Mike Raschilla and Alexander Hymowitz
“One good way to understand a complex system is to disturb it and then see what happens.”
– Michael Pollan, How to Change Your Mind
Often disassociated, physical pain and depression are, in fact, closely related. Whether depression causes pain, or pain causes depression, the two physical and mental incapacities are intrinsically linked. Typically, to combat either illness, medical professionals default to prescription opioids or anti-depressants, rather than looking for alternative treatments. In the United States alone, the number of people prescribed opioids for pain treatment continues to rise year-over-year. Moreover, the number of people on prescription medication for mental health related issues are trending in a similar direction, with an estimated 38.6 million Americans currently receiving treatment via opioids. Right now, there is a dramatic need for alternative therapies that will help elevate pain and depression, while also not creating a vicious cycle of addiction, abuse, and dependency.
Ketamine, is one alternative substance that has gained the attention and acceptance by the medical community. Psychedelic therapy is not a new phenomenon but rather has been studied and used throughout history as a treatment for pain and mental illnesses. Up until today, psychedelic therapy has shown a promise in alleviating some of the most common, yet hardest-to-treat conditions, such as depression, alcohol addiction, cluster headaches, and pain associated with terminal illness. While most psychedelics remain classified as a Schedule I substance in the United States, ketamine, a Schedule III substance, has gained recognition in both the medical and legal communities.
In fact, a growing number of studies show ketamine’s effectiveness in treating pain and certain mental illnesses is trending in a positive direction. Consequently, the drug has gained approval of certain regulatory agencies, pharmaceutical companies, medical insurance providers, and certain state governments. Although, like with most new medical treatments, hurdles remain for ketamine as lingering questions leave skeptics unpersuaded. However, both public and private research and clinical trials have begun to demystify same of these concerns.
Ketamine’s Use as an Effective Treatment for Pain and Depression Has Gained Positive Recognition by a Growing Number of Organizations & Countries
Clinical research on ketamine dates to its synthetic inception in the 1960’s, as medical professionals started to reckon with its unique and fascinating pharmacology. Colloquially known for its use as a recreational hallucinogenic, the public perception of the substance became stigmatized. However, research quickly surfaced to highlight the substance’s medical advantages. Within six years of its origin, scientist at the University of Michigan pioneered the first clinical study of ketamine, which showed overwhelming success as an anesthetic in human patients of all ages. Compared to the widely used anesthetic of the time, phencyclidine, ketamine showed profound analgesia, which could be safely given throughout a procedure, producing minimal side effects and a “lack of severe emergence delirium compared to phencyclidine.”
Consequently, the Food and Drug Administration (“F.D.A”) approved ketamine in 1970 for anesthetic use under the name “Ketalar,” and was quickly disseminated in hospitals around the United States. The prolific use of “Ketalar” and continued clinical studies of ketamine gave rise to its approval within the medical community, prompting a new wave of research.
However, outside the clinical setting, ketamine remains heavily scrutinized and regulated by state and federal governments, making it difficult to fully extract the potential health benefits of this unique substance. Despite the limited use as an anesthetic, research continued through the last sixty years, signaling that ketamine may have more beneficial qualities that extend beyond the F.D.A’s initial approval, which was specifically as a sole anesthetic agent for diagnostic and surgical procedures. For example, clinical trials and studies from around the world have concluded that ketamine may help with pain management and certain mental illnesses, like depression.
The use of ketamine for pain management dates to the 1980s. During that period, many people with Complex Regional Pain Syndrome (“CRPS”), a disease that causes chronic pain usually affecting an arm or a leg, that filed workers compensation claims were left helpless. Most cases were treated with temporary relief from prescription drugs, but the most extreme cases were referred to special clinics overseas. Since doctors in the United States could not administer this type of treatment, patients went abroad to be put into a ketamine-induced coma. After awakening, patients, at the very least, recognized a notable interruption in their intensity of pain. More recently, clinical trials have expounded upon the earlier studies, suggesting that ketamine’s use may extend not only to chronic pain, but also pain-related issues spanning from migraines to fibromyalgia.
