Taking the high road: turning to drugs to treat addiction
by Alyssa DiLeo | December 22, 2021
Despite the stigma of illicit drug use, researchers are once again pursuing psychedelic drugs as treatments for neuropsychiatric disorders, such as depression and substance use disorder. Times have changed quite a bit from the Wild West of clinical drug testing in the 1960s when drugs could be administered to patients with little governmental oversight. Modern studies with well-controlled clinical trials are replicating data from the 1960s that shows promising outcomes, especially in treating substance use disorder.
This comes at a crucial time when drug use and overdose deaths have increased during the ongoing COVID-19 pandemic. Current drugs used to treat addiction only target specific stages of addiction, have low prescription rates, and do not address any co-occurring mental illnesses. With more academic labs and pharmaceutical companies obtaining and testing psychedelics as addiction therapy, dozens of clinical trials are underway and psychedelic assisted treatment clinics are set to open across the UK, Canada, and the United States.
A short history of psychedelic research
While psychedelics have been an important part of medicinal, ceremonial, and personal use in Indigenous cultures for millenia, Western science only acknowledged psychedelics after Albert Hoffmann, a chemist from Sandoz pharmaceutical company, documented the hallucinogenic effects of LSD in the 1940s. This triggered a short, but intense period of research into the therapeutic potential of psychedelics. Approximately 40,000 subjects, including children, participated in over 1,000 studies on psychedelic treatment for neuropsychiatric disorders, including post traumatic stress disorder, substance use disorders, anxiety, depression, autism, and schizophrenia. By the 1960s, Hoffman had identified psilocybin in mushrooms, scientists were holding academic conferences about LSD use, and presidents of major pharmacology societies were openly discussing self-experimentation with hallucinogens.
Accounts of abstinence in alcoholics after experiencing delirium tremens — a symptom of severe alcohol withdrawal that can include hallucinations — led researchers to hypothesize that artificially recreating this effect with psychedelics could similarly reduce alcohol intake. A handful of hospital-led studies found LSD could reduce alcohol use in people with alcohol use disorder, but all of these studies were uncontrolled, had small sample sizes, and didn’t report detailed methodology.
By the end of the 1960s, the sun began to set on the promise of using psychedelics as clinical treatment for mental health illnesses. After news of research misconduct in psychedelic experiments and the rise of recreational use, especially among anti-war youth, scientific institutions and societies began distancing themselves from psychedelic research. Concerns began to arise over the quality of pharmaceutical clinical trials for new drugs. Then, it was discovered that thalidomide, a morning sickness drug given to pregnant women outside of the U.S., caused serious birth defects. This prompted Congress to pass the Kefauver-Harris Drug Amendments in 1962. Instead of relying on individual physicians’ judgement and assessment of new drugs, pharmaceutical companies now had to provide the Federal Drug Administration (FDA) with preclinical and clinical evidence that new drugs were safe and effective for specific medical indications — something that is commonplace today. In 1966, psychedelics were federally prohibited and research was banned.
Then, Congress passed The Controlled Substances Act of 1970, which federally regulated and organized illegal drugs into five categories based on the drug’s medical use and abuse potential. Although some National Institute of Mental Health labs continued research on LSD in the mid 1970s, psychedelic research was no longer accessible or profitable for most labs and companies. Today, if researchers want to work with Schedule I drugs, they must work with the FDA and Drug Enforcement Administration (DEA) for approval and licensing, a process that can take many months or years to complete. Labs can order psychedelic drugs through the federal government, specifically the National Institute for Drug Abuse (NIDA). However, drugs bought from NIDA are expensive and often do not reflect the potency or diversity of recreationally available drugs. This legislation curtailed research on these substances, effectively determining they would never have a medical use.
The failed “War on Drugs” created stigma & disparities
It has been 50 years since President Nixon declared a “War on Drugs” and we have little to show for the estimated trillion cumulative dollars the U.S. has spent unsuccessfully fighting drug use and addiction. According to the 2019 National Survey on Drug Use and Health, 20% of people aged 12 or older reported using an illicit drug in the past year. This amounts to 57.2 million people, a 3% increase from 2015, mostly attributed to marijuana use and prescription pain reliever misuse among adults 26 or older.
After all this time, how and why has drug use increased instead of decreased? For one, this fight heavily criminalizes drug use and drug users, framing drug use as a moral failing that requires punishment instead of medical treatment. This has led to high rates of incarceration for drug offenses, leading to massive racial disparities in drug arrests and sentencing. One in five people incarcerated in the U.S. are in prison for drug offenses. 24% of those arrested are African American, despite the fact that they make up 13% of the U.S. population and use drugs at the same rate of white people.
