Repeated low doses of LSD

This article was written by Victoria A. Cruz, an undergraduate at Florida International University, and Frank Rivero, an undergraduate at the University of Chicago, based on de Wit, H., Molla, H.M., Bershad, A., Bremmer, M., Lee, R. (2022) "Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study." Addiction Biology, 27(2): e13143.

In recent years, the practice of “microdosing” LSD—taking minute quantities to enhance mood and cognition—has seen a sharp rise in public interest. Typically, individuals take a dose every few days, with the goal of sustaining perceived benefits in mood and cognition. While anecdotal accounts suggest that regularly microdosing can boost mental abilities, alleviate anxiety, and improve mood, controlled research has lagged behind these claims. A study from 2022 conducted in the Human Behavioral Pharmacology Lab at the University of Chicago challenges popular opinion, offering fresh insight into the true effects of repeated low-dose LSD on mood and cognitive function in healthy adults.

The double-blind, placebo-controlled study enrolled 56 participants aged 18 to 35, who were randomly assigned to receive either a placebo, or a microdose of either 13 micrograms or 26 micrograms of LSD. Across four sessions spaced three to four days apart, participants took their assigned dose and completed assessments on mood and cognition. After the final session, a drug-free follow-up allowed researchers to observe any lasting changes.

The study found that the 26-microgram dose of LSD produced mild, stimulant-like effects, such as increased energy and focus, though these effects diminished with repeated doses, likely due to tolerance. Notably, the study did not find evidence that low doses enhanced mood or cognitive performance, raising questions about whether microdosing can deliver the benefits it’s often credited with.

Additionally, the higher dose of LSD led to slight changes in emotional response, reducing feelings of social rejection in a simulated exclusion test and decreasing the tendency to interpret faces as fearful. However, follow-up studies indicated these effects were brief, and did not persist after the session ended.

Interestingly, most participants could not accurately discern whether they had taken LSD or a placebo, suggesting that microdoses may be too low to produce noticeable effects for most people.

So, if controlled studies reveal only modest effects, why do many microdosing proponents report significant benefits to microdosing? The study suggests that the power of expectation and the placebo effect may play a substantial role. Given widespread media coverage and social reinforcement surrounding the topic of microdosing, people may be more likely to attribute any positive changes to the drug itself rather than other factors, such improved mindfulness or lifestyle adjustments.

These findings underscore the need for further research, particularly involving individuals with psychiatric conditions like depression and anxiety, where the effects of low-dose LSD may differ. Higher dosages, extended treatment duration, or combination with psychotherapeutic intervention could revel therapeutic benefits yet to be fully understood.

The Human Behavioral Pharmacology Lab remains dedicated to exploring these avenues as public interest and scientific research into psychedelics grows. While this study highlights limited effects of repeated microdosing in healthy adults, fully understanding the potential of psychedelics will require rigorously controlled studies that can distinguish between placebo effects and genuine pharmacological impacts.

LSD and Depression: is Microdosing the new Antidepressant?

This article was written by Anne-Sophie Geldmeyer, a summer research intern, based on Molla, H, R Lee, I Tare, H de Wit (2023) Greater subjective effects of a low dose of LSD in participants with depressed mood. Neuropsychopharmacology 49(5):774-781

Around 8% of people in the US struggle with depression, and some individuals don’t respond to traditional anti-depressants. Recently, a growing trend called “micro-dosing” has emerged as a potential alternative. This involves taking about one-tenth of a standard hallucinogenic dose of a substance like Lysergic Acid Diethylamide (LSD) every three to four days. While many people report that the drug improves mood and cognitive function, these claims are mostly anecdotal, that is, they have not been tested under blinded controlled conditions. The few studies that have examined LSD micro-dosing in healthy adults have shown no clear evidence of mood-enhancing effects.

However, a recent study conducted at the HBPL might change the conversation. This study is among the first to report that low-dose LSD may differentially affect people with depression. Thirty-nine participants completed two sessions and received either an inactive placebo or a single dose of 26 micrograms LSD, under double blind conditions. Half of the participants scored high on a depression scale at intake. During the sessions, changes in mood were monitored and 48 hours after the sessions, participants completed the depression questionnaire again. Unlike past research, this study found that a low dose of LSD had different effects in depressed individuals compared to healthy volunteers. It enhanced psychedelic effects and decreased depression in moderately depressed people.

In the current study, moderately depressed people reported feeling more spiritual, stimulated, and overall felt more positive psychedelic effects than healthy people after taking a low dose of LSD. This suggests that LSD might have a different effect on people with existing psychiatric conditions and it may explain why previous research has been inconclusive – previous studies only examined the effects of LSD on healthy adults. In addition to a greater psychedelic effect, depressed individuals experienced less anger, an increase in positive mood, and a decrease in depression two days after their LSD session, compared to no significant changes for the non-depressed individuals. These findings raise the possibility that low doses of LSD may be effective as a new psychiatric treatment for depression, especially for people who do not respond to traditional anti-depressants.

