamine.

Chronic pain continues to be a hot button issue, and psychiatrists need to be aware of non-opioid options, especially for their patients with substance use histories. Both ketamine and CBD are on the horizon as new treatments for chronic pain. Since both have risks for inducing substance use disorders, their use needs to be considered cautiously.

Dr Kosten is Professor at the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Staff Psychiatrist at Michael E. DeBakey VA Medical Center, Houston.

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The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

http://nationalacademies.org/hmd/reports/2017/health-effects-of-cannabis-and-cannabinoids.aspx

3. Vergnaud S. New ketamine-based antidepressant gets FDA approval. 

https://www.goodrx.com/blog/what-is-esketamine-spravato-nearing-fda-approval.

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.  August 2, 2019. doi:10.1001/jama.2019.10728

5. Greenwich Biosciences, Inc. EPIDIOLEX® (cannabidiol) oral solution. Highlights of prescribing information. 2018. Carlsbad: Greenwich Biosciences, Inc. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf

6. Urits I, Borchart M, Hasegawa M et al. An update of current cannabis-based pharmaceuticals in pain medicine. 

7. MartÃ­n-SÃ¡nchez E, Furukawa TA, et al. Systematic Review and Meta-analysis of Cannabis Treatment for Chronic Pain. 

8. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. 

9. MicÃ³ JA, Ardid D, Berrocoso E, Eschalier A. Antidepressants and pain. 

10. Romero-Sandoval EA, Kolano AL, Alvarado-VÃ¡zquez PA. Cannabis and cannabinoids for chronic pain. 

11. Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. 

12. Whiting PF, Wolff RF, Deshpande S et al. Cannabinoids for medical use: a systematic review and meta-analysis. 

13. Kumar RN, Chambers WA, Pertwee RG. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. 

14. Perucca E. Cannabinoids in the treatment of epilepsy: hard evidence at last? 

15. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. 

16. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. 

17. Sigtermans MJ, van Hilten JJ, Bauer MC et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. 

18. Cvrcek P. Side effects of ketamine in the long-term treatment of neuropathic pain. 

19. Kalsi SS Wood DM, Dargan PI. The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. 

This overview addresses two medications for analgesia of chronic benign pain, both of which have substance abuse risks themselves.

Innovative Non-Opioids for Chronic Pain: Ketamine and Cannabidiol

Chronic pain management has become a well-known challenge for psychiatrists and other addiction specialists, partly because almost half of primary care providers (PCPs) are refusing to treat chronic pain in patients, as reported in a recent 

 In the face of this PCP response to prescribing opioids, a new challenge is cannabinoid use for analgesia of chronic “benign” pain. The cannabinoids, particularly cannabidiol (CBD), have been hailed as non-addictive solutions to using escalating doses of opioids for chronic pain because cannabinoids potentiate the efficacy and reduce tolerance to opioids, although 10% of people who use tetrahydrocannabinol (THC) become addicted to it.

This potential for a reduced need for opioids has been further encouraged by early epidemiological data indicating that opioid overdoses and abuse have been significantly lower in states that have legalized cannabinoids. Recent data have cast significant doubt on those early epidemiological data and have instead found opioid overdose rates to be higher in states with legalization of cannabinoids and marijuana.

 This brief overview focuses on CBD, because data and legal regulation have been rapidly progressing for its potential role in chronic pain management within a PCP setting.

Cannabidiol is the second most prevalent of the active ingredients of cannabis (marijuana), and it is derived directly from the hemp and marijuana plants. While CBD is one of the approximately 100 cannabinoids found in the marijuana plant, by itself CBD does not cause a “high.”

 describes it as follows: “In humans, CBD exhibits no effects indicative of any abuse or dependence potential . . . To date, there is no evidence of public health related problems associated with the use of pure CBD.” All 50 states have laws legalizing CBD with varying degrees of restriction, and many people obtain CBD online without a medical cannabis license or physician prescription.

