Abstract
Ketamine is increasingly used in community clinics as a long-term treatment for different psychiatric and pain conditions, including substance use disorders. Data are lacking, however, regarding the potential influence of ketamine on other substance use. In this secondary analysis we aimed to explore the relationship between medical ketamine and other substance use among real-world patients by combining quantitative and qualitative data. In an online anonymous pilot survey (N=201), patients rated change in other substance use since medical ketamine initiation and elaborated on their subjective experiences. Most patients self-reported positive/desirable change (54.7%) or no change in substance use (44.3%). Participants reporting past problematic substance use had significantly greater positive change compared to the groups of participants reporting present or no history of problematic substance use (ps<.020). Participants reported positive outcomes such as reduced substance use due to reduced need to self-medicate for coping, reduced craving, or enhanced motivation to quit use. Among participants with minimal or no substance use, ketamine did not appear to induce or increase drug-using behaviors. However, there were some reports of risky behaviors such as openness to using other psychedelics, or ketamine used recreationally as a substitute for alcohol. Several implications for providers are discussed. More targeted quantitative and qualitative research is needed to fully characterize all patients, but especially those at risk for potentially harmful nonmedical substance use. Such research could inform regulation efforts on safety, screening, monitoring, and patient and provider education, to maximize benefits and minimize risks related to medical ketamine.
Keywords: ketamine, alcohol, substance use, mental health, pain
Ketamine, a widely used dissociative anesthetic has emerged as a rapid antidepressant medication when administered in sub-anesthetic doses (Marcantoni et al., 2020). Although depression is frequently comorbid with substance use disorders (SUDs; Swendsen & Merikangas, 2000, National Institute on Drug Abuse, 2020), patients with a current, or history of SUDs are commonly excluded from clinical trials investigating the antidepressant effects of ketamine (e.g., Singh et al., 2016, Phillips et al., 2019, Price et al., 2022). Concerns arise because ketamine is also an addictive club drug with long-term harms (Liu et al., 2016), and the long-term misuse/addictive potential among patients is still mostly unknown (Yavi et al., 2022), including the relationship with other nonmedical substance use. A few clinical studies assessing the antidepressant effects of ketamine reported that their participants (with no history of SUDs) did not report drug-seeking behaviors, craving, or incidents of using illicit substances during the trial or at follow-up (Phillips et al., 2019, Wan et al., 2014). These reports are sparse, peripheral to study aims, and some rely on spontaneous patient reports. Understandably, these clinical studies were not designed to evaluate drug-seeking or changes in other substance use. Thus, the indirect effect of ketamine on other nonmedical substance use in different populations is not yet understood. Ketamine might reduce, increase, or even substitute use of other substances and could affect the use of specific substances differently (e.g., alcohol, cannabis, opioids, other psychedelics). Ketamine may also differentially affect individuals with current, past, or no problematic substance use.
At the same time, initial evidence from a small number of specific studies suggests that ketamine delivered with psychotherapy (before, during, or after administration), may be a promising treatment component for SUDs for some patients (for reviews see Walsh et al., 2022, Goldfine et al., 2023, Drozdz et al., 2022). Ketamine, coupled with psychotherapy, was found to promote alcohol abstinence (Grabski et al., 2022, Dakwar et al., 2020) and reduce likelihood of heavy use of alcohol (Dakwar et al., 2020), promote abstinence and reduce craving among heroin users (Krupitsky et al., 2007), and cocaine users (Dakwar et al., 2019), as well as increase motivation to quit cocaine (Dakwar et al., 2014). Initial evidence from a proof-of-concept study similarly suggests that ketamine, coupled with behavioral therapy, may be effective in reducing cannabis use among individuals with cannabis use disorder (Azhari et al., 2021). Although ketamine appears to be promising as a treatment for SUDs, results can be mixed, and researchers stress the need for more research before efficacy, safety, and treatment protocols can be determined (Kelson et al., 2023).