So, how does LSD potentially help with depression? It is hypothesized that LSD and depression act on similar neural systems in the brain. Depression decreases activity in certain cortical regions while LSD promotes neuroplasticity in those same regions. Neuroplasticity is the brain's ability to form new neural connections. This may also explain why healthy individuals, with a healthy baseline cortical brain volume, experience less of an effect: the neuroplasticity that LSD induces is not as great because they have more brain volume to begin with.

Although this study is one of the first to conclude an effect of LSD on depressive symptoms, these results support a larger consensus that psychedelics can be a new alternative for mental health treatments. While traditional antidepressants often take months to kick in, LSD induces lasting effects within two days of taking it. Often, a micro-dose is so low (less than 26 micrograms), that the individual doesn’t experience immediate subjective effects such as sensory distortion or changes in mood. This allows micro-dosing LSD to be comparable to traditional dosing of anti-depressants.

While this study is a promising step forward, many questions remain unanswered. For instance, how do psychedelics, such as LSD, impact people with more severe depression? What is the effect of higher or more frequent doses? Could the enhanced psychedelic experience be crucial to reducing depression? And would low-dose LSD in conjunction with therapy be more effective?

It is exciting to see the field of psychedelic research evolve, and we hope to answer these questions soon. The results of this study allow us to envision a future where mental health treatment is more innovative, timely, and accessible, especially for people who don’t respond to traditional therapies.

What does an LSD microdose do to brain function?

This entry was written by Conor Murray, PhD, formerly a post-doctoral fellow in the de Wit laboratory, and currently at UCLA. (twitter : @conormurray)

“Microdosing” is modern cultural phenomenon, involving repeated uses of very low doses of psychedelic drugs like LSD or psilocybin every few days, with a wide range of purported health benefits. Studying this phenomenon is challenging and some studies suggest that the purported health benefits might boil down to being just a “placebo effect”. Here, we ran a placebo-controlled study in the laboratory to determine whether single, low doses of LSD have health-related effects on the brain. Healthy adults visited the laboratory on three occasions, when they received placebo or one of two low doses of LSD (13 and 26 micrograms). (For comparison, the doses people use for ‘trips’ are 100-200 micrograms.). On each of these days, we measured brain responses while subjects performed a task in which they could earn rewards. Previous studies have shown that the brain responses on this task are blunted in patients with depression and other psychiatric disorders. We predicted that the low dose of LSD might produce a pattern of brain response opposite to that seen with depression.In accordance with our hypothesis, we found that the low doses of LSD enhanced brain responses to reward in the task. Surprisingly, this effect was the strongest after lower of the two doses. At this low dose, subjects were not able to detect a drug effect, and yet it changed their reward-related brain responses. One interpretation of the results is that there may be a “sweet spot” in the range of what is called a “microdose” that can improve health-related responses in the brain without disrupting people’s lives with perceptual experiences

View the paper here

“Nothing Without Love Matters.” Can MDMA Change Sociopolitical Values?

This article was written by Katie Fesperman, an Research Assistant at the HBPL, based on AK Bershad…H de Wit (2021) Methylenedioxymethamphetamine (MDMA) change socio-political values? Insights from a research participant. Biological Psychiatry.

Recent experience from UChicago’s Human Behavioral Pharmacology Lab (HBPL) revealed that 3,4-Methylenedioxymethamphetamine (MDMA), a psychoactive substance used recreationally for its stimulating and prosocial effects, has the potential to induce epiphanic life-altering states. Life-changing psychological revelations are typically associated with classic psychedelics such as Lysergic Acid Diethylamide (LSD) or Psilocybin, the psychedelic compound found in “magic mushrooms”. Recently, a participant in the UChicago lab reported epiphanic states after receiving MDMA (1.5 mg/kg) (de Wit & Bershad, 2020), and reported that these states affected his sociopolitical values.  

Before participating in the study, the participant was an anonymous leader in a White supremacist organization. His identity had recently been revealed to the public, which left the individual alienated by friends and family, disparaged by the public and unemployed. Unrelated to these experiences, the individual volunteered as a participant in the present study. He underwent the usual medical and psychiatric screening.  The study was double-blind and placebo-controlled, meaning neither the participant nor the individual running the participant’s session were aware of what drug was administered, or whether it was placebo. During one of his sessions, the participant reported effects that instilled a sense of togetherness and empathy. He exclaimed “love is the most important thing…nothing without love matters”. The experience made him question his political views. Only after the study was the participant informed that he had received MDMA during that session.   

