# Computational chemoproteomics to understand the role of selected psychoactives in treating mental health indications

## Abstract

We have developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform to infer homology of drug behaviour at a proteomic level by constructing and analysing structural compound-proteome interaction signatures of 3,733 compounds with 48,278 proteins in a shotgun manner. We applied the CANDO platform to predict putative therapeutic properties of 428 psychoactive compounds that belong to the phenylethylamine, tryptamine, and cannabinoid chemical classes for treating mental health indications. Our findings indicate that these 428 psychoactives are among the top-ranked predictions for a significant fraction of mental health indications, demonstrating a significant preference for treating such indications over non-mental health indications, relative to randomized controls. Also, we analysed the use of specific tryptamines for the treatment of sleeping disorders, bupropion for substance abuse disorders, and cannabinoids for epilepsy. Our innovative use of the CANDO platform may guide the identification and development of novel therapies for mental health indications and provide an understanding of their causal basis on a detailed mechanistic level. These predictions can be used to provide new leads for preclinical drug development for mental health and other neurological disorders.

## Introduction

### Human use of psychoactive substances

We define psychoactives as compounds that cross the blood-brain barrier, target proteins expressed in the brain as their primary modes of action, and thereby perturb human mental states. Although proteins expressed in the brain are paramount for the prediction of compounds as potential therapies for mental health disorders, synergistic effects may occur due to interactions in the periphery. For example, it has been shown that the gut microbiome plays an important role in the central nervous system50 and multiple links between the peripheral mechanisms and depression have been found previously51,52. We have also benchmarked CANDO to show that best drug repurposing accuracies are obtained when all protein structures are used for interaction signature comparisons to determine compound similarity, suggesting the role of multiple networks working together in biology to achieve a certain phenotype/function, instead of specific proteins as used traditionally for drug discovery15,25. This approach makes CANDO different than other methods that are focused towards single target inhibitor discovery vs drug discovery. Therefore, we believe that the study of proteome-wide interaction signature for repurposing psychoactive compounds is suitable in the context of mental health indications.

Since the time of the earliest records, humans have been ingesting psychoactive substances for religious and spiritual purposes (for example, dimethyltryptamine in Ayahuasca, mescaline in Peyote), for medicinal purposes (opium), and for recreation (caffeine, nicotine, alcohol)53. The vast majority of pyschoactives are considered taboo for a variety of reasons and, with few exceptions, are not investigated for potential medicinal properties. In this study, we focus on the phenylethylamine and tryptamine classes of psychoactives described by Alexander Shulgin54,55 as well as additional cannabinoids.

Due to recent changes in legislation, a few of these compounds are available as approved drugs in some jurisdictions (for example amphetamine for diet control and attention deficit hyperactive disorder, and tetrahydrocannabinol for anxiety). The action of these compounds is thought to affect human physiology by their structural similarity/mimicry to neurotransmitters (for example, psilocybin and lysergic acid diethylamide both mimic the compound serotonin). There is an increasing amount of evidence for cannabinoids having the ability to treat epilepsy and epilepsy-related indications56,57, but its legal status is still diffuse as cannabinoids remain classified as Schedule I by the United States Federal Government (a classification possessing no medicinal use). Similarly, psilocybin and ketamine have been shown to treat depression via a mechanism not targeted by current antidepressants58,59.

These examples are the tip of a proverbial iceberg, and recent reinvestigations into the clinical relevance of illicit psychoactive compounds suggest further investigation into the potential of these compounds in treating mental health indications60. This clear disconnect between current research and current legislation warrants a more comprehensive investigation for the use of these psychoactive compounds for medicinal purposes but in vitro and in vivo verification is currently difficult given their scheduling status. The CANDO shotgun drug discovery and repurposing platform is therefore uniquely suited to conduct such an investigation to make a case for experimental verification.

While other classifications of psychoactives could be utilized (for example, all compounds known to cross the blood-brain barrier), our goal in this study was to see if any of the selected psychoactive compounds, primarily known without any therapeutic utility, are predicted to treat mental health indications. Our work also demonstrates the more general utility of the CANDO platform in assessing the effect of drug classes on this specific class of indications.