Although research illuminates ketamine’s positive effects on pain management, it most notably has gained recognition for its use in treating depression. In 2016, the FDA took further steps to recognize the substance’s positive effects as a therapeutic substance to combat mental illness. Consequently, the agency issued a “Breakthrough Therapy” designation for the use of ketamine to treat severe depression. To be designated as “Breakthrough Therapy”, clinical evidence needs to indicate that the substance demonstrates substantial improvement to the intended output over readily available therapies for “serious or life-threatening conditions.” Specifically, the FDA designation was extended to esketamine, “a nasal spray derived from ketamine and aimed at addressing severe forms of depression with imminent risk for suicide.” Known as Spravato, this nasal spray was created by a group of doctors or scientist at Janssen, a subsidiary of Johnson & Johnson. In its press release, Dr. Husseini K Manji, Global Head of Neuroscience Therapeutic Area at Janssen, gave reason to the groups’ creation of esketamine by explaining the grim landscape of people who unfortunately commit suicide as a result of untreated or poorly treated major depression. With an estimated 41,000 suicides per year, Dr. Manji’s team created one of the first new approaches to treat major depression disorder in the last 50 years.
Since its creation, esketamine gained further approval by the FDA in 2019 and 2020 for its Breakthrough Therapy designation, while also being further extended for patient use as a short-term treatment for suicidal thoughts. Taken together with an oral pill, Spravato clinical trials showed a 70 % success rate of people feeling, at least, a 50% improvement, while the control group reported a mere 35% improvement. The positive trend of the drug’s effectiveness has spurred a wave of ketamine clinics arising throughout the United States, where patients are legally administered ketamine for treatment of mental illness and pain. As states continue to combat the elevated rates of suicide that stem from mental illness, either by assisting in the process or prescribing more opioids, alternative treatments, like ketamine, are likely to pave the wave for other psychedelics to show its effectiveness in pain and mental health treatment. In fact, last year, state legislators in California began to recognize the benefit of psychedelics for medical treatment. In turn, the state proposed a bill, S.B 519, aimed to decriminalize the use and possession of certain psychedelics that gained sponsorship and approval by the state’s Senate. However, it remains with the Appropriations Committee awaiting approval.
Ketamine’s Positive Benefits vs. Its Long-Term Effects, Administration Process, and Potential Abuse
Research and experimentation with psychedelics are not a new phenomenon and can be traced back to the pre-colonialized Americas. However, the recent proliferation of clinical research involving psychedelics, especially ketamine, as a medical treatment continue to answer the lingering question of whether there are any long-term effects associated with the substance. In addressing this concern, a well-established, workers’ compensation defense attorney and a proponent of alternative treatments believes that the upside for ketamine in treating pain and depression is vast, IF data and research finds that the substance is “less addictive, less lethal, and less subject to abuse than opioids, especially if pain reduction is equal or better.” With Spravato being the only derivation of ketamine that is being used for depression treatments and for off-label use, data remains infant. However, clinical researchers are maximizing this opportunity to find results, which can be seen by the vast amount of funding both private and public organizations are receiving for this type of research.
In 2021, there was an uptick in private start-ups that received funding to conduct such research. For example, an east-coast start-up, MindMed, has received millions in private funding with the purpose of conducting research under the name, “Project Angie”. Project Angie is a comprehensive study of different types of psychedelics and their effects on treating pain and mental illness, with an emphasis on longevity, reliance, and bodily resistance. Across the country, a California research start-up, Tryp Therapeutics, is doing much of the same, but partnered with the University of Michigan to study not only the treatment effects of psychedelics, but also coupling the research with clinical trials on treating fibromyalgia. Further, Tryp recently added one of the world’s top researcher in psychedelics, Robin Carhart-Harris, to its scientific advisory board to play a critical role in the project.
Aside from private companies and labs conducting research, there has been an uptick in interest by some of the world’s leading research institutions, such as Johns Hopkins University, Yale University, Imperial College London, and the University of California-Berkeley. Outside of the United States, funding attitudes are quite similar. For example, in Oxford, England, a notable pharmaceutical start-up, Beckley Psytech, raised an astonishing $80 million for research aimed specifically to address questions pertaining to low-dose treatments of psychedelics. Although these labs are conducting research on different forms of psychedelics, the medical communities’ acceptance, along with the FDA, of ketamine has allowed research to move forward faster than other forms of psilocybin in United States, providing insight and establishing standards for safe and effective administration.
Whether it be MDMA, ketamine, or other forms of entheogens, there is vast confusion and skepticism surrounding the administration process in a clinical setting. Compared to the time it takes to swallow a pill, there are dramatic differences between administration of opioid prescriptions and these alternative treatments. Typically, more potent forms of psilocybin, such as MDMA or LSD, are typically administered with an intense screening process in a controlled setting, either at the office or a therapeutic center, supervised by high trained professionals and researchers, and guided by a group of people to achieve a positive therapeutic outcome. These sessions will typically last anywhere from 4-8 hours, depending on the substance and the patient’s response to the drug. This focus is part of the “set and setting” ideology that has long been proffered as a key component of successful entheogenic therapy. Ketamine, unlike the other entheogens, is administered in a less-potent form than other psilocybin derived substances and can be distinguished from its counterparts, because of its practicality in our current, fast-paced world.