It’s interesting and thought provoking to learn how a single pharmacological intervention can lead to such profound realizations and long-lasting changes in perspectives. One possible explanation for this may be the effects of MDMA on the oxytocin system, a hormone involved in social bonding. MDMA is known to increase levels of oxytocin circulating in the blood, and acting on brain receptors. However, the exact mechanisms by which MDMA produces its unique effects remain unknown.  

Months after this session, researchers followed up with the participant regarding their experience. During these follow-ups, the participant stated that “in that moment [during the MDMA session], love… was the sort of feeling they should strive for to permeate across the world.” In summary, he felt that the drug widened his empathetic capacity and deepened his understanding of the human condition. As the participant continues to recognize the lasting effects of this one experience, we might consider the possibility that drugs have the potential to change priorities, values and beliefs.  

LSD: the new antidepressant?

This article was written by Dr. Hanna Molla, PhD. Post-doctoral Fellow at the Human Behavioral Pharmacology lab.

For thousands of years, humans have used natural psychoactive substances in a variety of ways, including in religious ceremonies and for medicinal purposes. More recently, we’ve begun to develop synthetic psychedelics like lysergic acid diethylamide — better known as LSD. Whether gathered from the woods or produced in labs, these substances can have powerful effects on our minds and our memories, and may have untapped potential as treatments for a variety of psychiatric conditions.

Drugs act on the brain by binding to proteins called receptors. Upon activation, these receptors can elicit numerous biological responses, which can alter brain activity, and ultimately, behavior. For example, LSD has been shown to increase the release of the neurotransmitter serotonin in the brain, which acts on a subclass of receptors called 5HT-2A. These receptors are expressed throughout the brain and are thought to be the main reason that LSD produces changes in perception and other mind-altering subjective effects.

Brain cells in the cortex become more excited after the receptors are activated, making the cells communicate more with each other. Under LSD, on a whole brain level, the connections between brain regions that normally communicate with one another frequently become weaker. Instead, electrical activity increases, inciting more cell chatter across new brain networks.

This disintegration of typical networks creates new connections, and on a cognitive level, big changes in perceived consciousness. These disruptions may create new ways for a person to view and process thoughts and emotions. As a result, researchers are studying this drug class as a potential avenue for treating certain mental health disorders. Finding novel ways to treat such conditions is important, particularly for individuals who may not respond to standard antidepressant medications and traditional forms of therapy.

Among the general population, there is increasing interest in the consumption of "microdoses" of LSD, the idea being that a very small dose of the drug would allow one to tap into the positive drug effects without being fully intoxicated and unable to carry on with daily functions. Microdoses of LSD, approximately a tenth of the typical recreational dose, would presumably elicit a fraction of the effects that a high dose would. Many advocates of the practice claim that microdoses help improve a number of different factors including productivity, creativity and mood.

In the Human Behavioral Pharmacology Lab directed by Harriet de Wit, PhD, my colleagues and I are interested in studying the effects of various psychoactive substances like microdoses of LSD on changes in cognition and overall mood in healthy volunteers. In one recent study from our lab, adult volunteers received four microdoses of LSD every three to four days. We assessed improvements in mood, emotional processing, and certain cognitive aspects, like working memory. We found small effects on mood, including increases in feelings of euphoria, and a reduction in negative emotions during a task that mimics social rejection.

In another study, we used EEG to understand more about the effects of very low doses of LSD on neural activity while the brain was at rest and during performance on certain tasks. We found that low doses of LSD produce similar effects that have been reported at higher doses, including increases in brain activity during resting state. We’re still trying to determine whether this change in brain excitation correlates with the positive subjective effects of the drug. Nonetheless, this research suggests that microdoses of LSD may hold some advantageous elements. These controlled studies help give us more insight into how lower doses of LSD influence brain activity and human behavior, and whether there are clinically relevant factors.

Beyond research focused on understanding the effects of these kinds of drugs, the biopharma industry has become interested in tapping into their potential therapeutic benefits. In recent years, companies within this area of the health industry have begun seeking to harness the pharmacological properties of psychedelics — either alone, or in combination with therapy — to treat mental health conditions such as depression, anxiety and addiction.

These companies are developing new compounds with similar properties to those of classic psychedelics, with the idea of minimizing intrusive effects such as hallucinations, and maximizing the effects such as increases in openness and positive emotions. Other biopharma research is interested in developing new therapeutic approaches, combining drugs with mental health therapy. In this design, psychedelics would be administered by a therapist. Patients would open themselves up to the unique or meaningful emotions that arise for a deeper, more introspective look into their issues, working through them in ways that would ultimately help alleviate symptoms and allow for healing.

