Where is the difference between drugs and medicine?
Una Meistere
A conversation with Wim van den Brink, Emeritus Professor of Addiction Psychiatry at the Amsterdam University Medical Centre
Wim van den Brink is Emeritus Professor of Addiction Psychiatry at the Academic Medical Center of the University of Amsterdam and used to be the Director of the Amsterdam Institute for Addiction Research (AIAR). His primary scientific interests include the neurobiology of substance use disorders and behavioral addictions, the pharmacological treatment of substance use disorders and related comorbidities and reducing the stigma surrounding patients with addiction.
In 2014, he received the Lifetime Achievement Award for Science from the Netherlands Association of Psychiatry, and in 2015, he was honored as an honorary member of the Spanish Society for Dual Disorders. In 2017, he was awarded the European Addiction Research Award by the European Federation of Addiction Societies (EUFAS). He is a (co)author of more than 700 international peer–reviewed scientific papers and has supervised over 75 PhD students.
Wim van den Brink has chaired workgroups that developed Dutch Treatment Guidelines on Alcohol Use Disorders, Opiate Addiction, and Drugs other than opioids. He is one of the founders and the president of the International Collaboration of ADHD and Substance Abuse (ICASA). He also served as the chair of the Scientific Program Committee of the European College of Neuropsychopharmacology (ECNP).
He is a co–author of the Dutch State Committee MDMA report, “MDMA: Beyond Ecstasy”, which was presented to the Dutch Minister of Medical Care in June this year. This 233–page report explores the multifaceted dimensions of MDMA, including its recreational use, potential therapeutic benefits, and broader implications for public health and policy.
In this report, the Dutch State Committee proposed a plan for a “naturalistic study” that, if approved, would provide MDMA–assisted therapy to 400 to 500 people with PTSD within the next five years.
In our conversation, we discuss the current state of addiction treatment, the need to establish a rational drug policy, and the safe availability of psychedelic–assisted treatment as an additional tool in dealing with mental disorders.
Like in the Netherlands, a serious discussion about decriminalization has started recently in Latvia as well. The controversy surrounding it has also illuminated a significant communication problem: people still classify cannabis and psychedelic substances simply as drugs, putting them together with opioids and other highly addictive substances. What makes the difference between a drug and medicine? You tested and implemented heroin assisted treatment on heroin dependent patients...
This is a really important question – the difference between a drug and medication. In English, the word “drug” is used for both medications and recreational substances, which can lead to confusion. You might also think about doping when considering the use of certain compounds in sports activities. So where is the difference between drugs and medicine? To be honest, pharmacologically, there is no difference. Some pharmacological substances are used both recreationally and as treatments, and this has been the case for many substances over a long period of time.
You already mentioned opiates. For certain types of pain, such as chronic cancer pain and acute postoperative pain, opiates are very effective medications. However, there’s always the possibility of abusing these substances, leading to either recreational use or dependency. This makes it difficult to draw a clear distinction between their medical and non-medical use.
The same challenge arises when we think about stimulants used in treating youngsters with Attention Deficit/Hyperactivity Disorder (ADHD). Medications like methylphenidate and dexamphetamine are stimulants that have mechanisms of action similar to those of cocaine or amphetamine. Again, the difference between a medication and a drug lies in the purpose of use and who is providing the substance, rather than in the chemical characteristics of these substances.
So, when we talk about drugs, we’re often referring to either recreational use or cases where people, having started with a prescription, become dependent. The distinction between a medication and a drug is not based on the chemical properties but rather on the intent behind its use and the context of its prescription.
The distinction between a medication and a drug is not based on the chemical properties but rather on the intent behind its use and the context of its prescription.
What is the current concept of addiction, and how does it shape the way we, as a society, deal with it?
The concept of addiction has evolved significantly over the last few decades. In the 1800s, people primarily thought of drugs in terms of alcohol, which was considered the most significant drug at the time. Those who excessively used alcohol were often seen as weak individuals with flawed character. Addiction was viewed as a moral weakness. If someone couldn’t control their alcohol consumption, they were often sent to what were called correctional centers – essentially prisons – to be “re-educated” and restored to moral integrity.