Ketamine can be administered in two ways for pain or mental health treatment – racemic infusions (IV) or nasal spray (Spravato). The first method of receiving ketamine through an IV continues to be relevant; however, for purposes of anesthetic, which was previously discussed. This is because of the long lasting, dissociative effect to help patients feel essentially no pain during a procedure with minimal side effects. However, the FDA has specifically restricted use of IV administration for any off label uses. The second method, which is how ketamine gets distinguished from its counterparts, is through a nasal spray. Compared to the 4-8 hours of treatment recommended for other forms of psilocybin, the typical Spravato session is, at most, 2 hours to protect against the common side effect of sedation and dissociation.
Given the FDA’s approval and dosing regulation of Spravato, there have been ample organizations, regulatory agencies, and corporations overseeing and implementing safe administration procedures to combat some of the side effects, as well as the potential for abuse. There is a strict screening process that takes place to ensure positive treatment, while removing the risk of abuse. Specifically, patients need to be “opioid resistant” or exemplify signs or thoughts of suicide. Further, even if a patient is screened and approved for treatment, there are additional screenings that take place before each session to ensure the patient’s vitals and mental state are proper to maximize the treatment.
Moreover, Spravato cannot be taken out of the facility or office in which it is administered. Meaning, the facility or prescribing doctor will remain in full possession of the substance for the entirety of the treatment and remains with the patient during the full time. Patients are not required to drive or operate machinery after treatment and cannot be released until a full screen is performed by the medical staff. As safety remains the number one concern for most facilities and offices, these safeguards and meticulous administration requirements exemplify the scalability, practicality, and efficacy surrounding the therapeutic use of ketamine.
The Public’s Misconception of Ketamine
Typically, when the public thinks of ketamine, there is a non-association to its therapeutic benefits. Rather, the substance has coined the street name “Special K” due to its ability to trigger hallucinations and other mind-altering status when taken in excess amounts. Increasing in recreational use after the Vietnam War, ketamine quickly earned a spot on the controlled substance list. Given its effects when abused, the drug became associated with other entheogens without merit. However, as previously discussed, clinical and therapeutic administration processes and procedures continue to demystify ketamine’s tarnished reputation, amongst other psychedelics. Even if there is consensus surrounding the positive effects of its use during a guided session, skepticism remains regarding the potential abuse of the substance, given the disastrous landscape the opioid pandemic paved. However, data and renowned research implicate quite the contrary.
The World Health Organization (“WHO”) has gone to great lengths to produce studies and opinions on ketamine. In fact, WHO listed the drug as an essential medicine in 1985. Establishing that there should be an adequate supply always available for health care needs across the globe. Further, WHO extended its appreciation for the drug, considering it “extremely safe” especially regarding its use as an anesthetic. Since 1985, the drug has remained on the “WHO Model List of Essential Medicines” for adults and children. More recently, the positive trend continued to be recognized by WHO, and, in 2015, WHO Expert Committee on Drug Dependence recommended for a fourth time that Ketamine should not be controlled under the international drug control conventions due to its essential role in the clinical setting, especially for low-research countries, disaster situations, and conflict zones.  Aside from its practicability that has been recognized throughout the world, WHO has further addressed dependency and abuse issues that are contrasted noticeably against opioids.
In a report published in 2016, WHO addressed the safety concerns surrounding abuse of ketamine. The organization conclusively stated that “the illicit use of ketamine has been reported on a relatively small global scale for several decades. Ketamine dependence and overdose is rare.” Availability of data has been present for several decades, and, in the countries that have reported the presence of ketamine, trends suggest that the illicit use remain muted. In fact, in the major countries where ketamine has established a presence, illegal use has decreased since 2011. Even with a minimal percentage of the population that reported using the substance, England reported a decrease in the rate of users from 0.6 percent to 0.4 percent over a 5 year time period. Comparing those figures with the staggering 5.5 percent of the global population that uses opioids, the risk of illegal use of ketamine remains low.