In 2018 the US Congress passed an amendment to the Farm Bill that legalized the growing and production of hemp, which launched a rapidly growing industry for the production of CBD. This legislation initiated FDA action that included legislative hearings about regulation of CBD, which recently began in mid-June 2019. One potential outcome from these hearings will be that regulation of CBD will depend on the dose of CBD. Low-dose CBD may become a nutraceutical, while higher doses will be regulated as a pharmaceutical because of the toxicities of higher dose CBD in producing fatigue and irritability as well as gastrointestinal effects including liver toxicity. In animal models, CBD applied on the skin can help lower pain and inflammation due to arthritis.

 confirmed that CBD inhibits inflammatory and neuropathic pain, two of the most difficult types of chronic pain to treat.

We do not know the most effective therapeutic dose of CBD for most medical conditions including pain, except for two rare seizure disorders: Dravet syndrome and Lennox-Gastaut syndrome. However, some preliminary estimates are available, such as the 5mg/kg twice-daily dose of Epidiolex for these two disorders.

 Moreover, to compare analgesic effects in a wide range of medications a metric used is the number needed to treat (NNT), with tricyclic antidepressants and opioids having the lowest NNT for treating neuropathic pain (2.6 and 2.1, respectively).

 This means that for every one patient showing a therapeutic response to the treatment agent, the NNT is the number of patients who need to be treated. In other words, for every two patients whose pain is treated with opioids, one will have satisfactory analgesia from chronic neuropathic pain.

The oral CBD spray used in studies have found it to have an NNT of 5.0, which is comparable to many routine agents used in treating neuropathic pain, including SSRIs (NNT 5.0) and gabapentin (NNT 6.4).

 A similar meta-analysis of 18 double-blind, randomized controlled trials on the efficacy of CBD also showed modest cannabinoid analgesia, but also analyzed the harms associated with CBD. They found the number needed to harm (NNH) with CBD, which ideally would be high, ranged from 5 to 8 persons, which is relatively low, and is substantially higher (above 20) for other analgesics.

 Specific adverse events were impaired motor function, NNH=5; altered perception, NNH=7; altered cognitive function, NNH=8. Future studies clearly must assess the efficacy of CBD balanced against the potential for harm in the management of neuropathic pain.

The pharmaceutical industry is well poised to make CBD widely available under various types of individual state level regulation and both with and without prescriptions. The CBD oral solution Epidiolex®, which is available in the US for management of refractory epilepsy, but may offer therapeutic relief to chronic pain conditions as well. The most recent data about Epidiolex report that heroin cue induced craving was significantly reduced in subjects allocated to 400 mg or 800 mg of an oral CBD solution given once daily for three consecutive days.

 These subjects then were assessed for cue-induced craving and found to have significantly reduced craving for seven days after this treatment. Furthermore, in animals they report that the anti-craving effect may last for five months.

GW pharmaceuticals also produces the drug nabiximols (Sativex®), which is a marijuana extract currently approved in the UK to treat neuropathic pain, such as spasticity, overactive bladder, and other symptoms associated with multiple sclerosis (MS). GW Pharmaceuticals is currently planning to conduct Phase 3 trials for nabiximols in the US. Current investigative drugs developed by Cara Therapeutics (CR701) and Zynerba Pharmaceuticals (ZYN002) are synthetic cannabinoids that 

 to specific neuropsychiatric conditions and chronic pain symptoms such as neuropathy and allodynia.

Thus, through exploratory studies in the evolving role of CBD as a therapeutic agent, we can expect greater scientific evidence regarding the potential for cannabinoid alternatives to opioids for chronic analgesia. Whether CBD simultaneously becomes diverted as a potential drug of abuse, however, is a cause for concern and remains to be seen.

Dr Kosten is Professor at the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Staff Psychiatrist at Michael E. DeBakey VA Medical Center, Houston, TX. He is on the Editorial Board of 

 Dr Domingo is Assistant Professor at the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.

This article was originally published on August 8, 2019, and has since been updated. -Ed

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The cannabinoids (particularly CBD) have been hailed as non-addictive solutions to using escalating doses of opioids for chronic pain. More in this research update.

Cannabinoids for Chronic Pain: An Opioid Alternative?

A Case Built on Current Research Findings

Ketamine has caused quite a stir in psychiatric practice. Sub-anesthetic administrations of ketamine have been shown to markedly improve symptoms of depression and anxiety.