This perspective shifted dramatically in the 19th century when society began to understand that the problem wasn’t necessarily the individual’s weakness, but rather the powerful nature of alcohol as a drug. The focus then shifted to making alcohol illegal, as it was deemed too dangerous for public consumption. In America, this led to a situation where legal alcohol was no longer available, and similar movements were seen in many European countries, often led by churches, aiming to “dry out” their nations.
However, this prohibition led to unintended consequences: people turned to illicit alcohol, often homemade and consumed in secret. In the United States, the mafia took over the illegal alcohol industry. This was, in many ways, an early example of what could be called a “war on alcohol”. It shifted the blame from the individual’s weakness to the pharmacological power of alcohol, marking it as the first drug considered so dangerous that it needed to be banned.
Then, I think, in the early 20th century, people started to say that addiction is not a condition in itself but rather a symptom of an underlying personality disorder, as they called it. Psychoanalysts referred to it as character neurosis. They suggested that treatment should focus on addressing these individuals’ character flaws within therapeutic communities. While some people may find help in these communities, there is not a lot of evidence that they are the best way forward.
It wasn’t until the 1940s that people began to view alcohol as a disease, with some genetic factors involved. In the 1970s, the perspective shifted again, suggesting that addiction was not so much a disease but rather a psychological issue, maladaptive learned behavior. It was seen as something people needed to unlearn through treatments like cue exposure therapy and cognitive behavior therapy. By the end of the 1970s, the view had evolved to consider not only biological and psychological factors but also social ones.
This understanding continued to develop until 1976 when the World Health Organization had a committee that stated addiction is biopsychosocially determined. The concept of alcohol dependence syndrome was developed, which now forms the basis of what is generally referred to in medicine as substance use disorder. However, since the 1990s, within the biopsychosocial model, biological factors, such as genetic predispositions, and psychological factors gained more attention and became crucial in determining who becomes dependent on substances. The definition of this is any maladaptive pattern of alcohol or drug use that leads to clinically significant suffering or dysfunction.
So, if you use alcohol, even if it’s a little too much, but there is no clinical dysfunction and no clinical suffering, we say it’s still normal behavior. However, it is a maladaptive pattern of alcohol use leading to these kinds of suffering. What are the symptoms of that? There are basically four:
Craving: An irresistible urge to use alcohol in situations where it is unwise.
Lack of Control: Using more alcohol or using it in situations where it shouldn’t be used.
Withdrawal Symptoms and Tolerance: Experiencing withdrawal symptoms and needing more alcohol to achieve the same effect.
Social, Psychological, and Physical Consequences: Experiencing negative social, psychological, and/or physical impacts.
These are the four characteristics of what we call addiction, and there is general agreement about this in Europe and the United States. In the United States, this is defined in the DSM–5, and in Europe and the rest of the world, it is defined in the ICD–11.
You mentioned craving, and I think the development of habit is also very involved. We often speak about implementing healthy habits in our lives, but at the same time, unconsciously, we develop many habits, including unhealthy ones.
Absolutely, you’re right that this is the general description of addiction. In the early stages of addiction, the drug’s reward is very important. However, in the later stages, it’s less about the reward and more about relieving negative feelings and symptoms. The behavior shifts from being driven by reward to being driven by relief. Eventually, neither reward nor relief becomes very important. At that stage, addiction becomes a habit, independent of both reward and relief.
For example, many people are familiar with the experience of smokers. They smoke a cigarette and no longer feel any reward, nor does it help with the craving; they just continue to smoke as chain smokers. I was a smoker myself 37 years ago, and I would find myself with one cigarette in my mouth and one cigarette in the ashtray, simply exchanging them without any conscious effort. Even 10 years after I stopped smoking, I would still find myself looking for a lighter in my jacket that hadn’t been there for a decade. The behavior had become so ingrained that it was completely automatic.