### Analysing the role of psychoactives in mental health indications using CANDO

Most of our selected psychoactive compounds are illegal to synthesize and thus difficult to study in vitro (much less in vivo). Cannabinoids are in the process of being legalized for medicinal uses in some jurisdictions, and this serves as a justification for studying these drugs further. The cause of many mental health indications is not characterized by one protein, but by several proteins in several different categories61,62,63,64,65. Thus, the traditional high throughput screening methodology of testing one compound against one protein is not a suitable approach for mental health drug discovery. The CANDO platform allows evaluation of all selected psychoactives across a large library of protein structures, providing a logical and reasonable method to develop leads for medications that may be suitable for treating mental health indications. Our goal here is to study, analyse, and characterize these psychoactive compounds using the CANDO platform so that the potential medicinal properties of these compounds can be assessed and evaluated in further bench and clinical studies. The outcomes for this study are not necessarily to predict mental health therapies but rather to generate hypotheses if the predicted psychoactives serve as the most promising leads for different mental health indications based on similar chemoproteomics perspective.

## Results

We describe our results based on two approaches of examining the relationships between the selected psychoactives and mental health indications using the top-ranked predictions by the CANDO platform. An example of these predictions is given in Table 1, where we are careful to list potential issues with the predicted psychoactive. At the outset, we examined the distributions of percentages of psychoactive compounds (relative to total compounds) in the top-ranked predictions for mental health indications. Conversely, we can compare the distributions of percentages of mental health indications selected by the psychoactive compounds in the top-ranked predictions. We further analyse the latter distributions broken down by psychoactive classes and the distributions of mental health indications. We conclude with three case studies illustrating the application and utility of the CANDO platform in discovering psychoactive therapeutics to treat mental health indications. We again caution that applying these predictions for the development of new therapeutics must be done judiciously.

### Putative psychoactives for mental health indications

The results showing the distributions of percentages of psychoactives for mental health indications are given in Fig. 2, and the values used to create the figure are provided in Table S7. This figure shows that the difference in the random and non-random distributions. Since these distributions are statistically different, we conclude the selected psychoactive compounds are better at treating mental health indications on average than non-psychoactive compounds selected at random. As the number of compounds considered increases, the normal and randomized distributions become more alike. This result is expected as there are a larger number of non-psychoactive compounds than the selected psychoactive ones and, therefore, the addition of a new compound is more likely to be non- psychoactive than psychoactive. Therefore, as the number of compounds in the result list increases the percentage of psychoactives predicted for any indication will decrease (Fig. 2a–d).

### Selection of mental health indications by selected psychoactives

The distributions for the selection of mental health indications by selected psychoactives relative to all indications are shown in Fig. 3 (raw values provided in Table S8). The greater the percentage of mental health indications, the more selective the psychoactive. Furthermore, the indications selected by psychoactives using the CANDO platform yield a high percentage of mental health indications relative to random controls, illustrating that these psychoactives are more likely than non-psychoactives to be effective at treating mental health indications.

### Comparison of randomized compound and indication distributions

The two randomized distributions in Fig. 3 (shown in green and blue) are distinct. The distribution representing randomized compounds is less uniform and has a larger average percentage (p-value less than 2 × 10−16 from a one-tailed student t-test for all four plots) than the randomized indication distribution. These data show that a single drug is more likely to treat multiple indications than a single indication is to be treated by multiple drugs. This has been shown previously by the ability to repurpose drugs66,67,68 and is an important feature of the CANDO platform. The ability to repurpose previously approved compounds is increasingly important69. This result highlights the utility of the CANDO platform for drug repurposing.

### Comparison of different psychoactive classes

Figures 4 and 5, Tables S8 and S9 differentiate the psychoactives by compound class: amphetamine, cannabinoids, cathinones, phenethylamines, and tryptamines. These figures and tables illustrate that the classification of a compound has an impact on which indications it is predicted to treat. Therefore, we will continue the discussion based on psychoactive compound-classes. The details to classify psychoactive compounds used in this work is given in the Supporting Information section entitled: “Classification of psychoactive compounds via substructure searching”.

### Relationships between mental health indications

Our predictions for indication-indication associations are shown in Fig. 6. Interestingly, some indication relationships have been verified clinically. These include: Epilepsy with Seizure, Cocaine-related disorders with depression70, Seizures with Substance Withdrawal Syndrome71, Depression with Anxiety,72 and possibly relating binge-eating and personality disorder73. The ability of our repurposing platform to reproduce known indication relationships suggests that our chemoproteomic signatures can capture key biological interactions. In addition, the number of overlapping psychoactive compound predictions strongly relate multiple mental health indications (width of the chords in Fig. 6). These psychoactives interact with multiple proteins (similar chemo-proteome signatures) suggesting common biochemical pathways. We are confident that our method may be useful to discover new disease pathways relating these indications. Identifying and validating these new pathways are beyond the scope of this work.