Although ketamine is currently not FDA-approved for psychiatric conditions, off-label use is becoming widespread in private community clinics across the United States, and globally. In community clinics, medical ketamine treatment commonly starts with an (initial) induction series of 4–8 intravenous or intramuscular doses during 2–4 weeks, followed by periodical booster or maintenance doses. Intravenous ketamine doses begin at 0.5 mg/kg and may be titrated up to 3.0 mg/kg (O’Brien et al., 2022). The maintenance treatment is individually tailored (dose and frequency) to the patient’s needs and preferences (O’Brien et al., 2022), and may continue for months, years, or potentially lifelong. Patients are primarily treated for depression, and evidence regarding the antidepressant effectiveness of ketamine among thousands of real-world patients is accumulating (e.g., Alnefeesi et al., 2022). In addition to depression, patients are also treated for other psychiatric and several chronic pain conditions (O’Brien et al., 2022, Voute et al., 2022). And although the evidence is still limited, some community clinics already advertise ketamine as a treatment for SUDs (Crane et al., 2023). Consequentially, patients with SUDs are already treated in the community, yet are still understudied and data are underreported. Characterizing the relationship between medical ketamine and other nonmedical substance use among patients with or without problematic substance use is crucial, as unique clinical challenges may exist, just as treating pain with opioids in patients with SUDs raises concerns about increasing or legitimizing other substance use and necessitates attention (Chang & Compton, 2013).
The need to study real-world patients is urgent. Unlike highly controlled clinical trials, in community clinics, patients with a variety of comorbidities are being treated; the treatment is longer-term (potentially lifelong) and involves multiple and higher doses (O’Brien et al., 2022). Before long-term protocols and safety of medical ketamine across different populations can be determined, it is crucial to understand the associations with other nonmedical substance use among real-world patients; including all patients, but specifically, patients who currently misuse other substances or misused substances in the past (given that ketamine treatment may increase or legitimize other substance use). The association between ketamine and the use of other substances among patients who report no problematic use is also important to characterize. These patients, who may be at risk of SUD comorbidity, are repeatedly introduced to a dissociative substance, warranting more data collection on the risks of initiation of drug-using behaviors and/or substance misuse throughout the ketamine treatment.
Therefore, the purpose of this secondary analysis was to explore whether and how medical ketamine might indirectly change other nonmedical substance use (e.g., alcohol, cannabis, nicotine cigarettes, other psychedelics) among real-world patients, using quantitative and qualitative data. Ketamine patients were asked whether they experienced any changes in their typical substance use since the initiation of the medical ketamine treatment, and in what way. We assessed and combined self-reported quantitative rating of change and qualitative reports of the individual’s experiences of change to better characterize the relationship. Additionally, we distinguished between three groups of patients: those reporting present, past, or no history of problematic substance use, all populations with unique considerations for the purpose of minimizing risks, patient education and/or continued monitoring.
Method
We report how we determined our sample size, all data exclusions, all manipulations, and all measures in the present study. This secondary analysis was not preregistered. Materials and analysis code for this study are available by emailing Shahar Almog or Meredith S. Berry.
Participants and Procedures
Based on our inclusion criteria, real-world adult patients (age 18 and older) currently or previously treated with medical ketamine for any condition were invited to participate. Participants were determined for exclusion if using non-medical ketamine only, outside of a clinical context. The data were collected from March 2023 to March 2024 via an anonymous online pilot Qualtrics survey. Participants were recruited via (a) ketamine providers that sent out the study’s invitation and survey link to their patients via email, (b) social media posts in relevant groups, and (c) ResearchMatch (https://www.researchmatch.org/). Participants completed questions on their demographics and treatment history, whether they had a past, present, or no history of problematic substance use, whether they experienced changes in other substance use, and in what way. The survey included quantitative and qualitative items. The parent study included additional measures on benefits and risks of medical ketamine including the misuse potential of ketamine (not yet published). Median duration of survey completion was 35.5 minutes (Q1–Q3: 25.3–52.2). Participants were not compensated monetarily. We used three primary data quality checks aligned with online research, and also note that given the survey was unpaid, there was no incentive for multiple submissions or known misrepresentation. First, we extensively reviewed the qualitative responses for quality of the written English language and familiarity with the topic, an effective measure for detecting bots (Storozuk et al., 2020) and poor-quality responses or misrepresentation (Kumarasamy et al., 2024). There were no identical responses across surveys, and all open-ended questions were of overall good quality writing. Second, we used the bot detection Qualtrics feature to carefully review responses that were flagged as suspicious. Third, we evaluated the reliabilities of anxiety and sleep disturbance scales which were administered to all participants. Cronbach’s alphas of the scales were all high above 0.9, which is associated with samples that provide good quality data overall (Peer et al., 2014). We did not exclude any participants due to low-quality data. All procedures were approved by the Institutional Review Board of the University of Florida under protocol #IRB202202571.