These kinds of behaviors are often very difficult to change. As long as there is a change in reward or relief, there is something to work with. However, once the behavior becomes a habit, it becomes much harder to address with psychological interventions. This is also reflected in brain activity. In the early stages of addiction, showing the drug, whether alcohol or another substance, activates the reward part of the brain, the ventral striatum. In contrast, in individuals with chronic alcohol dependence, the ventral striatum is no longer activated. Instead, the dorsal striatum becomes active, which has a direct connection with the motor cortex. This means that even without the reward, the behavior continues because the dorsal striatum, involved in motor control, is activated in response to cues. This development has been well-documented for many years.
And as you said, overcoming it is really monumental work, especially for the patient...
Absolutely, and it is very difficult; we must recognize that. Just think about one of the most difficult to treat addictions to treat, smoking. Nicotine dependence is a very hard addiction to treat.
Interestingly, there are now developments suggesting that certain psychedelics might be helpful in treating these kinds of disorders. Psychedelics can significantly shake up the brain and potentially address these behavioral automatisms.
Nicotine dependence is a very hard addiction to treat. Interestingly, there are now developments suggesting that certain psychedelics might be helpful in treating these kinds of disorders.
Also, there is a growing body of evidence that early childhood trauma could be one of the factors that stimulate the development of addiction later in life. It is just a speculation, but maybe this is also a reason why the mechanism of punishment towards drug use simply does not work, and often has the opposite effect?
I’m not sure about the direct connection, but I would say that many people with addiction have a history of childhood traumatization, such as sexual abuse, violence, and/or emotional neglect – all of which are forms of trauma. It’s common to find that between 40% and 80% of patients with addiction have experienced some form of chronic childhood trauma, which can be devastating for normal development.
On the other hand, there are also indications that childhood problems might precede the development of addiction. For example, children with ADHD are more likely to develop addictive disorders later in life. Most studies suggest that if a child has ADHD, the probability of developing an addiction by age 25 is about 50%. However, this also means that 50% do not develop an addiction. There is evidence that treating ADHD at an early age with stimulants, such as methylphenidate, or with newer treatments like ketamine, can reduce the likelihood of developing an addiction later.
Similarly, there is emerging evidence that treating childhood trauma might help in managing addiction. Initially, there was concern that patients with addiction and trauma might be too vulnerable to decompensation following intensive trauma exposure therapy. However, views are shifting, and treatments such as exposure therapy and EMDR (Eye Movement Desensitization and Reprocessing) are now being recognized as safe and potentially significant for trauma in addicted patients.
Therefore, there are important developments both in preventing addiction by early treatment of childhood mental disorders like ADHD and in treating addiction by addressing trauma through exposure therapies.
Could we also discuss the biological and psychological mechanisms in our bodies that show why punishment almost never works effectively?
I’m not an expert on that, so I should be cautious. Generally, I think punishment is an outdated approach to parenting, and we try not to rely on it too much anymore. I know from the treatment of young offenders with conduct disorder that teaching better communication skills, rather than using punishment, is what works best. For example, there is strong evidence that for young patients, aged 8 to 10, with conduct disorder, starting treatment with communication therapy can significantly reduce the likelihood of them becoming serious criminals or developing addictions. So, even children with behavioral disorders can be treated not with punishment but with communication and psychological therapies.
Overall, it’s clear from our field of addiction prevention that punishing and thus stigmatizing messages about drug use or users are counterproductive. If we want to effectively prevent drug use or addiction, we should use informative and communicative messages rather than punitive, blaming, or stigmatizing ones.
It’s clear from our field of addiction prevention that punishing and thus stigmatizing messages about drug use or users are counterproductive. If we want to effectively prevent drug use or addiction, we should use informative and communicative messages rather than punitive, blaming, or stigmatizing ones.
The problems with addiction have always been closely tied to politics in one way or another. The opioid epidemic primarily started because of the pharmaceutical industry. Politics is still the main issue – could the Duch MDMA report that came out this year be a turning point, not only for the Netherlands but for other European countries as well?
In that report, we clearly stated that the Netherlands is a place where ecstasy is very prevalent. About 4% of the population in the Netherlands has used ecstasy in the last 12 months, which equates to almost 600,000 people. This percentage is much higher than in most other countries in Europe. However, the way it is used here is relatively safe, and we believe this is due to the harm reduction-focused prevention messages. These messages emphasize not using ecstasy every day, avoiding high dosages, and ensuring that if you attend festivals, there is always enough free water available, chill-out rooms, opportunities to test the quality of your drugs, and first aid services readily accessible.