## Discussion

The Top10, Top25, and Top40 predictions in Fig. 2 for three mental health indications, Seasonal Affective Disorder, Circadian Rhythm Sleep Disorders, and Jet Lag Syndrome, consist only of psychoactives belonging to the tryptamine class (indication rank of 100%). The only compound known to treat all these indications is melatonin (also a tryptamine)74,75,76, indicating that its proteomic interaction signature is most similar to the interaction signatures for these predicted psychoactives. This result demonstrates that the proteomic shotgun drug repurposing approach adopted by the CANDO platform makes sensible predictions of related compounds based on their similarly of interaction signature with all proteins, compared to traditional single target approaches. As a result, we present class specific breakdowns of Fig. 2 in the Supporting information (Fig. S1). Studies by an Israeli pharmaceutical company give experimental evidence demonstrating that some of these tryptamine psychoactives are indeed likely to treat the aforementioned three indications77. These studies provide corroborative evidence for the efficacy of the CANDO platform and highlight its potential of finding new drugs for treating any indication that has at least one approved drug.

The remainder of this discussion will be used to highlight case studies which are verified in the literature. For a complete list of psychoactive predictions, please see the tables in the supporting information.

The indication with the largest number of high ranking psychoactives in the top-ranked predictions is cocaine-related disorders belonging to the cathinone class of stimulants, a summary of which is given in Table 2. The similarity between the effects of cathinone and cocaine on behaviour has been previously established as part of a similar pathway78. We are aware that some of these predictions are unlikely to have any potential for the development of new therapeutics for cocaine-related disorders due to their associated toxicity79,80. A cathinone of interest is the anti-depressant bupropion, which is well known for promoting smoking cessation and has also been proposed for the treatment of methamphetamine and cocaine substance abuse disorders81,82. These findings and related uses further showcase the ability of CANDO platform to accurately associate compounds/drugs and indications. While this example is successful in showcasing CANDO’s ability to find the relationship between compounds and mental health disorders, one needs to be cautious as these predictions may mimic cocaine and lead to adverse reactions depending on the dose. For example, Bupropion is perceived as a stimulant to those with a history of cocaine use83,84. Further, the effects of dextromethorphan may be due to its stimulant properties85. However, in some cases we can obtain therapeutic benefit from potentially problematic compounds, e.g. methadone is an approved treatment for opioid abuse, but is known to have several opioid-related effects when given in high enough dosages86.

The highest-ranking phenethylamine predicted to treat cocaine-related disorders is the antitussive drug, dextromethorphan. This compound, generally available over the counter, is known for its hallucinogenic side effects at high doses, which is reflected both in the predictions by CANDO and is reinforced in the literature87,88,89,90,91. The use of the CANDO platform for making predictions to treat specific mental health indications is strengthened by the accurate identification of bupropion and dextromethorphan (both selected psychoactives) in treating cocaine-related disorders.

The two psychoactive cannabinoids, tetrahydrocannabinol and cannabinol are predicted to treat Epilepsy and Absence Epilepsy by the CANDO platform, and cannabinol is also predicted to treat Status Epilepticus. While the cannabinoids are not the highest ranked compounds relative to other psychoactives for these indications, our findings are validated by recently published studies for the use of cannabinoids to treat epilepsy-related indications56,57. The non-psychoactive cannabinoid (cannabidiol) is not predicted to treat any epilepsy-related indications, leading to an intriguing hypothesis concerning the likelihood of a cannabinoid treating epilepsy corresponding to its psychoactivity. However, given the limited data available, further study is warranted to verify this hypothesis. Our work illustrates the recovery of known corroborative associations between cannabinoids and epilepsy but also demonstrates how predictions made by the CANDO platform can be used to develop hypotheses on the biology of diseases for experimental investigation.

## Methods

An overview of the CANDO platform is described in Supporting Information. Here, we describe the approach used to analyse the data generated by this platform to characterize the role of the selected psychoactives in mental health indications.