After the U.S. government failed to police drug use away, the scientific research community moved to classify addiction as a relapsing, but treatable, brain disease. Alan I. Leshner, the director of NIDA from 1994 to 2001, introduced the biophysical framework of “addiction as a brain disease” that incorporates the biological, social, and environmental factors that enable addiction. Building on this, Nora Volkow, the current NIDA director, published recommendations to treat addiction as a public health crisis instead of a stigmatizing activity through the criminal justice system. Even as federal and private research priorities shifted towards understanding the biological basis of addiction, public health and federal drug enforcement policies haven’t quite caught up. Recently, the city of Boston executed mass evictions and arrests at Mass and Cass in Boston, an area that attracts people who are homeless and/or use drugs.
Addiction treatments are effective, but under-used
Drug use and addiction usually doesn’t happen on its own. About 38% of adults with substance use disorders also have a co-occuring mental illness, which predispose them to use substances. Currently, an estimated 8% of the U.S. population need substance use treatment, but only 1.5% of people receive it, leaving a significant portion of substance users without help. In fact, less than 20% of people with a substance use disorder will be prescribed drug dependence medications, compared with 64% of people who receive medication for psychiatric illnesses. Barriers to treatment accessibility include cost, stigma, and simply not wanting to stop using drugs. To further complicate medical treatment, people using drugs with co-occurring disorders, like depression or anxiety, need treatment that addresses both disorders simultaneously.
Current treatment for substance use disorders differs based on the substance, but generally consists of medication for withdrawal and relapse prevention coupled with individual or group therapy (see table below). Even though FDA-approved treatments and effective behavioral therapies for addiction exist, rates of drug abuse and overdose deaths remain high. Addiction is by definition a chronic, relapsing disorder and people in recovery have relapse rates comparable to other well managed chronic illnesses, like asthma. Substance use disorders need to be treated in the same way, either with long term maintenance medication and support or short term drug treatments that have long lasting effects. Treatment also needs to address any underlying causes of drug use, which could include mental illness. Therefore, a treatment that targets both mood and substance use disorders, as is the case for psychedelics, could potentially simplify treatment for those living with co-occurring disorders. This has driven basic science and therapeutic research towards new treatments for substance use disorders.
Table 1: Current FDA approved treatments for substance use disorders
|Drug||Substance||Effects||Mechanism of Action|
|Acamprosate (Campral)||Alcohol||Decreases craving||NMDA antagonist and positive allosteric modulators of GABAARs|
|Naltrexone (Vivitrol)||Alcohol & opioids||Blocks reinforcing effects of drugs||Opioid receptor antagonist|
|Disulfiram (Antabuse)||Alcohol||Causes illness with alcohol||Inhibits acetaldehyde dehydrogenase; sensitivity to alcohol|
|Methadone (Dolophine)||Opioids||Detox and maintenance from use||Opioid receptor agonist|
|Buprenorphine||Opioids||Reduces withdrawal symptoms||Opioid receptor agonist & antagonist|
|Bupropion (Wellbutrin)||Smoking||Reduces craving||Norepinephrine/dopamine reuptake inhibitor & nicotinic receptor antagonist|
|Varenicline (Chantix)||Smoking||Reduces craving||Nicotinic receptor partial & full agonist|
Investment in psychedelic treatment for alcohol use disorder
Based on anecdotes that psychedelic experiences stopped alcohol use, studies in the 1950s found that LSD could separately reduce alcohol and opioid use in people with substance use disorder. Modern clinical studies and self-reported psychedelic experiences confirm this. Real reductions in alcohol use and improvement of abstinence rates have been reported by The Johns Hopkins Center for Psychedelic and Consciousness Research. “The subjective effects of the psychedelic experience are significantly correlated with lasting treatment outcomes for people with depression, addictions, and cancer-related distress,” said Dr. Albert Garcia-Romeu, a researcher with the center. However, patients can have different effects to the same dosage of psychedelics. “We are still not able to predict very well how people will respond to psychedelics,” Dr. Garcia-Romeu said. This poses a challenge for clinical trials, which currently don’t allow for flexibility in dosage.
What would clinical administration of psychedelics look like? It’s still unclear what the exact treatment regimen would be, but Dr. Garcia-Romeu thinks it would include two to three doses combined with supportive therapy, with additional boosters for some. “Ideally this would be something that could be administered a limited number of times and continue to have persisting positive effects long-term for many people,” he said. “[This] sets these psychedelic therapies apart from many other types of treatment currently available.”
