A clinical trial at the University of Wisconsin–Madison is studying psilocybin therapy in the treatment of methamphetamine and opioid use disorders.
The innovative trial design will recruit patients actively using methamphetamine and opiates, with the flexibility to increase the dose of psilocybin administered.
In the last year, three million people in the United States have struggled with opioid use disorder, and another 1.5 million people have dealt with methamphetamine misuse. The Psychedelics as Medicine Report revealed opioid use disorder alone costs the US economy US$227 billion a year.
In 2020, over 56,000 deaths involving synthetic opioids were recorded, largely due to the widespread use of fentanyl in the illicit drug supply. This equates to more American lives lost than in the entirety of the Vietnam War.
To discuss clinical trials into the treatment of opioid use disorder and methamphetamine misuse, PSYCH spoke with Professor Paul Hutson, a co-investigator for both psilocybin studies at University of Wisconsin–Madison.
To mitigate opioid withdrawal in the opioid use disorder study, patients will be given buprenorphine, a similar drug to methadone, which is widely prescribed in the UK.
‘Buprenorphine is an opioid with a long half-life,’ explained Hutson. ‘It is used to dose individuals with an opioid so that they don’t go into withdrawal if they’re not taking heroin, fentanyl or other illicit drugs.
‘We are going to give them a long-acting opioid once a day so that they can avoid going into withdrawal. In many cases, those addicted to opioids are not doing it for the initial rush anymore, which is hard to achieve time after time, but just to prevent themselves going into withdrawal.’
While buprenorphine will be used to manage opioid withdrawal, PSYCH was interested to learn whether patients with methamphetamine use will also receive an alternative during the study.
‘That is the problem,’ recognised Hutson. ‘There is no similar drug for methamphetamine abusers. There is no buprenorphine or methadone equivalent to keep them from going into withdrawal. It is one of the things that makes methamphetamine addiction so difficult to treat.
‘In the opioid study, we can give patients buprenorphine to keep them from using illicit drugs, in the hope that it puts them on a path to being able to stop. Addiction is a chronic disease and it may not be possible, but if we can keep them on buprenorphine – or methadone in the case of the UK – then they can go on with their lives.
‘With methamphetamine we simply do not have that option. We are hoping that with one or two doses of psilocybin we will see a drop in the use of methamphetamine, similar to decreases seen in the use of tobacco or alcohol.’
The studies have attracted wide acclaim in the psychedelic medicine community due to their innovative design, tackling indications with large patient populations through repeat administrations of psilocybin and the flexibility to increase dosage.
‘In both cases, we’re giving individuals two doses of oral psilocybin after careful screening for other mental illnesses and psychological issues that may preclude their eligibility.
‘In terms of preparation, there is a similarity with cognitive behavioural therapy in terms of setting intentions and goals. I’ll be honest with you, the primary goal of both of these studies is not to decrease their use of methamphetamine or opioids; it is to see if we can do this safely.
‘Our secondary goals are, of course, to decrease methamphetamine and opioid use, but the way the studies have been written is to see if we make things worse by giving them psilocybin. Do we cause more adverse events or make the addiction worse? Do we accentuate the effects of methamphetamines or opioids?’
With methamphetamine and opioid abuse being such a large issue, particularly in North America, PSYCH was interested to learn why other studies have shied away from enrolling active users. PSYCH asked if this was due to the increased risk of using a vulnerable section of the population.
‘I don’t think it’s the risk of the clinical trials,’ mulled Hutson. ‘I think this is a population that has behaviours which make it difficult for them to fit into a clinical study in terms of reliability. Some may not have the resources to show up for multiple visits as required, or they may not have a consistent dwelling. There are many considerations to take into account.
‘These individuals can be frail; they are typically poorly housed without good nutrition or good health care. These individuals may have more side effects from these medications. Psilocybin commonly produces an elevation in blood pressure and heart rate, but we’re not sure if that’s the action of the drug or if it’s the excitement of the experience. We haven’t had to treat many people for adverse effects with psilocybin, but some will get a headache that we treat with paracetamol or acetaminophen about 12 hours after the dose.’