### Selection of specific phenethylamines, tryptamines, and cannabinoids

We collected a total of 428 compounds (structures in Tables S1S6) to be investigated using CANDO and categorized them into 291 phenethylamines and 109 tryptamines described by Alexander Shulgin54,55, and 6 cannabinoids (cannabinol, cannabidiol, and tetrahydrocannabinol) using a subgraph based search methodology based on the structure of the parent molecule (see Supporting Information for full description of this method). An additional 22 compounds are not strictly classified as phenethylamines but have structural similarity to the phenethylamine class are included as unclassified. We further subdivided the 291 phenethylamine compounds into 149 amphetamines and 20 cathinones, the remaining 122 phenethylamines are simply referred to as phenethylamines. The CANDO v1 compound library includes these 428 psychoactives and their proteomic interactions signatures to repurpose psychoactives for indications/diseases9. Most of these psychoactives are classified as Schedule I substances by the United States Drug Enforcement Agency, indicating they have no known medicinal use, no accepted standards for safety, or have a high potential for abuse. Thus, when such a substance is discussed, the potential pitfalls are presented along with that substance. We selected this set of compounds as almost all of them are known to affect mental physiology upon ingestion54,55,92. A notable exception in the compounds evaluated is cannabidiol which is not strictly psychoactive92 but is structurally similar to other cannabinoids and therefore warrants an investigation into its potential therapeutic value.

The CANDO v1 compound-proteome interaction signature (see Supporting Methods) includes all associations of treatment and side effects caused for each compound via the proteomic signature as this is composed of all target, anti-target, and off-targets proteins for each indication/disease. The compound proteomic interaction signature similarity yields therapeutic predictions by considering similarity to known drug signatures for each disease. It should be noted that this methodology can also match a psychoactive to a compound known to worsen a given indication in addition to predicting a compound known to ameliorate the same indication. Therefore, the set of compounds that were used as therapy for a given indication did not include any of the aforementioned psychoactive compounds given that the nature of these compounds as treatments is still controversial. As a result, the ability of the platform to predict a psychoactive from another psychoactive compound-proteome signature is not investigated in this work. Most importantly, all predictions are made based on similarity to an approved non-psychoactive drug for a mental health indication, without any knowledge of therapeutic target associations for making predictions for psychoactive compounds. Therefore, no association between an indication and a protein target is used to weight the similarity between two compounds. For example, the interaction score of a psychoactive and the dopamine receptor is not given a special weight for Schizophrenia.

### Selection of mental health indications

The Medical Subject Headings (MeSH) vocabulary is used to specify the diseases, disorders, and conditions that are classified as mental health indications. The U.S. National Laboratory of Medicine division of the National Institutes of Health (www.nlm.nih.gov) includes the latest version of the MeSH database. It should be noted that this database is compiled at the clinical level and does not consider the underlying biology leading to a specific indication. Therefore, some spurious and non-traditional indications may be included as mental health indications. Since a biological mechanism study is beyond the scope of this paper, we used all the indications suggested by MeSH.

The MeSH database is divided into tree structures with a specific tree (F03) denoted for Mental Disorders. The specific branches of the Mental Disorder Tree used in this study are Anxiety Disorders (F03.080), Dissociative Disorders (F03.300), Feeding and Eating Disorders (F03.400), Neurocognitive Disorders (F03.615), Somatoform Disorders (F03.875), Conduct Disorders (F03.250), Neurodevelopmental Disorders (F03.625), Mood Disorders (F03.600), Neurotic Disorders (F03.650), Personality Disorders (F03.675), Schizophrenia Spectrum Disorders (F03.700), Sleep-Wake Disorders (F03.870), and Substance-Related Disorders (F03.900). All the indications listed in these branches were used along with Dyspareunia, Erectile Dysfunction, Paraphilias, Fetishism, and Paedophilia from the Sexual Dysfunctions (F03.835) branch yielding a total of 108 mental health indications that are analyzed in this work. A separate MeSH identification paradigm was done for epilepsy-related indications as these indications are placed in a separate MeSH tree because they are neurological disorders, not psychiatric disorders. The MeSH tree evaluated for epilepsy is C10.228.140.490 which includes Drug-Resistant Epilepsy, Myoclonic Epilepsies, Partial Epilepsies, Benign Neonatal Epilepsy, Generalized Epilepsy, Post-Traumatic Epilepsy, Reflex Epilepsy, Landau-Kleffner Syndrome, Lennox-Gastaut Syndrome, Seizures, and Febrile Seizures. A total of 29 additional epilepsy-related indications are presented in this work.