Psychedelics represent a new and innovative approach for the treatment of various mental health conditions, and we are just getting to understand more about this phenomenon. The research done by those of us in the Human Behavioral Pharmacology Lab and others around the world will contribute to a better understanding of the effects of psychedelics and, in turn, will support the study and use of psychedelics in the mental health space.

Women and Weed

This article was written by Katie Fesperman, an Research Assistant at the HBPL, based on E Pabon…H de Wit (2022) Acute effects of oral delta-9-tetrahydrocannabinol (THC) on autonomic cardiac activity and their relation to subjective and anxiogenic effects. Psychophysiology.

Cannabis is one of the most commonly used drugs in the United States. However, the cardiovascular and subjective effects of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in Cannabis, are not fully understood.  This is especially true for women. Because females have often been excluded from studies with drugs, there are gaps in our understanding of how drugs affect women. Preclinical research (i.e., research with animals) suggests that females are more sensitive to THC, and in humans, women tend to have more adverse reactions (i.e. paranoia or anxiety) to the drug. One theory of why there are sex differences in responses to drugs is that fluctuating hormone levels across the female menstrual cycle might interact with THC, and affect drug responses in women. 

The present study investigated the effects of THC administered orally in healthy female occasional Cannabis users. In order to test the interaction between hormonal fluctuations and THC, the researchers tested women during one of two phases of the menstrual cycle: the early follicular (EF) or late follicular group (LF), which are characterized by lower and higher levels of estrogen respectively. The researchers hypothesized that responses to THC would be greater in the late follicular (LF) phase compared to the early follicular (EF) phase, due to higher levels of estrogen in the LF. Women participated in an experimental study in which they attended three in-person lab visits where they took a capsule containing an inactive placebo, 7.5 mg, or 15 mg of oral THC. Throughout each session, researchers took a variety of cardiovascular (i.e.heart rate (HR), blood pressure (BP) and self-reported subjective measures (i.e. ratings of their current mood, including anxiety). 

On most measures, women’s responses were similar during the EF and LF phases and estrogen levels did not strongly affect responses to THC. However, their reports of wanting more of the drug and feeling anxious occurred sooner after taking the drug in women tested during the EF phase compared to the LF phase. Why this difference on onset of effects occurred is unclear. Future research is needed to investigate how circulating ovarian hormones interact with the effects of psychoactive drugs. 

Anecdotal evidence suggests that people vary markedly in their responses to Cannabis, and this variability has been confirmed in laboratory studies. However, many questions remain about the sources of individual variation in responses to THC and Cannabis. Why do some people like the drug while others don’t, why do some people feel anxious after use, whereas others feel calmer? The shifting socio-political attitudes about Cannabis use, coupled with legislative changes, makes it important to identify sources of variability in response to the drug to make it safer for use, both medicinally and recreationally. 

How does THC affect your memory?

This article was written by Kaela Allen, an undergraduate at U of Chicago, based on M Doss, D Gallo, H de Wit (2019) D9-tetrahydrocannabinol during encoding impairs perceptual details yet spares context effects on episodic memory. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Impaired memory is a common side effect of cannabis consumption.

A common side effect of cannabis consumption is impaired memory. With the increasing legalization, acceptance, and use of cannabis, it’s important to know exactly how the drug actually affects the memory of users. While the exact effects and mechanisms of cannabis-induced memory impairment is a large question to tackle, researchers are making great strides in this topic. Researchers typically study two phases of memory: the encoding phase, the acquisition of new information, and the retrieval phase, the “remembering” phase of memory. Drugs may affect these stages in different ways.  For example, previous studies in this laboratory showed that when subjects are sober during encoding but consume THC at the time of retrieval the drug increases false memories. On the other hand, when they consume THC before encoding but are sober during retrieval the drug decreases memory overall but does not increase false alarms. In fact, according to the authors, THC taken before encoding may actually reduce some false memories. One of the hypotheses regarding how THC impairs encoding is that it may impair memory of the context within which the object was studied. Typically, reinstating the context in which the object was studied is thought to improve memory.  However, one recent study without drug manipulation showed that context reinstatement can also increase false memories of similar items, a phenomenon known as context illusion.

False memory refers to cases in which people remember events differently from the way they happened or even events that never happened at all. These can be extremely vivid and held with high confidence.