Measures
Change in Typical Substance Use Rating
Participants were asked to compare the time before and after the ketamine treatment and rate any changes in their typical substance use (e.g., alcohol, cigarettes, cannabis, opioids, other) on a 7-point scale from −3 to +3 (strong/moderate/slight negative change that I consider undesirable, no change = 0, to slight/moderate/strong positive change that I consider desirable). Participants were able to choose Not Applicable (N/A I have not used any substances in the past or present). The item was developed following questions used in Griffiths et al. (2006) assessing persisting changes after participating in a psilocybin administration study.
Other Psychedelics Use
To assess whether medical ketamine leads to openness to using other psychedelics, participants were asked whether they had experienced other psychedelics before and after the initiation of the ketamine treatment, with possible responses of no, yes, not sure, and prefer not to respond.
Change in Typical Substance Use Experiences
The qualitative data presented here are derived from the participant’s response to a single open-ended question. The question asked the participants to reflect on their lives before and after the ketamine treatment and describe whether they felt their regular substance use had changed, whether they felt it was related to the ketamine treatment, and in what way. It was prompted that “change” might refer to change in the quantity or frequency of consumption, as well as change in context (e.g., with other people, alone, time of day, place), or in reasons for consuming substances (e.g., coping with negative emotions, celebrating with friends). There were no word limits. Participants were asked to write N/A if never used substances or if felt there was no change to report.
History of Problematic Substance Use
To categorize the participants into three groups based on history of problematic substance use, participants were asked whether they felt they have (or had in the past) problematic use of a substance (e.g., alcohol, opioids, stimulants, cannabis). Participants endorsed one of three options to categorize substance use: past (but not current) problematic substance use, present problematic substance use, or no history of problematic substance use. Participants who reported past or present problematic use were asked to specify the substance(s).
Patient Characteristics
Participants were asked about the health condition they were being treated for with ketamine (e.g., depression, anxiety, pain, substance use). The conditions were categorized as Mental Health (all psychiatric conditions), Pain, Mental Health and Pain, or Other. Participants were asked about their current stage of the ketamine treatment (e.g., receiving the initial series of treatments or booster periodical treatments), time of last treatment, and month and year of initiation of treatment. These details were not directly relevant to the present report and thus not presented, however, were inspected when additional context was needed during the qualitative analysis. Participants were asked to estimate the total number of ketamine treatments received overall, and whether they engaged in any other form of therapy. Participants who reported any type of psychotherapy (e.g., CBT, meeting a counselor) or integration therapy were categorized as receiving psychotherapy.
Demographics.
Participants were asked about their age, sex and gender, race, ethnicity, education, household annual income, and the state in which they were being treated.
Data Analysis
We described the sample, the rating of change in substance use, and the percentage of participants using other psychedelics before/after the initiation of ketamine for the full sample and per the three groups: participants who reported past problematic substance use, participants who reported present problematic substance use, and participants who reported no history of problematic substance use. To assess differences in substance use change ratings across the three groups, we used a one-way between-groups analysis of variance (ANOVA), with post hoc comparisons using Bonferroni correction. Effect size was calculated using eta squared. Description of the sample and analysis were conducted in SPSS (version 29.0.0).