## Calculation

### Ranking the importance of predicted psychoactives for mental health indications

We generated Top10, Top25, Top40, and Top100 ranked compound lists for all indications (mental health related and otherwise) using the CANDO v1 platform for each indication and counted the number of times a compound prediction is present in each of the ranked lists. A compound may be predicted to treat an indication several times if there are numerous known drugs for that indication.

For example, 65 known drugs are used clinically for schizophrenia and are included in the CANDO platform. Therefore, a set of 65 chemoproteomic signature similarities are used to predict an uncharacterized compound for schizophrenia. It is possible that the same uncharacterized compound may be predicted at most 65 times for schizophrenia. The number of times such a compound is predicted for a given indication is termed as the ‘consensus count,’ which is normalized as the percent occurrence. We compute percent occurrence as the ratio of consensus count to the maximum number of times a compound could be predicted for an indication using signature similarity (i.e. the number of known treatments for the indication).

We hypothesized that the higher the number of times a compound is predicted to treat a given indication, the greater the confidence in the prediction made because different drugs treat indications due to different biological pathways on the proteomic level. The combination of proteomic similarity implicitly includes a combination of all pathways to yield efficacy and is denoted by the frequency of compounds predicted for each indication. To investigate the general role of psychoactives for mental health, we took the frequency of psychoactive compounds predicted as putative drugs for each indication as a percentage of all compounds predicted for the given indication. The ratio of psychoactive to all compounds for a given indication is referred to as the normalized indication rank and quantifies the overall performance of psychoactive compounds versus non-psychoactive for a given indication.

A similar procedure is used to measure the propensity of a compound to be predicted for mental health indications and is used to ask the question: how many times an indication is (or percentage of mental health and non-mental health indications) listed either as a prediction for treatment by each psychoactive compound and is referred to as the normalized compound rank. This measure allows us to express the preference of a given compound towards mental health indications. To illustrate metrics of normalized compound rank, and normalized indication rank, we consider a simple example where a psychoactive compound ergoline and a non-psychoactive compound aspirin are only predicted for the mental health indication Pica (an eating disorder) and Stomach pain (non-mental health indication). Now consider ergoline that is predicted seven times for Pica, and three times for Stomach pain based on the similarity of chemo-proteome analysis while the non-psychoactive drug aspirin is predicted to treat Pica four times and Stomach pain six times. The normalized compound rank for this simple example will be 70% [100 * 7/(7 + 3)] for ergoline and 40% [100 * 4/(4 + 6)] for aspirin. Using the above example, we can also determine the normalized indication rank for Pica and Stomach pain. Since seven psychoactives and four non-psychoactive compounds were predicted for Pica, the normalized indication rank is 64% [100 * 7/(4 + 7)] for Pica and similar calculation yields an indication rank of 33% for Stomach pain. Together these metrics suggest the importance of psychoactive compounds and their preference for mental health compared to non-mental health indications.

### Computational randomized controls

To further ensure that our results were not arrived at by chance, the order of the predicted compounds is randomized, and the above procedures repeated. All compounds predicted to treat an indication are randomized regardless of whether the indication is categorized as a mental health indication. Thus, a compound not predicted initially to treat a mental health indication may, due to random chance, be predicted to treat a mental health indication in the randomized data set. If a random compound replaces a predicted compound multiple times for a single indication, the random compound replaces the original (non-random) compound for every prediction. This randomization process is repeated 1000 times, and the compound and indication ranks for all the randomized searches are averaged.

A second random control is performed in addition to the one described above where the indications (mental health or otherwise) are randomly rearranged. Thus, a non-mental health indication may be classified as a mental health indication by chance (and vice versa). This procedure provides a second control that allows us to assess whether selected psychoactives are more likely to be predicted for mental health indications than non-mental health indications.