Doss et al sought to reconcile the data showing that the presence of THC during encoding caused a decrease in false memories with the fact that context reinstatement can increase false memories. The authors hypothesized that THC impairs object-context binding during encoding, thereby reducing the impact of context reinstatement at retrieval. Participants were required to memorize object pictures that were superimposed over scenes (e.g. a gray cat superimposed on a beach) after pretreatment with placebo or 15 mg of THC. Two days later, under sober conditions, their memory was tested by having them discriminate between previously studied objects or perceptually similar objects (e.g. a different grey cat). Context reinstatement was manipulated by presenting objects on their original or different scenes. The researchers found that THC at encoding decreased memory of studied items, and that context reinstatement under sober conditions increased memory of studied items as well as false memories of similar lures, as expected. The presence of THC at encoding did not seem to affect the context illusion. However, more detailed analyses showed that THC did magnify the context illusion when objects were semantically congruent with their encoding contexts (e.g. a frog shown with a pond) but abolished the context illusion when object-context pairs were semantically incongruent (e.g. a frog shown in the tundra).

This study provides evidence that THC impairs memory of perceptual details of objects. This is important in the case of eyewitness testimonies, where distorted memories could be damaging.

This study corroborates the existing evidence that THC impairs memory of perceptual details of objects, but it also provides enlightenment regarding THC’s impact on the relationship between the context of encoding and the object being memorized. A specific instance in which this relationship is important is in the case of eyewitness testimonies involving individuals under the influence of cannabis, known as “highwitness testimonies”. While fewer details of the witnessed event may be remembered, the use of context reinstatement techniques to jog the memories of witnesses could distort these memories, at least in the cases where the objects and contexts are considered to be semantically congruent. As always, there is still much work to be done. 

Can oxytocin dampen stress-induced cigarette cravings?

This summary, written by Autumn Mitchell, is based on an article by Van Hedger, Lee, Kushner and de Wit (2019): Effects of intranasal oxytocin on stress-induced cigarette craving in daily smokers. Nicotine and Tobacco Research, 21:799-804.

This research study explored the effects of intranasal oxytocin on cigarette cravings in daily smokers. Previous studies suggested that oxytocin may reduce stress-induced cigarette cravings. Because there is a need for new approaches to assist individuals who are trying to quit smoking, the present research sought to further elucidate this relationship. 

Oxytocin is a hormone nicknamed the love hormone because of its’ role in bonding. In a 2003 study, both humans and dog oxytocin levels in the blood rose after five to 24 minutes of a petting session.

In this study, daily smokers came into the lab for two sessions after abstaining from cigarettes for 12 hours.  On each session, they received a substance, either oxytocin or placebo, both before and after performing a task. In one session, the task was a low-stress conversation with a research assistant. In the other session, the task was a high-stress public speaking exercise (the Trier Social Stress Test, or TSST). Participants were randomly assigned to one of three experimental conditions:  Placebo-Placebo (PP), Oxytocin-Placebo (OP), and Placebo-Oxytocin, PO. Participants in the PP group received a placebo before and after the task, participants in the OP group received oxytocin before the task and placebo after, and participants in the PO group received a placebo before the task and oxytocin after. They received these drugs on both the stress and the no-stress sessions. The purpose of the OP group was to see if oxytocin dampens the initial response to stressor and the purpose of the PO group was to see if oxytocin dampens the response once it has been induced by the stress-task. Throughout all the sessions, participants rated their cigarette cravings and mood. Additionally, cardiovascular measures and saliva samples for cortisol analysis were taken from participants periodically throughout the sessions. 

Cortisol is the result of the body’s stress response system. In our study, we measured subject’s cortisol to gather information on their stress levels.

As predicted, the stressful-task increased salivary cortisol levels as well as their cigarette cravings. However, the intranasal oxytocin had no effects on anxiety, craving, and cardiovascular function when compared with the placebo, whether it was administered before the stress task or immediately after.  This finding is not consistent with previous literature which found a reduction in stress-induced cigarette cravings when participants ingested oxytocin. One potential source for this discrepancy may be the emotional health of the participants in the study; previous studies reported higher effects of oxytocin in individuals with disordered emotion regulation. In contrast, the present study excluded any participants with these disorders. 

This null report emphasizes the need to expound the exact conditions under which oxytocin affects cigarette cravings and stress levels. 

What if you could predict, and possibly prevent, impulsive and addictive behaviors such as drug and alcohol addiction, binge eating/obesity, and problem gambling?

This summary, written by Kaela Allen, is based on a paper published from our lab (available online): Weafer, J, NA Crane, SM Gorka, KL Phan, H de Wit (2019). Neural correlates of inhibition and reward are negatively associated. NeuroImage, 196:188-194. PMID: 30974242

Based on the results of Weafer et al (2019), a negative correlational relationship between inhibition and reward suggests that the answer may be yes. Compared to healthy controls, individuals with addiction and impulse control disorders exhibit both lower activation of their inhibitory circuitry and hyperactivation of their reward circuitry to disorder-specific stimuli. These two processes, response inhibition and reward sensitivity, are often thought of as independently influencing the propensity for impulsive and addictive behaviors.  However, it is also possible that inhibition and reward reactivity are related to each other, and possibly exerting reciprocal influences on each other. What is unknown is if the imbalance between inhibition and reward circuitry is present before the onset of a disorder, acting in a causal role, or if it develops as a result of a disorder. If certain people have both poor inhibition and greater reward reactivity, they may be at high risk for future problematic behaviors. Moreover, these behaviors might be a target for preventing problem behaviors.  