We believe this approach has resulted in very few ecstasy-related overdose deaths compared to some other countries. Despite the high number of users – around 600,000 – we only see about four or five deaths annually attributed to ecstasy.
We also emphasized in the report that, when it comes to prevention, it’s crucial not to blame or stigmatize the user. Instead, focus on specific subgroups and provide them with information without stigmatizing their use. If users feel stigmatized, they might avoid testing their drugs, ignore other safety messages, or hesitate to seek medical help if problems arise.
Additionally, we noted that compared to most other drugs, ecstasy is relatively safe. We don’t advocate for the use of ecstasy, but we do state that if someone chooses to use it, it is relatively safe in the sense that there is no evidence that ecstasy is addictive. Despite being available on the Dutch market for over 40 years, we don’t see people seeking treatment for ecstasy addiction at the freely available addiction treatment centers. This lack of evidence for addiction is also supported by the fact that ecstasy primarily affects the serotonergic rather than the dopamine or opioid system. After a single use, the serotonin system is depleted, leading to strong and quick tolerance, which reduces the risk of addiction.
We don’t advocate for the use of ecstasy, but we do state that if someone chooses to use it, it is relatively safe in the sense that there is no evidence that ecstasy is addictive.
There is also, as we now understand, no clinically relevant, long–lasting effects on cognitive functioning associated with ecstasy use. There were always concerns about this, but recent research has shown that it is not an issue. While there are short-term effects on the cognitive system, there are no lasting, clinically significant effects. If ecstasy is used under the conditions mentioned earlier – moderate doses, availability of water, and chill-out rooms at venues – we don’t typically see serious adverse problems. So, it is considered a relatively safe drug.
We tried, as a committee, to classify ecstasy in the same category as cannabis. In the Netherlands, cannabis is listed under List II, which includes what we call “soft drugs”, while List I contains “hard drugs”. However, we couldn’t reach an agreement within the committee. As you may know, the Netherlands is one of the main production hubs for ecstasy worldwide. Some committee members felt that reclassifying ecstasy as a soft drug would send the wrong message to the public, and especially to organized crime, implying a form of acceptance. This decision was not based on the pharmacological properties of the drug itself but rather on concerns about the criminal activities associated with its production and trafficking.
What’s perhaps more important now is the committee’s stance on the potential clinical use of ecstasy, specifically referring to MDMA in this context. MDMA is a legally produced pharmaceutical medication, distinct from the illicit drug form generally referred to as ‘ecstasy’. We reviewed the literature and, contrary to the FDA’s stance, concluded that there is strong evidence supporting the effectiveness and safety of MDMA-assisted psychotherapy as a treatment for Post-Traumatic Stress Disorder (PTSD). We also examined its use for other disorders, such as eating disorders and alcohol use disorders. While there are indications that MDMA might be effective for these conditions, there isn’t enough evidence to recommend its standard use beyond PTSD right now.
We reviewed the literature and, contrary to the FDA’s stance, concluded that there is strong evidence supporting the effectiveness and safety of MDMA-assisted psychotherapy as a treatment for Post-Traumatic Stress Disorder (PTSD).
Given the significant need for effective treatments, we advocated for making MDMA-assisted therapy available in the Netherlands as soon as possible. However, we encountered a challenge: we initially believed that the FDA would approve MDMA-assisted therapy for PTSD, which hasn’t happened yet. We also anticipated that the company Lycos Therapeutics would not file a registration dossier with the European Medicines Agency (EMA), meaning MDMA-assisted treatment wouldn’t be available in Europe soon.
To address the medical need for this new therapy, we explored alternative ways to make MDMA-assisted treatment accessible in the Netherlands. One option was off-label use, but this is only permissible for medications that already have an approved treatment indication, such as ketamine, which is approved for anesthesia. Since MDMA doesn’t have an existing treatment indication, off-label use wasn’t a viable strategy.