### Determination of relationships between mental health indications

We relate two mental health indications when at least two different psychoactive compounds are predicted for both indications. The frequency of prediction for common psychoactive compound predictions is termed as ‘indication-indication association counts.’ Next, to strongly relate the two indications, we also calculated the ‘consensus count’ for all psychoactives predicted for each mental health indication. Note that a predicted psychoactive could have a different consensus count for each indication. For example, 1-naphthyl(1-pentyl-1H-indole-3-yl) methanone is predicted 10 times for seizures and 8 times for sleep initiation and maintenance disorders (SIMD). Therefore, the consensus count of 1-naphthyl(1-pentyl-1H-indole-3-yl) methanone for seizures is 10 and 8 for SIMD. Another compound, 2-(5-methoxy-2-methyl-1H-indole-3yl)-n,n-dimethyl ethanamine has consensus count of 3 for seizures and 2 for SIMD. Since two different compounds are common predictions for the two indications, the indication-indication association count for these two indications is 2. To strongly relate the indications in Top lists and limit a large number of associations, we selected indication pairs with predicted psychoactive compound consensus count as follows: >=2 for the Top10 set, >=3 for the Top25 set, >=4 for the Top40 set, and >=6 for the Top100 set.

### Tests for statistical significance

A one-tailed Kolmogorov-Smirnov test93 was used to compare the distributions of psychoactives in the randomized and non-random distributions as this statistical test is typically used to show two distributions are dissimilar. For all statistical tests performed in this work, we formulated the null hypothesis to be that the distribution of psychoactives predicted to treat mental health disorders can be obtained by chance. Our alternative hypothesis is that the true distribution of psychoactives is greater than the randomized control (hence a one-tailed test). We also performed a one-tailed paired T-test to ensure that the mean of the differences between the test distribution and the randomized distribution is greater than zero. The raw p-values obtained for all statistical tests are given in Tables S10S11.

## Conclusions

Traditional drug discovery is limited by its narrow focus on one or a few targets. Drugs approved for one indication interact with multiple proteins and thereby work across multiple indications. The CANDO platform improves upon the traditional approach by examining all interactions between a compound and a universal proteome. This novel approach enables the study of drugs in a holistic chemoproteomic manner that is especially relevant for the development of compounds intended for treating mental health indications as these complex disorders are mediated by multiple proteins and pathways. In this study, we investigated the compounds previously described by Alexander Shulgin along with additional cannabinoids to identify potential therapies for mental health indications. The results of this study indicate the selected psychoactive compounds perform better than compounds selected at random for mental health indications.

Conversely, the percentage of mental health indications selected by psychoactives is better than randomly selected compounds. This shows that psychoactives may represent promising leads for the development of therapeutics for the treatment of mental health indications. Specifically, the set shows promising results for sleep-related disorders, binge eating disorders, seasonal affective disorder, and cocaine substance abuse disorder. In addition, the other non-psychoactive compounds predicted by the CANDO platform present in the top-ranked predictions may also represent putative repurposable therapies for mental health indications, which will be explored in future studies. In a broader context, our work illustrates the advantages of using a computational chemoproteomics approach for drug discovery and repurposing by providing mechanistic information on which proteins are involved in the mediation of the therapeutic effect.

## Data Availability

The 3,733 × 46,784 compound-protein interaction matrix, canpredict executables to calculate similarity with additional dependency files, output from canpredict for top10, top25, top40, top100, files for analysis, SMILES for 3,733 compounds, entire 46,784 list of proteins, R workspace and analysis scripts used to generate all figures presented in this work are available at http://github.com/chopralab/candiy_fun.git.

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## Acknowledgements

This work was supported in part by a Purdue University start-up package from the Chemistry Department, Ralph W. and Grace M. Showalter Research Trust award, the Integrative Data Science Initiative award, and the Jim and Diann Robbers Cancer Research Grant for New Investigators award to Gaurav Chopra and a Lynn Fellowship to Jonathan Fine. Additional support, in part by a NIH Director’s Pioneer Award (1DP1OD006779), a NCATS Clinical and Translational Sciences Award (UL1TR001412), a NCATS Clinical and Translational Sciences Award from the Indiana Clinical and Translational Sciences Institute (UL1TR002529), and the Purdue University Center for Cancer Research, NIH grant P30 CA023168 are also acknowledged. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

## Author information

Jonathan Fine and Gaurav Chopra wrote the manuscript, and Jonathan Fine prepared the figures and performed the analysis of the chemoproteomic methods. Rachael Lackner was involved in the initial analysis of the psychoactives. Gaurav Chopra and Ram Samudrala conceived the idea and developed the chemoproteomic methods.

Correspondence to Ram Samudrala or Gaurav Chopra.

## Ethics declarations

### Competing Interests

The authors declare no competing interests.

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