 While the growing off-label use of ketamine speaks to the need for novel approaches to psychiatric care and treatment-resistant illness, it also presents an ethical dilemma, wherein widespread adoption has once again leaped ahead of scientific understanding.

The current literature suggests that therapeutic effects of ketamine involve modulation of glutamate neurotransmission, Î±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor potentiation, downstream influences on neurotrophic signaling cascades and neuroplasticity, and functional changes in assorted neural networks. Additional work is necessary to clarify the importance and reliability of these biological findings.

Another arc to the ketamine story dates back to a decades-old era of psychedelic research and search for medications with transformative power. Indeed, although primarily conceptualized today as a dissociative anesthetic, ketamine has also been classified more broadly as a hallucinogen. Hallucinogens function by various pharmacological mechanisms of action but exhibit similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes.

Current biological theories involving ketamine’s antidepressant effect may be inseparable from these non-ordinary experiences of consciousness, but we can only know the answers to questions we ask. Here we examine findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

There has been a resurgence of interest in hallucinogenic psychedelics (eg, psilocybin, lysergic acid diethylamide (LSD), mescaline, N,N-Dimethyltryptamine (DMT)) and entactogens (eg, 3, 4-methylenedioxymethamphetamine [MDMA]) in psychiatric research, which are hypothesized to achieve clinical benefit due to, in part, experiences of altered consciousness and fundamental shifts in mental frameworks.

These drugs have been associated with cognitive states of enduring personal importance and have been compared with mystical experiences that might emerge over the ordinary course of life and carry sacred or spiritual meaning. Furthermore, these experiences may powerfully influence existential concepts of self, including moral values, self-identity, and purpose. There is converging evidence that these psychedelic effects are mediated in part by activity at 5HT-2A receptors. Ketamine may induce alterations in consciousness and personal frameworks similar to those achieved by serotonergic psychedelics while also sharing a common glutamatergic pathway of drug effect.

 However, there has been little investigation into how such changes might mediate the therapeutic potential of ketamine.

Preliminary data suggest that ketamine produces meaningful, transformative experiences that may help patients accept healthier values, behaviors, and beliefs related to abstinence from drugs and alcohol.

 Other evidence suggests that dose-related mystical-type experiences mediate the effects of ketamine on motivation to quit in cocaine-dependent research volunteers.

 Few recent studies have examined whether ketamine’s hallucinogenic properties are implicated in antidepressant effects; however, psychiatric vulnerabilities to depression plausibly involve an existential dimension. This dimension includes depressive symptoms of hopelessness, guilt, and suicidality, which appear to be ketamine-sensitive.

Given the paucity of modern literature exploring the psychedelic and mystical properties of ketamine in depression, more widespread data on psychotomimetic and dissociative effects of ketamine provide some initial groundwork. Berman and collegeagues

 and Zarate and colleagues10 suggested that the antidepressant effects of ketamine (0.5 mg/kg over 40 min) were disconnected from ketamine-induced psychotomimetic symptoms. The antidepressant effects, measured by the Hamilton Depression Rating Scale (HDRS), were significant even after positive symptoms on the Brief Psychiatric Rating Scale (BPRS) returned to baseline. However, it was also noted that initial changes in BPRS positive symptom scales from baseline trended to predict a greater decrease in HDRS scores within a day of treatment with ketamine.

A small study further demonstrated a substantial relationship between psychotomimetic effects 30 minutes after ketamine administration (0.54mg/kg over 30 min) as measured by BPRS and antidepressant effects in the following week.

 A larger study involving 108 patients found that dissociation measured by the Clinician Administered Dissociative States Scale (CADDS) at 40 minutes was associated with HDRS score improvement at 230 minutes and 7 days after infusion.

 Although no relationship between initial BPRS positive subscale scores and antidepressant effect was found, a correlation between CADSS and BPRS scores was found at 40 minutes postinfusion.

In a small study by Valentine and colleagues,

 the proposed correlation between ketamine-induced dissociation and antidepressant efficacy was not observed. However, a larger analysis found that greater intra-infusion dissociation as measured by CADDS was one of the strongest predictors of extended antidepressant response.14 Both of these studies utilized a single 0.5 mg/kg ketamine infusion delivered over 40 minutes.