Although concerns surrounding illegal use outside of the clinical setting remain relatively low, the addictive abuse that could lead to fatal overdose is even more conclusive relative to opioids. In fact, the WHO Expert Committee on Drug Dependence addressed this issue in its entirety. Acknowledging the concerns about abuse, the Committee found that ketamine does not appear to pose a significant enough global public health risk to warrant any type of scheduling, or restrictions. Opioids, however, continue to pose a significant threat to our public health. Specifically, WHO has recently tried to minimize the use of opioids given its high dependency, diminishing returns on chronic users, and synthetically altered substances. In its report, WHO addressed its main concern about illegal use and cultivation. Given the staggering number of people addicted or taking opioids, the demand continues to shift parabolically. In its entirety, WHO is expressly concerned with the number of opioid-related deaths that result from an overdose from illicitly cultivated or manufactured drugs. 
In 2017 alone, more than 11 million people in the United States misused prescription opioids, while prescription opioids accounted for 35 percent of all opioid overdoses. Yet, countries that reported a presence of ketamine has identified that less than 1% of overdoses have been attributed to ketamine, with only 3 deaths involving ketamine as the sole substance over a 12 year period. With the total economic burden of prescription opioids totaling to an estimated $78.5 billion per year, according to the CDC, there is a dramatic need for alternative therapy in which a substance, like ketamine, can offer a safe and viable alternative.
Regulations & Legalization
Recent legalization and decriminalization efforts, like those in Canada, Oregon, and Denver are demonstrative of a changing entheogen landscape. As the demystification of entheogenic therapy continues to grow, legalization efforts will undoubtably follow suit. Ketamine is paving that legal landscape because of it’s “off-label usage”. Ketamine has been prescribed for its off-label usage for some years now, with studies on its off-label effectiveness for depression dating back to 2017. Off label usage is the unapproved use of an approved drug, and it is completely legal. Simply put, “Off-label” usage means the medication is being prescribed and used for a disease or a symptom that it did not originally get FDA approval for. In fact, one in five prescriptions written today are for off-label use. Ketamine’s usage as an anti-depressant falls into this category. While there are very strict laws and regulations about off-label promotion for drug manufacturers, healthcare providers are not subject to those same restrictions. In fact, a healthcare provider has the absolute right to discuss and recommend drugs for off-label uses with patients. However, healthcare providers are still obligated to abide by state and federal regulations.
Since 1999, ketamine, including its salts, isomers and salts of isomers, have been listed as a Schedule III non-narcotic substance under the Controlled Substances Act. Although dedicated researchers and health organizations around the world are working to demystify the stigma of not only ketamine and MDMA, as well as other psychedelics, (1) price, (2) availability, (3) legality and (4) a general lack of information about these entheogens, remain issues for those looking to utilize these lifesaving substances. As more countries, states and municipalities continue to decriminalize and legalize entheogenic use for therapeutics, it is important to continue learning and understanding ketamine’s usage, benefits, risks, and guiding regulations.
 Hales CM, Martin CB, Gu Q. Prevalence of prescription pain medication use among adults: United States, 2015–2018. NCHS Data Brief, no 369. Hyattsville, MD: National Center for Health Statistics. 2020.
 Davis MA, Lin LA, Liu H, Sites BD. Prescription Opioid Use among Adults with Mental Health Disorders in the United States. J Am Board Fam Med. 2017 Jul-Aug;30(4):407-417.
 Li, Linda, and Phillip E Vlisides. “Ketamine: 50 Years of Modulating the Mind.” Frontiers in human neuroscience vol. 10 612. 29 Nov. 2016.
 Bilhimer MH, Groth ME, Holmes AK. Ketamine for Migraine in the Emergency Department. Adv Emerg Nurs J. 2020 Apr/Jun;42(2):96-102.
 The Long Trip: A Prehistory of Psychedelia by Paul Devereux
 Hartogsohn I. Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology. J Psychopharmacol. 2016 Dec;30(12):1259-1267.
 Regulations Amending Certain Regulations Relating to Restricted Drugs (Special Access Program): SOR/2021-271
 Measure 109
 Ordinance 301, Psilocybin Mushroom Initiative (May 2019)
 Wilkinson, Samuel T, and Gerard Sanacora. “Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders.” JAMA vol. 318,9 (2017): 793-794.
 Wittich, C. M., Burkle, C. M., & Lanier, W. L. (2012). Ten common questions (and their answers) about off-label drug use. Mayo Clinic proceedings, 87(10), 982–990.
 Buckman Co. v. Plaintiffs’ Legal Comm., 531 U.S. 341, 350–51 (2001) and Smith v. Medtronic, Inc., No. 13-451, 2014 U.S. Dist. LEXIS 78473 (W.D. La. June 4, 2014)