Binge drinkers are at a higher risk for developing substance abuse disorders. In our study, binge drinkers had a more pronounced negative correlation between brain activation during inhibition and reward, which supports the idea that inhibition and reward reactivity are related at the neural level and could be risk factors for drug use.

One way to determine if inhibition and reward reactivity are related to each other even before drug use begins is to study them in healthy volunteers who have no drug problems.  This study looked at the degree to which brain function during inhibition tasks relates to brain function during reward tasks in healthy young adults with no history of addictive or impulse control disorders. Participants also reported their habitual alcohol consumption so that the results could also be examined in relation to binge drinking, as binge drinkers are at higher risk for developing substance use disorders. On the day of the fMRI scanning session, subjects abstained from drugs and alcohol for 24 hours to ensure that they were drug-free.  In the scanner they completed a task involving inhibition (the stop signal task), and a task involving monetary rewards (the doors task). The researchers found a negative correlation between brain activation during inhibition and reward. In other words, individuals with less prefrontal activity during response inhibition had greater activity of their reward circuitry during monetary reward. Interestingly, this correlation was more pronounced in binge drinkers than non-binge-drinkers. These findings support the idea that inhibition and reward reactivity are related at the neural level, and that they may be risk factors for drug use.

Our study found that an imbalance between inhibition and reward circuitry may be a risk factor or cause for problematic behaviors.

These findings provide further evidence that the imbalance between inhibition and reward circuitry may not be a consequence of a disorder but may instead be a cause and risk factor for problematic behaviors. While the results are promising, this is only a first step. This study was done in healthy individuals with no addictive or impulse control behaviors and the findings are correlational. The best way to study this issue is in a longitudinal study, assessing the imbalance between inhibition and reward as predictors of onset and escalation of disorders later in life. A study of this kind, the Adolescent Brain Cognitive Development (ABCD) Study, is now underway with adolescents to study predictors of problem behaviors. Additional research is needed to determine the mechanism behind the negative correlation. 

How does methamphetamine affect neural response to visual stimuli?

This summary, written by Ilaria Tare, is based on a paper published from our lab and available on our website: Van Hedger, Kathryne, et al. “Effects of Methamphetamine on Neural Responses to Visual Stimuli.” Psychopharmacology, 236:1741–1748, 2019.

When we say methamphetamine, you may think of something like this—commonly known as crystal meth. However, methamphetamine itself is a man-made stimulant similar to amphetamine (a more common drug name you know) that is approved for treatment for ADHD (Desoxyn) and some treatment for obesity. We administer the drug (acquired from professional pharmacology labs after receiving IRB approval) orally in a pill form and under supervised conditions.

In the past, studies have shown links between stimulants and behavioral and reward-seeking effects, some of which appear to be related to the abuse potential of stimulants. These effects include enhanced cognitive performance, reduced inattention and impulsive behavior and improved memory. Previous brain scans have even shown a single dose, 20 mg, of methamphetamine (MA.) increases neural response during cognitive and attentional processing. However, very little is known about the effects of stimulants, like MA, on sensory processes, or information received from our 5 senses. Do stimulants affect the neurons that process sensory stimuli, and do these effects depends on the images shown? The Human Behavioral Pharmacology lab recently conducted a study in which a group of 18 healthy, adult participants received  a single dose of MA, and then viewed a series of visual images. 

Sensory processing is the process that organizes sensation from one’s own body and the environment, thus making it possible to use the body effectively within the environment.

Participants came in for two sessions, one where the drug was administered and one when a placebo was administered. They were shown a series of images of nature scenes that varied in complexity while being monitored by an fMRI machine. The complexity of the images was categorized by the degree of “non-straight edges” (NSE), which reflect the proportion of curves present in an image. Images with a high NSE are more complex than images with a low NSE. For the sake of this study, examples of high NSE images were more complex and included plants, like a mountain with flowers. Low NSE images were less complex and consisted of simpler scenes, like a desert with sand dunes. Drug effects on sensory perception were evaluated by the brain activation of participant fMRI scans as well as self-reported drug effects (e.g., “how high are you.”) Originally, researchers hypothesized that high NSE images would cause more activation in areas of the brain dealing with sensory processing, like the visual cortex, than low NSE images, and these effects would increase with the administration of MA. However, researchers found that, overall, high NSE images showed more activation in the primary visual cortex than low NSE images, but that stimulus-induced activation in the brain did not differ when administered MA versus placebo. They also found a significant interaction between the drug and the more complex images in areas of the brain that deal with visual processing-- specifically the left fusiform, the right cingulate/precuneus, and the posterior right middle temporal gyrus. Whereas activation in these areas was greater when shown high NSE images during the placebo sessions, the drug had a greater effect on activation in these areas when subjects viewed low NSE images.