Further investigation is needed, but there is an emerging rationale for a connection between the psychotomimetic or dissociative effects of ketamine and its antidepressant efficacy. Perhaps the experience of these effects simply un-blinds patients as to whether they are receiving ketamine or placebo in randomized trials; it may also be that such symptoms are only a “side effect” of ketamine’s mechanism of action. However, it is also worth considering that the psychotomimetic or dissociative effects associated with ketamine treatment are markers or mediators of subjective experiences of potential therapeutic value seen with other hallucinogenic agents.

The recommended doses of ketamine for anesthetic induction are typically 1 to 4.5mg/kg IV and 6.5 to 13 mg/kg IM, with alternate, off-label recommendations for 0.5 to 2 mg/kg IV and 4 to 10 mg/kg IM, primarily in the context of adjuvant drug use. For use in depression, ketamine is most commonly administered at a sub-anesthetic dose of 0.5mg/kg IV across 40 minutes.

Interestingly, in a study of electroconvulsive therapy (ECT) and anesthetic induction with either a near-anesthetic dose of IV ketamine (0.8mg/kg) alone, sub-anesthetic ketamine (0.5mg/kg) plus propofol (0.8mg/kg), or propofol alone (0.8mg/kg), predicted a more rapid antidepressant effect and a higher remission rate than propofol use. The near-anesthetic dose of ketamine was associated with superior antidepressant effects than the mixed, sub-anesthetic dose.

In a study of ketamine alongside psychotherapy for heroin addiction, Krupitsky and colleagues

 compared the effects of 2 doses of ketamine (0.2 and 2.0 mg/kg IM) and found that only the higher dose was associated with a “full psychedelic experience” as measured by the Hallucinogen Rating Scale (HRS). The lower dose was considered a “sub-psychedelic” active placebo, but was nonetheless associated with some positive drug effects: patients were still affected by their experiences and considered them useful and therapeutic. The high dose group ultimately experienced higher rates of abstinence, greater effect on emotional attitudes related to abstinence, and lower rates of relapse and drug craving than the low dose group. Both doses resulted in post-treatment reductions in measures of depression and anxiety; there were no significant differences between the groups.

 compared the effects of 0.41 mg/kg and 0.71 mg/kg doses of IV ketamine given to cocaine-dependent patients. Dose-dependent mystical-type effects as measured by Hood’s Mysticism Scale (HMS) were seen as well as a relationship between HMS scores and the motivation to quit cocaine 24 hours post-infusion.

A different study involving a lower dose of intramuscular (IM) ketamine did not generate the same mystical-type phenomena.

 Perhaps these results highlight the importance of calibrating dosing and delivery. Clements and colleagues

 demonstrated that ketamine had reduced bioavailability with IM administration compared with IV administration. Taken together, these findings support the idea that positive treatment outcomes for ketamine may be dose-dependent and its psychoactive effects are based on delivery parameters.

One criticism of ketamine has been its short duration of antidepressant effect, with benefits peaking at 24 hours post-infusion and generally subsiding by 72 hours. The most promising approach to this challenge thus far seems to be the strategy of repeated-dose ketamine infusions, which have observed extended time-to-relapse and increased rates of antidepressant response.

If ketamine’s therapeutic effect is indeed mediated by psychoactive experience, it may be that repeated dosing of ketamine improves outcomes by increasing opportunities for personally meaningful events to occur. One caveat is that some studies have shown repeated dosing to be associated with fewer dissociative symptoms over time-at first glance this suggests that the antidepressant value of serial ketamine administration might be independent of hallucinogenic effects.

While this requires further investigation, it is also important to consider other interpretations of that evidence: that acclimation to altered states of consciousness may contribute to recall bias, that experimental protocols that frame dissociative symptoms as a “side effect” or “adverse event” may lead to underreporting if overall patient experiences of ketamine are positive, or even that the benefit of repeated dosing may be less related to cumulative drug effect than other factors, such as repeated interactions with care providers or increased opportunities for reflection and synthesis.