We also considered compassionate use, which allows for the use of certain medications in life–threatening situations or when the medication is under review for registration. However, since MDMA is not going to be under review soon by the European Medicines Agency, compassionate use was not a viable option either.
Finally, we explored the possibility of expanded access, a strategy that has been employed in Switzerland and Australia. While not impossible, it is highly complex because it requires permission for each individual patient, making it cumbersome and difficult to implement for large groups of PTSD patients.
Ultimately, we decided that the best approach would be to initiate a large naturalistic trial in the Netherlands. This would involve treating patients with MDMA-assisted therapy in a setting that closely mirrors real-world conditions. Before treatment, patients would undergo an initial assessment, and then we would conduct assessments every six months during the treatment to monitor their progress. This approach allows us to gather data and learn from the treatment without the constraints of a complex research design.
There is funding available in the Netherlands for such a naturalistic study, and this proposal will be discussed in parliament in the coming months. We also emphasized that while this is an important issue, we must recognize that it will take some time before we have the necessary capacity. It’s not just about providing the medication; it involves medication plus psychotherapy. Therefore, psychotherapists need to be trained, which means setting up a comprehensive training program. Meanwhile, there is a serious risk that individuals in the gray area might begin offering MDMA-assisted treatment without proper regulation. We issued a warning against this and recommended that advice be provided to psychotherapists and psychiatrists on how to handle these issues. Additionally, we suggested developing a hotline or helpline for individuals who have had negative experiences with MDMA-assisted treatment in the alternative sector.
Finally, we emphasized that MDMA–assisted treatment should not be considered a “golden wonder pill”. While it appears to be a very effective treatment, it will not benefit everyone. Approximately 50–60% of patients might see positive results, but 40–50% may not benefit. Therefore, it’s important not to oversimplify this treatment as a solution for everyone. We advised caution in how this treatment is communicated to both the public and the professional sector.
We emphasized that MDMA–assisted treatment should not be considered a “golden wonder pill”. While it appears to be a very effective treatment, it will not benefit everyone.
And the question about psychotherapists who are specially trained to work with MDMA and other psychedelics is also very important. Do you have them in the Netherlands?
We have a few therapists who have been trained by MAPS, the organization responsible for the studies on MDMA for PTSD. These therapists were part of a study organized by MAPS. However, the number is small-only about eight or ten people were trained in the context of the studies conducted in the Netherlands with MAPS. Recently, some additional therapists have been trained by MAPS. So, while we do have some trained therapists, there aren’t many. Therefore, we have advised the government to task the psychiatric and psychological associations with setting up training programs specifically designed for this kind of treatment.
There is also an ongoing discussion about how specialized these psychotherapists need to be. Perhaps we can talk later about the possible reasons behind the FDA’s rejection of MDMA-assisted treatment.
Yes, that’s my next question. What is your opinion on why, despite all the work done and the scientific research conducted, there was a denial vote?
One of the reasons for the rejection, or at least what it seems to be, is the psychotherapy component. However, the exact reasons aren’t public yet because the rejection letter was only sent to the pharmaceutical company, Lycos Therapeutics. It’s not entirely clear why the FDA rejected it, but one possible reason might be concerns about whether the psychotherapy was too specific or perhaps not specific enough to be replicable.
There are various reasons why this concern might not be justified. First, the psychotherapy used in MDMA-assisted therapy studies was quite strongly protocolized. However, in psychotherapy, even with strong protocols, there will always be some variation. However, what we know from the literature is that any form of psychotherapy is generally better than no psychotherapy, and if you try to prove that one form of psychotherapy is better than another, it’s often difficult to find significant differences. So, the concern about the specificity of the psychotherapy might not be farfetched.
Moreover, if you look at ketamine studies in addiction treatment, they’ve been conducted using different types of psychotherapy – such as motivational enhancement therapy, cognitive behavioral therapy, and mindfulness-based relapse prevention. Despite these variations, they have all shown similar positive results. So, the issue of the type, specificity, and integrity of the psychotherapy might be more of an excuse than a substantial concern.
Another possible reason for the FDA’s rejection might be the concern that MDMA could have rewarding effects, leading to a risk of dependence and addiction. However, I believe this concern is unfounded. MDMA, or ecstasy, has been around for 45 years in many countries, and we have not seen evidence of addiction in patients. This issue of addiction is therefore quite nonsense.