Under placebo conditions, activation in the areas of the brain that deal with visual processing was greater when shown high NSE images. However, once drug was administered, the drug had a greater effect on activation in these areas when subjects viewed low NSE images.

So what does this all mean? Like previously predicted, neural processing of sensory stimuli was greater with the more complex images than with the less complex images, as one might intuitively guess. However, when MA was introduced, not only did sensory processing for the more complex images increase, which suggests a stronger conditioned response in the primary visual cortex, it also increased for the less complex images. This tells us that MA indeed does enhance sensory processing in the primary visual cortex, but less complex images may be more susceptible to drug influence. The authors conclude that  more research is needed to better understand the exact effects MA has in sensory processing and its neural mechanisms. 

Could a history of hypomanic experiences potentially affect the chances of developing a substance use disorder?

This summary, written by Becca McWilliams, is based on a paper published from our lab and available on our website: “Subjective responses to amphetamine in young adults with previous mood elevation experiences”.

We studied young adults with a history of hypomanic episodes or mood elevations— a history of having repeated, exaggerated highs and lows in mood.

This study aimed to further understand the relationship between hypomanic experiences—or periods of mood elevation—and responses to drugs as a predictor for the likelihood of developing substance use disorders in young people. Previous research suggested that young adults who previously had hypomanic experiences reported less subjective effects when given a low dose of alcohol, and this may foreshadow future risk of addiction. The previous finding of a lower subjective response may be seen in other drugs beyond alcohol, such as amphetamine, and this was the topic of this research.

Dextroamphetamine, known as d-amphetamine, is commonly used to treat ADHD and narcolepsy. It is also a commonly abused substance.

For this study, d-amphetamine was administered to healthy, young 18 and 19-year old participants recruited from the University of Chicago and its surrounding area. The participants had experienced various amounts of hypomanic experiences which had been measured using the Mood Disorders Questionnaire (MDQ) used to infer the possibility of an individual being diagnosed with BP.

Medical and psychiatric screening including an electrocardiogram, drug use and medical history, a physical exam, and a modified structural clinical interview (SCID) were also conducted by a clinical psychologist. The participants all participated in three 4-hour laboratory sessions where they received a placebo, 10mg, or 20mg d-amphetamine under double blind conditions; that is, both the participant and the researcher were blind as to which was administered at each session.

The results were similar as they previously were for alcohol: participants with higher MDQ scores experienced less stimulation after 10mg (the lower dose), but not 20mg (the higher dose), d-amphetamine, than individuals who had scored lower on the MDQ. This suggests that a previous history of hypomanic states is related to a dampened response to lower doses of psychostimulant drugs, as previously seen in alcohol. It is possible that the lower subjective effect on these participants contributes to a greater risk of subsequent drug use and/or misuse.

PODCAST: Effects of MDMA on attention to positive social cues and pleasantness of affective touch

The recreational drug MDMA, also known as Ecstasy or Molly, is particularly popular in social settings and raves, in large part because of how socially connected it makes the users feel. It's being studied for use in psychotherapy — there's a phase III clinical trial for the use of MDMA to treat PTSD. What's clear is that the drug affects how users experience social interactions. But there are questions: Does the drug make positive social interactions feel better, or reduce the negative feelings associated with negative social interactions?

Listen to Anya Bershad, MD, PhD discussing our recent research on the Neuropsychopharmacology BRAINPOD.

Could microdosing LSD make you happier?

This summary, written by Luke Johnson, is based on a paper published from our lab and available on our website: Bershad, AK, S Schepers, M Bremmer, R Lee, H de Wit (2019) Acute subjective and behavioral effects of microdoses of LSD in healthy human volunteers. Biological Psychiatry.

Over the past few years the popularity and public familiarity with the concept of “microdosing” has rapidly increased. Microdosing consists of taking a low, sub-perceptual dose of a psychedelic drug, most often psilocybin or lysergic acid diethylamide (commonly known as mushrooms and LSD, respectively), typically twice a week. What used to be a fringe practice in the tech offices of Silicon Valley has become a popular topic of interest and practice in the general population. People who microdose claim it has numerous beneficial effects on their mental health--particularly in regard to their mood, creativity, and cognitive capabilities. Yet, until now, there has been no placebo-controlled, double-blind studies to empirically test whether or not microdosing, specifically with LSD, actually has these positive effects that users report. The Human Behavioral Pharmacology Lab enrolled 20 healthy young adults in an experimental study to do just that. Participants attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in a randomized order at ≥1-week intervals. 