One study of repeated infusions demonstrated that antidepressant response very early in the course of treatment strongly predicted subsequent response; conversely, a lack of rapid response was a poor prognostic indicator for improvement after additional infusions. Whether positive early responses to ketamine are mediated by psychological factors, biological susceptibility, or both: it is necessary to clarify these factors in shaping sustainable strategies for treatment.

A cautious approach also seems imperative given evidence that ketamine demonstrates agonist activity at Î¼-opioid receptors and dopaminergic effects that may confer acute relief of depressive symptoms but also greater risk for positive drug reinforcement and dependence. With further insight into psychological responses mediated by ketamine, it may be that a therapy-based framework for ketamine administration optimizes treatment efficacy and sustainability, while also minimizing unnecessary drug exposure, adverse effects of chronic use, and dependency risk.

In one study, long-term abstinence in persons who were substance dependent was achieved with Ketamine Psychedelic Therapy (KPT), which incorporates 1 or 2 sessions of ketamine-facilitated existential reappraisal into an existential psychotherapy.

 Additional exploration would be needed to determine which therapeutic approaches most beneficially augment ketamine treatment and minimize risks for harm. Nevertheless, a more holistic approach to ketamine as a treatment modality may be better suited to recreate the marked, persistent effects of MDMA in patients with PTSD. For example, in one study sustained symptom reductions were achieved with 12 weeks of psychotherapy but with limited MDMA exposures of only three 8-hour sessions.

Another area that requires further investigation is how a patient’s past history might shape psychoactive responses. These personal and quite variable histories have been explored for some hallucinogenic agents but minimally for ketamine. The expectations and personal experiences of the individual user along with the external environment of use have been identified as critical factors in influencing subjective drug effects-coined “set” and “setting,” respectively-and are now considered well-established elements of human hallucinogen research.

Therapies aimed at the pharmacological production of a transformative experience may depend on factors such as patient personality structure, preparation for treatment, emotional activation before drug intake, treatment context, and perceived quality of the experience. Given the unique psychological risks of hallucinogen administration, it is recommended that clinicians screen for personal or family histories of psychotic or other severe psychiatric disorders prior to treatment. Clinicians are also encouraged to facilitate careful patient preparation for sessions, provide a safe physical environment for treatment administration, and allow for interpersonal support during sessions. These and other insights from hallucinogenic research might valuably inform treatment protocols for ketamine administration.

Ketamine is uniquely poised to make a tremendous impact on psychiatric care, even redefining boundaries for patients with variations in depressive disorders that were once thought to be “treatment resistant.” Our synthesis of this emerging and old literature points to the unexplored hallucinogenic potential of ketamine. By further understanding the desirable psychoactive effects of ketamine, clinicians can build on initial treatment successes and maximize patient successes.

  • Further investigating the relationship between ketamine-induced psychotomimetic and dissociative effects and treatment efficacy

  • Clarifying the connection between these effects and potentially desirable hallucinogenic experiences

  • Exploring the therapeutic value of such elicited experiences

  • Revisiting dosing strategies that account for existential phenomena and looking beyond dissociation as simply being an “adverse event”

  • Incorporating psychotherapy-based frameworks into ongoing investigation

  • Assessing set and setting factors that may shape treatment responses

Some answers and clues are likely to be found in the forgotten works of older psychedelic research. Agents like ketamine can exert their greatest therapeutic effect in the afterglow of profound alterations of consciousness, revealing a propensity for growth and healing that has not been evident to the suffering, depressed patient. Wherever the journey takes us, it is exactly the right time to bring together all the strands-brain and mind, old and new, caution and thrill-in assembling the unfinished story of ketamine.

Dr. Mathai is PGY 1 Psychiatry Resident, Dr. Mathew is Professor of Psychiatry, Dr. Storch is Professor of Psychiatry, and Dr. Kosten is Professor of Psychiatry, Baylor College of Medicine, Houston, TX.

 Feifel D. Breaking sad: unleashing the breakthrough potential of ketamine’s rapid antidepressant effects. 

 Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. 

 Perry EB, Cramer JA, Cho HS, et al. Psychiatric safety of ketamine in psychopharmacology research. 

 Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 

An exploration of findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

Thomas R. Kosten, MD

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