Now, there is an issue that might be important: the issue of blinding in trials with MDMA-assisted therapy. There have been around eight or ten randomized controlled trials, with eight of them being phase two trials and two being phase three trials. All these trials were randomized and placebo-controlled but blinding in studies with psychedelics is inherently problematic. The subjective effects of psychedelics are so strong that blinding is difficult. Critics argue that we can’t be sure whether the effects are due to MDMA or just due to a placebo effect or expectation. This argument seems strange, especially since the FDA was aware of the trial designs and acknowledged that, despite the double–blind randomized controlled trials, blinding was an issue. The FDA had previously recognized the potential of MDMA–assisted treatment as a breakthrough, knowing all these facts. It is inconsistent to later dismiss these trials based on blinding concerns.
Furthermore, there are reports that the FDA is asking Lycos Therapeutics to conduct an additional phase three study. However, conducting another double–blind randomized controlled trial will still face the same blinding issues, as blinding with psychedelics remains problematic. The notion that the observed effects are solely due to placebo is not convincing, because placebo effects and expectancy effects are typically short-lived, lasting a week or two months at most. In contrast, the effects of MDMA-assisted therapy have been shown to last six months or longer.
Moreover, sensitivity analyses have differentiated between patients with previous MDMA experience and those without, showing no difference in outcomes despite potential differences in expectancy. This further suggests that blinding issues should not be a decisive factor against MDMA-assisted treatment.
Now, finally, there are two issues that might have played a role in the FDA rejection. One is the issue of sexual abuse in one case. While it is undoubtedly unfortunate and despicable, sexual abuse can occur in various medical situations where intimacy is involved. It happens in treatments by gynecologists, psychiatrists, and other medical professionals. Although it is a serious concern, it should not be a reason to reject the medication based on a single case.
If the FDA suggested excluding the site where the abuse occurred, it’s important to note that Lycos Therapeutics has indicated that excluding such sites from studies does not change the overall effect.
There is one other issue that plays an important role: the assumed scientific integrity issues in some of the studies. I use the term “assumed” because these issues are frequently mentioned, but I have never seen concrete proof of these so–called scientific integrity problems. Without solid evidence, these remain merely rumors.
So, these are the reasons behind the rejection that I can identify, as well as those discussed in the FDA’s advisory committee meeting. However, I do not find them to be entirely trustworthy or credible. I cannot see how a third Phase III trial would address these concerns. Conducting another Phase III trial would take many years, during which time patients would be denied access to this much needed and very promising treatment.
Conducting another Phase III trial would take many years, during which time patients would be denied access to this much needed and very promising treatment.
Yeah, it’s a really sad paradox because, as the latest research has shown, and as was known even before the “war on drugs”, psychedelics are a very promising treatment for psychiatric disorders. Otherwise, we would be stuck with tools that no longer work or are ineffective. As recognized by the World Health Organization, we are facing a mental health pandemic, yet we see such setbacks.
I wouldn’t go so far as to say that old medications and psychotherapies don’t work. They do work, but their effectiveness is limited. They should still be used, but their impact can be quite restricted. I do agree with you that there has been a sort of crisis in biological psychiatry, with very few new drugs coming to market, especially in areas like psychosis, depression, and anxiety. While there have been some new developments in addiction, the overall pace of innovation has been slow.
In that sense, I agree that there has been a standstill in the biological treatment of mental disorders. Furthermore, combining psychotherapy with psychedelics offers a new perspective on the interaction between psychotherapy and pharmacotherapy, which is quite intriguing. This approach might also change how we use existing medications and how we respond to patients’ experiences with these traditional treatments.
Combining psychotherapy with psychedelics offers a new perspective on the interaction between psychotherapy and pharmacotherapy, which is quite intriguing. This approach might also change how we use existing medications and how we respond to patients’ experiences with these traditional treatments.
Speaking a bit more specifically about the mechanisms of how psychedelics work and why they could be helpful, one idea is that they might “reopen” critical windows in the brain, allowing for new learning and changes in thought patterns. Is this the main reason why they could be effective and used as medicines?