We found that LSD produce mild, dose-related subjective effects across the three doses. On the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC), participants reported increased feelings of unity and blissfulness on the 13 μg and 26 μg dose relative to placebo, without the sensory disturbances typical of higher doses (aka hallucinations or “trips”). On the Profile of Mood States Questionnaire (POMS), they reported greater feeling of vigor, and a slight increase in anxiety after the 26 μg dose relative to placebo. There were no effects on tasks measuring cognitive and motor functioning, suggesting that these doses could be appropriate for use without impairing daily functioning. Unexpectedly, at the 13 and 26 μg doses, LSD slightly decreased positivity ratings of images with positive emotional content. LSD significantly increased systolic blood pressure from 105.35 mmHg on the placebo session to a peak of 111.5 mmHg at 13 μg and 115.3 mmHg at 26 μg. The 6.5 μg dose did not produce any significant effects as compared to placebo. The study provides a basis for future testing of low repeated doses in individuals with mild depression--a big step!

Read the whole article here. And another short article on the subject here.

Phone app that tells you how high you are?

This summary is based on a paper published from our lab and available on our website through the hyperlink on the “Published Research” page (or the link below): Pabon, E., & de Wit, H. (2019). Developing a phone-based measure of impairment after acute oral ∆9-tetrahydrocannabinol. Journal of Psychopharmacology, 33(9), 1160–1169. https://doi.org/10.1177/0269881119862533

With legalization of recreational cannabis use spreading across the nation, one question remains on many minds--how can we measure cannabis-induced impairment?

Biochemical measures, like Breath Alcohol Content (BAC), do not exist for detecting cannabis use. Tools currently on the market, such as the standardized field sobriety test or cannabis/THC breathalyzers, are ineffective as roadside measurements of driving under the influence. We wish it was that easy!

This question does not have a simple answer. Prior research indicates variables such as gender, age, body mass index (BMI), age of onset of cannabis use, and frequency of use all factor into how intoxicated someone may become after using cannabis. People who use cannabis more often are less likely to feel as strong effects as an occasional user. Unfortunately, accurate and effective biochemical measures (like Breath Alcohol Content (BAC) for alcohol) do not exist for detecting cannabis use.

Tools currently on the market, such as the standardized field sobriety test or cannabis/THC breathalyzers, are ineffective as roadside measurements of driving under the influence. Elisa Pabon, a fourth-year doctoral candidate studying behavioral neuroscience in our lab, decided to take a different approach: a behavioral measurement of intoxication symptoms using a phone-based application. She took the first step in validating this novel measure by conducting two double-blind, placebo controlled clinical studies (the first of their kind).

Why not let people just smoke weed? Scientists need to maintain the same conditions across all participants in studies. Using smoked cannabis requires careful consideration of strain and standardizing how much is smoked. This would have led to far too many inaccuracies, plus our results would be restrained to that specific strain!

In the first study, participants identifying as occasional to more frequent cannabis users ingested capsules containing delta-9-tetrahydrocannabinol (THC) (0, 7.5, 15 mg doses; which produce plasma levels similar to those attained with recreational cannabis use) and completed the phone-based app measure. Neither they nor the experimenter running the study knew what drug was administered on each session, to reduce expectancies.  Three sessions were conducted, one for each dose. Drug-induced impairments in cognitive performance, reaction time, and working memory were detected on standard computer-based tasks, and fine motor coordination impairment was detected on the phone-based app at the 15 mg dose of THC. These results confirmed that at least fine motor impairment due to THC intoxication could be detected via our brief phone-based app under controlled conditions!

A follow-up study was done, adapted with new knowledge from Study 1 results. The phone-based app measure was lengthened and its difficulty increased, and two new tasks were added to measure time perception and time estimation (time estimation and production are impaired under the influence of smoked cannabis and oral THC and is likely to affect driving performance. Unfortunately, the new phone-based app did not detect any consistent THC intoxication impairment. The sensitivity of the phone-based app was too low to detect impairment, most likely due to the briefness of the measure. It would require additional research to develop a sensitive tool that could accurately and effectively detect cannabis impairment, but also be brief and convenient enough to use roadside.

Furthermore, these two studies were conducted under highly controlled conditions, and each person’s intoxicated performance was compared to their own respective placebo control performance. If an app like this were to be used as a roadside sobriety test,  law enforcement officers would have to compare each person’s personal baseline/sober performance to their possibly intoxicated performance to accurately determine whether driving ability was impaired. Ultimately, with additional research and field work a cannabis or THC roadside field sobriety test may one day be established and validated. For now, we have a long way to go.