What do you believe is the most important thing for people to understand about the future of psychedelics as medicine?
It is important to keep in mind that all of the typical challenges associated with the pharmaceutical industry and drug development will also apply to psychedelic drugs. Although psychedelics are a unique drug class, they still have to pass through the traditional drug development pipeline. I think psilocybin will be licensed within the next five years or so. And then, more slowly, a few other psychedelic drugs will also be approved. But once that happens, it will become more and more difficult to move new psychedelic medications through the pipeline. The FDA prioritizes clinical trials that include an active comparator – basically, they want to see evidence that new medications have superior efficacy or offer some other benefit compared to existing therapeutic agents. With psilocybin that isn’t a problem because it is being developed for indications where existing treatment options are limited. But once psilocybin and other psychedelics are licensed, it will be necessary to show that new compounds have an improved profile. Showing that a new drug is demonstrably more effective than psilocybin in a clinical trial may prove difficult, at least in some cases.
The fact that psilocybin is likely to be the first drug from this class to be approved is also going to complicate things. Psilocybin is an unusual first-in-class molecule because it is off-patent, making it highly susceptible to generic competition. If psilocybin ends up being relatively inexpensive then that will put considerable pressure on companies selling other psychedelic medications to reduce the amount they charge for their products. Insurance companies and health systems will not pay top dollar for medications if inexpensive alternatives are available with similar therapeutic profiles. So, the key is going to be to identify ways to maximize the therapeutic value of new psychedelic medications, for example by identifying compounds with improved efficacy, better selectivity profiles, or more targeted effects.
What made you personally want to get involved in psychedelic research?
I became interested in psychedelics during my seventh grade biology class. That was way back in 1988, during the DARE era, and we were learning about drug abuse and illicit drugs. I happened to ask a question about how LSD worked in the brain, and my teacher told me that no one had really figured that out. I couldn’t believe that was true! I ended up going over to the local community college library to read more about psychedelics. Although it was true that no one had really figured out why LSD produced hallucinations, a lot was known about its action at the receptor level. In the early 1980s, the 5-HT2A receptor had been identified as an important site of action for LSD and other psychedelic drugs. Reading about that work served as my introduction to receptor pharmacology. I ended up reading a lot of material about psychedelics and I found them fascinating. They are interesting on so many levels. These are substances that have been used by humans for thousands of years. It is amazing that a few milligrams of an alkaloid can alter consciousness so profoundly.
Which current studies are you most excited about and why?
We recently launched the Psychedelics and Health Research Initiative (PHRI) at UCSD. The PHRI is an interdisciplinary team of UCSD researchers who are conducting clinical studies with psychedelic drugs. Currently, we are gearing up to start a clinical trial investigating the use of psilocybin as a treatment for phantom limb pain. After an arm or leg is removed, some amputees can still feel the limb, and the sensation can be extremely painful. Unfortunately, it is very difficult to treat phantom pain using existing medications, so the end result is that some amputees suffer from chronic and debilitating pain. Case reports indicate that psilocybin and LSD can reduce or even eliminate phantom pain in amputees, but controlled trials are necessary to determine whether psychedelic drugs are actually effective for this indication. I’m excited to find out whether psilocybin can relieve the suffering of amputees with phantom pain.
How do you feel about all of the recent hype and investment interest in the psychedelic space?
Overall, I think the attention and interest that psychedelic drugs are receiving is a good thing. The potential medical applications of psychedelic drugs were ignored for many years, which represents a huge missed opportunity. That is really a shame. So, I think it is great that there is a renewed focus on these substances. Let's hope that it turns out better this time!
Which achievements are you most proud of at UCSD to date?
On the preclinical side of things, we’ve made a lot of progress optimizing laboratory assays that can be used to screen novel psychedelics. Preclinical assays play a crucial role in the drug discovery process. Since drug development has a very high failure rate, a large number of compounds must be tested in order to identify suitable lead candidates. But developing preclinical assays for psychedelic drugs has been challenging. Over the last decade or so, my lab has been working to optimize an assay known as the head-twitch response (HTR) so that it can be used as a high-throughput screening tool for new psychedelics. It has been known since the 1960s that psychedelic drugs cause mice to shake their head. Although the HTR has limited relevance to the psychedelic experience in humans, it is very useful as a pharmacological assay. The head twitches are mediated by the 5-HT2A receptor (the same receptor that is responsible for the psychedelic experience), so if a drug induces the HTR in mice then you can be fairly confident that it will produce hallucinogenic effects in humans. In addition, we recently published a paper showing that there is a strong relationship between the activity of psychedelic drugs in the HTR assay and their potency in humans, which makes the assay useful for evaluating novel compounds. The downside to the HTR assay, however, is that it can be time-consuming. Someone has to watch the mice and count the number of head shakes. After running a few experiments, I realized that the assay was never going to be useful for screening unless it was automated. So, I modified the assay in two different ways. First, I designed a system to record head movement electronically, which facilitates data collection and increases the reliability of the technique. More recently, I developed an artificial intelligence approach that uses a neural network to completely automate the process of detecting and counting head twitches. Now we can test large numbers of compounds using the HTR assay and generate very reliable data using a consistent set of procedures. Even before the task was completely automated, my lab used the HTR assay to test almost two hundred different psychedelic drugs, so I’m convinced these new procedures will make the HTR assay even more useful for screening new psychedelics.
Who would you like to see Psychedelic Finance interview next and why?
You could talk to Drs. David Nichols, Mark Geyer, and Franz Vollenweider. Dave founded the Heffter Research Institute and Mark was a cofounder. Franz was one of the first scientists to receive funding from Heffter, and he has been conducting human studies with psilocybin for over two decades. Their hard work over many years helped to move psychedelics back into the realm of mainstream science.
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