There have been different theories about why psychedelics work and why they seem effective across a broad range of mental disorders. One possibility is that traditional psychiatry has divided symptoms and patterns into narrow disorders, and there is significant overlap among these disorders. This overlap might indicate a flaw in the classification system, which could explain why psychedelics appear to be effective across various mental health conditions.
On the other hand, some people suggest that there may be an underlying mechanism related to psychedelics that explains why they work across various mental disorders. One theory is that psychedelics induce a form of temporary chaos or entropy in the brain, leading to increased connectivity between different brain areas and reduced fixed connections within specific areas. Psychologically, this could mean that established cognitive and emotional pathways are shaken up a little bit, allowing new pathways to develop. This disruption may address the compulsivity in thinking and feeling observed in many mental disorders, which could be an effect of psychedelics.
For example, in obsessive–compulsive disorder, people think and behave in the same repetitive way. It seems as though they follow a fixed path and are unable to break this pattern. In depression, the main issue is ruminating over the same negative thoughts repeatedly, which reflects a similar pattern of repetitive thinking. In both cases, the persistent pathways in thinking and behavior are a core problem.
If you consider addiction, it involves the feeling of craving. When exposed to certain cues or triggers, your brain follows a repetitive pattern that leads from cue exposure to cue-reactivity, craving, and relapse. Similarly, in psychosis and eating disorders, similar repetitive pathways are observed. It’s possible that psychedelics induce a period of “entropy” in the brain, disrupting these fixed pathways and allowing for the development of new ones. However, psychotherapy may be necessary to help establish these new pathways. While psychedelics can help make cognitive and emotional systems more flexible, psychotherapy is crucial for integrating and reinforcing the new patterns. In that sense, psychedelics act as a catalyst for developing new pathways through psychotherapy. I think this is one of the explanations. There are many other theories being tested, but this is one reason why psychedelics are effective and show promise for a range of different conditions.
While psychedelics can help make cognitive and emotional systems more flexible, psychotherapy is crucial for integrating and reinforcing the new patterns. In that sense, psychedelics act as a catalyst for developing new pathways through psychotherapy.
Now, there’s one caveat that I should mention. Once, we had medications called antidepressants that primarily worked against depression, but they also had effects on other conditions. For example, they were found to be somewhat effective against bulimia, obsessive-compulsive disorders, and anxiety disorders. Similarly, antipsychotics, originally developed for psychosis, are now also used for bipolar disorder and as an adjunct treatment in depression. So, our traditional medications were not highly specific either; they often showed effectiveness across multiple disorders. This is also relevant when considering the effectiveness of psychedelics in treating mental disorders.
But what is the connection between psychedelics and neuroplasticity? There are also some trials exploring the possible use of psychedelics in the treatment of Alzheimer’s disease.
It’s a very interesting development, especially considering the challenges of treating dementia and Alzheimer’s disease. Despite extensive research using imaging techniques in various mental disorders – such as ADHD, psychosis, and depression – imaging studies have shown only small and specific differences in brain function, which are difficult to replicate. Functional MRI, PET, and SPECT scans have identified differences on a population level, but these differences are often minimal.
In contrast, Alzheimer’s disease involves dramatic functional and structural brain changes and degeneration. The question is whether these structural changes can be reversed as easily as the relatively small functional abnormalities in other mental disorders. While the potential for psychedelics to influence neuroplasticity is intriguing, it’s important to approach this with cautious optimism. We need to wait for concrete data demonstrating significant differences in cognition and behavior in patients with Alzheimer’s before drawing definitive conclusions.
One interesting point that emerged from my conversation with Rick Strassman a few years ago is that psychedelics could be valuable tools for understanding the placebo response. They may offer new ways to explore and utilize the placebo effect both scientifically and medically.
I fully agree that the placebo effect is itself a very interesting phenomenon. There has been extensive research on the placebo effect, and most studies indicate that it is primarily driven by the brain’s reward systems, activated by expectations and hope, rather than by specific neurotransmitter systems. Given this, it is questionable whether the placebo effect, based on expectation or hope, plays a significant role in psychedelic treatments. This is because classical psychedelics primarily interact with serotonin receptors, such as 5–HT2A, rather than significantly affecting the reward system.