Currently, there are a dozen clinical trials recruiting participants in the United States to evaluate psychedelic treatments in substance use disorders. Many of these studies focus on the use of ketamine or psilocybin for alcohol use disorder. In the United Kingdom, Awakn Life Sciences focuses entirely on treating addiction with psychedelic assisted therapies. The company believes its therapy has an advantage over current medications because it can disrupt full brain circuits involved in developing addiction. In November, Awakn announced the completion of a phase IIb clinical trial to test the effectiveness of ketamine assisted therapies in alcohol use disorders. The results are expected to be published in the American Journal of Psychiatry. This is big news for the field of psychedelic treatment, as it paves the way for clinical use of ketamine in Awakn clinics in the UK and Europe.
Making psychedelics a viable treatment option
As clinical testing of psychedelics moves forward, the field has some issues to address. The first is to simplify the process for researchers obtaining and testing psychedelics. Scientists in the field argue the federal government needs to reschedule psychedelic drugs. This would not only make it cost effective for researchers to access and study psychedelics, it would advance research in the field overall. In 2018 and 2019, the FDA granted two psilocybin drugs “breakthrough therapy” status to fast track development and approval for their use treating different types of depression. The FDA also recently approved Spravato (Esketamine), a ketamine analog that is administered in clinics for treatment of depression. The levers to open up psychedelic research and clinic use are there, the government is just being selective as to which ones to pull.
Although the potential abuse of psychedelics is still unclear, the risks in using them for treatment are no different than any other new pharmaceutical drug that goes through rigorous clinical testing. It might seem counterintuitive to treat a population with a history of substance abuse with drugs, but reviews have found psychedelics have low abuse potential when appropriately administered and pose no more danger than other addictive drugs. In fact, medications that treat opioid use disorder, such as methadone, engage the same receptors in the brain as opioids do. But just because a treatment engages the same receptors as the drug of abuse, doesn’t mean it will be ineffective or lead to abuse.
If psychedelics do show efficacy and safety in clinical trials, can psychedelic treatment be integrated into current substance use treatment programs that hinge on drug abstinence, such as Alcoholics Anonymous and other 12 step programs? Total abstinence is only one model towards recovery, according to Dr. Garcia-Romeu. He said psychedelic treatment can be integrated into harm reduction approaches that allow a person to have better control over their substance use by avoiding the worst harms and living a balanced life. Deciding if, how, and when to use psychedelics as part of addiction recovery will likely be a personal choice.
Lastly, psychedelic treatment should be accessible and equitable. This isn’t easy to do in a country with privatized and for-profit healthcare like the United States. Psychedelic therapy may only be attainable for the wealthiest patients, given that the treatment is expensive, not covered by insurance, and people will need to take time off for treatment. In addition, the psychedelic field should be thoughtful about an equitable and sustainable rollout of these therapies. The war on drugs disproportionately affected Black and Hispanic people who were arrested for drug charges at higher rates than white people. Yet, the legal marijuana industry is dominated by white people. The field of psychedelic medication and treatment must be careful not to follow suit. It must figure out how to give back to communities that have been negatively affected by drugs and addiction.
Since certain psychedelics — such as psilocybin mushrooms, Ayahuasca, and peyote — are still used by Indigenous communities, Dr. Garcia-Romeu argues that use of these drugs will need to be acknowledged as legal practices. “Environmentally sustainable approaches for their use and cultivation will need to be put in place, not just in medical clinics, but in wider traditional contexts,” he said. There are calls to decolonize the current scientific and pharmaceutical framework by centering Indigenous communities’ knowledge and practices that psychedelics are based on. This means embracing diverse research teams and study subjects, as well as valuing the voices of those who have been disproportionately impacted by the criminalization of drugs.
Several organizations have begun to pursue equitable psychedelic research. The Chacruna Institute for Psychedelic Plant Medicines has committed to include traditionally excluded communities in the field of psychedelic medicine. The Oregon Psilocybin Society, a non-profit providing assisted psychedelic experiences, will dedicate funding for low income communities and people of color to access these treatments. They have also launched a scholarship to train people of color and people from low income communities to become psilocybin facilitators.
Psychedelics for what ails you
Substance use disorders aren’t the only focus for companies investigating the use of psychedelics in clinical trials. Several companies are testing psychedelic treatments for other conditions such as major depressive disorder, eating disorders and neurodegenerative disorders. One thing is clear: the efficacy of psychedelics in treating substance use disorders is leading investigators to ask — what else could we treat? Scientists will also need to determine how doses and regimens will be personalized for patients, as well as who is an ideal candidate for these drugs.
As the COVID-19 pandemic continues to exacerbate mental health and addiction crises around the world, there is an urgent need for effective medical treatment of these conditions. The scientific community may turn to psychedelics as a possible solution to these global challenges.
Alyssa DiLeo is a 5th year Ph.D. candidate at Tufts University Graduate School of Biomedical Sciences where she studies the effects of alcohol on the brain.