People affected by opioid and methamphetamine abuse often have large physical, as well as mental, dependencies. For this reason, cognitive behavioural talk therapy often falls short in treating these patients, with high rates of relapse. Taking these factors into account, PSYCH asked how confident Hutson was on the ability to maintain the participation of patients for the full three months.
‘That is a key question. Quite honestly, one of our key goals is to show that we can recruit motivated patients and retain them through preparation and into dosing sessions. Three months is a long time when people are living complex lives, and it will be a big barrier to successfully completing the studies.’
One of the features that sets this study apart from others taking place is the ability to increase the dose of psilocybin. PSYCH pressed Hutson for more detail on increasing the second dose of psilocybin administered, from the initial 25mg dose.
‘In our first study with psilocybin, we escalated the doses twofold to doses that are even higher than what we’re using here,’ explained Hutson. ‘We have had no greater toxicity or adverse effects from even the highest dose used in healthy volunteers, so we are more than confident that we can administer these escalated doses safely.
‘We are asking the question: “When we combine it with methamphetamine or opioid use, do we still see the same safety profile?” It is an important question to answer, so we have the option to not escalate the second dose if the therapist or subject feels it is inappropriate.
‘In terms of timelines, we are hoping to finish enrolling subjects in the first quarter of 2023. Then, we could complete subject interventions by the end of the year, which would give us the ability to report results by the middle of 2024.
‘In terms of what a Phase II trial would look like, we would need to look at what we compare it to in terms of safety and efficacy. The comparison may just be the standard of care, but whether the FDA would require us to use a placebo control arm is unclear. When you ask people who have had active placebos, such as Niacin or Benadryl to make them feel unusual, they know that they have not had psilocybin.
‘One of the things we may be doing next is a weightless control, where individuals are randomised to either get psilocybin with psychotherapy or just psychotherapy on its own. After receiving two months of just psychotherapy, we would add psilocybin to see if there is a significant improvement.
‘As we expand Phase II trials with a weightless or another active control, there would be a lot of merit in including other sites in our studies for multiple reasons. This includes ethnic diversity, cultural diversity, socioeconomic differences, and just to ensure that this is something that can be transported and utilised in different places.
‘As we look ahead to Phase III, it would be an important component that we conduct multi-site clinical trials. However, we would need the budget to support this.
At the university we have what we call the “Wisconsin idea”. It is the concept that what we do here on campus is intended to expand and benefit not only the citizens of Wisconsin, but also the world. We take the Wisconsin idea very seriously.’
In the absence of effective treatments for opioid and methamphetamine use, PSYCH asked Hutson whether the team was considering applying for the FDA’s breakthrough therapy designation, given the severity of conditions
‘Psilocybin therapy has already received breakthrough therapy designation for treatment-resistant depression because of promising data in early studies. I hope that our work might also induce the FDA, and possibly other regulatory agencies, to recognise the potential of psilocybin to treat addiction.
‘However, at the moment we don’t know what the optimal dosing is going to be, and that is why we are looking at two doses, with the second possibly escalated. We do not know if a booster dose six months or a year down the road would be helpful, or if we should escalate the dose even higher than 40 or 50 milligrams. Even if we did receive breakthrough therapy designation, there would still be a lot of investigation work left to be done.’
With opioid use disorder so widespread across the United States, PSYCH asked Hutson for his thoughts on how the creation of psilocybin frameworks in Oregon and Colorado would impact the epidemic.
‘One of the barriers we are going to face is not access to the drug, as I believe psilocybin will be widely available in a few years, but the number of trained therapists available to prepare subjects and sit with them through the experience. We need to make sure people are treated in a safe and well-prepared environment, to maximise the benefits of psilocybin therapy. Quite honestly, we do not have enough therapists to satisfy the demand that exists, whether it’s for treating the addictive behaviours we have been talking about or for depression – the most likely first indication for psilocybin approved by the FDA.
‘At the University of Wisconsin-Madison we hope to have a therapist training programme ourselves within a year, which will be focused on the clinical research application of psychedelic medicine.’