But again, I agree that we should strive to improve study designs to address the challenges of blinding. There have been proposals to use different dosages of psychedelics to examine dose–response relationships. Some have suggested administering psychedelics under full anesthesia to eliminate blinding issues. Additionally, there are proposals to measure objective changes rather than relying solely on subjective outcomes.
For example, in depression studies, instead of asking about mood or similar symptoms, you could recognize cognitive changes using cognitive tests. So, I think it’s interesting to start looking for solutions to the blinding issue, and there are some solutions. However, studying the placebo effect by itself is more of an academic topic than a practical clinical use. Because, as I mentioned, placebo effects are often short-lived. This is also true for alternative or complementary medicine. I’m not saying that people shouldn’t use it; they should do what they prefer. However, in general, what we observe is that when people start using alternative or complementary medicine, their symptoms often return or new symptoms may appear, usually after a relatively short period of time.
Yeah, there are many things we still do not know about psychedelics, but I think one thing is clear: as also research by Professor David Nutt has shown, classic psychedelics are not addictive substances.
That is absolutely correct. Now, you need to make a distinction: classic psychedelics, such as 5–HT2A agonists, are not addictive, neither theoretically nor in practical terms. With the serotonergic medication MDMA, which has a different mechanism of action than the classic serotonergic psychedelics, there is also no significant risk of addiction. However, with ketamine, there is definitely some addiction liability, so we need to be careful. I’m not saying we shouldn’t use it, but we should be more aware of the potential for abuse and addiction and handle the treatment accordingly.
With ketamine, there is definitely some addiction liability, so we need to be careful. I’m not saying we shouldn’t use it, but we should be more aware of the potential for abuse and addiction and handle the treatment accordingly.
And my last question is quite broad. What are the most significant challenges regarding the implementation of psychedelic-assisted therapies in our current healthcare system?
Very good question. I think there are two challenges. One is to prevent people from believing that psychedelics are the solution to everything. They’re not. They are promising, and the effect sizes we see are very encouraging, but they don’t solve all problems for all patients. We should communicate clearly that while psychedelics are promising, they are not a simple solution for everyone. The treatment involves psychedelic-assisted therapy, which means it has to be combined with psychotherapy. This makes the treatment quite expensive and, given the current economic climate, even more challenging. It is also labor-intensive, requiring many trained therapists. I don’t know about your country, but in most European countries, there is limited access to financial resources and even more limited access to personal resources.
So how can we ensure that people who are well-suited for psychedelic-assisted treatment have access to sufficient psychotherapy and psychotherapist services? One potential solution for the future might involve adapting our current practices. For instance, instead of providing all psychotherapy on an individual basis, we could explore group therapy for integration sessions, which would be more cost–effective and less labor-intensive. Additionally, we might consider using online sessions. These are important questions that we need to address as we move forward.
Ultimately, we lack concrete evidence regarding the exact amount and type of psychotherapy needed. Even after completing the initial treatment, aftercare should remain available. While many individuals may not require aftercare, there will be some who do, and we should be prepared to offer this support.
Finally, I think the discussion about the effectiveness of psychedelics in treating mental disorders might also stimulate non-professional circuits that offer retreats and other services. Don’t misunderstand me; I have nothing against people attending psychedelic retreats, especially those without mental disorders or vulnerabilities. However, if individuals with mental disorders are drawn to these organizations, there is a risk that more people might believe in their efficacy without proper evidence. Given our current capacity limitations, there is a concern that individuals might turn to profit-driven and gray-market sectors, potentially leaving these vulnerable patients without the benefit of effective treatments.
I have nothing against people attending psychedelic retreats, especially those without mental disorders or vulnerabilities. However, if individuals with mental disorders are drawn to these organizations, there is a risk that more people might believe in their efficacy without proper evidence.
So, these are some of the things that I worry about, but potentially I’m very positive, and I very much hope that the FDA may change its judgment. At the end, we will have psychedelic assisted treatments. but why should we wait years for them to become available?
Thank you!