The qualitative data analysis began with collating all text data provided by the participants regarding the “change’ they felt from before the ketamine treatment into a single Excel document. The free text written by the participants ranged from one to 15 sentences (M = 2.34, SD = 1.89), with total of 2 to 229 words (M = 30.41, SD = 28.32). The text analysis focused on mainly two themes: (1) types of substances for which positive outcomes were mentioned, and (2) outcomes of change described. Two independent blinded coders manually coded each of the text segments and reached a consensus before collating codes under larger themes. Themes, subthemes, codes, definitions, and whether the subtheme/code appeared in each substance use-related group (i.e., past, present, no history of problematic substance use) were summarized in a table (presented in the Results section). Example quotes are presented below with individual characteristics including age, gender, health condition, problematic substance use (i.e., past, present, no history of), stage in treatment (i.e., completed initial series stage, receiving booster treatments, or receiving long-term booster treatments, if received more than 15 treatments total), and rating of change in substance use.
Results
Participants
After one participant was excluded from analysis for using only self-prescribed nonmedical ketamine, data from 201 patients in community ketamine clinics with complete data were analyzed. Table 1 presents the characteristics of the full sample and groups based on problematic substance use (i.e., past, present, no history of). The sample had mean age of 46.0 years (SD = 12.55), of whom 64.7% were female, 88.6% were White, and 5.5% were Hispanic/LatinX. For education, 60.7% obtained a Bachelor’s degree or higher, and the median annual household income was $100K (Q1-Q3: 60K-150K). Of the sample, 71.1% reported being treated for mental health conditions (e.g., depression, anxiety, post-traumatic stress disorder, SUD), 18.9% for both pain and mental health conditions, and 9.5% for pain conditions. Five participants (2.5%) specifically mentioned they were treated for SUD, of which four were also treated for depression and anxiety. Median number of ketamine treatments received was 11 (Q1-Q3: 6–20). Most patients (n = 198) were from 30 different states in the United States and 3 from two other countries. Of the 201 participants, 65.2% (n = 131) reported no history of problematic substance use, 25.9% (n = 52) reported past problematic use, and 9.0% (n = 18) reported present problematic use. Most participants (68.2%) reported engaging in some form of psychotherapy.
Table 1.
Sample Characteristics of Full Sample and Problematic Substance Use-Based Groups.
| Problematic Substance Use |
||||
|---|---|---|---|---|
| Full Sample N = 201 |
Past n = 52 |
Present n = 18 |
No n = 131 |
|
|
| ||||
| Age, M (SD) | 46.0 (12.55) | 45.3 (11.82) | 48.2 (14.67) | 45.9 (12.58) |
| Female, n (%) | 130 (64.7%) | 35 (67.3%) | 10 (55.6%) | 85 (64.9%) |
| Race, n (%) | ||||
| White | 178 (88.6%) | 47 (90.4%) | 17 (94.4%) | 114 (87.0%) |
| Black or African-American | 3 (1.5%) | - | - | 3 (2.3%) |
| Asian | 2 (1.0%) | - | - | 2 (1.5%) |
| Other/Mixed | 18 (8.9%) | 5 (9.6%) | 1 (5.6%) | 12 (9.2%). |
| Ethnicity | ||||
| Hispanic/LatinX | 11 (5.5%) | 4 (7.7%) | 1 (5.6%) | 6 (4.6%) |
| Education | ||||
| High school or less | 13 (6.5%) | 2 (3.8%) | 2 (11.1%) | 9 (6.9%) |
| Some college but no degree | 42 (20.9%) | 13 (25.0%) | 3 (16.7%) | 26 (19.8%) |
| Associate degree | 24 (11.9%) | 5 (9.6%) | 4 (22.2%) | 15 (11.5%) |
| Bachelor’s degree | 60 (29.9%) | 19 (36.5%) | 5 (27.8%) | 36 (27.5%) |
| Master’s degree | 44 (21.9%) | 9 (17.3%) | 1 (5.6%) | 34 (26.0%) |
| Doctoral degree | 18 (9.0%) | 4 (7.7%) | 3 (16.7%) | 11 (8.3%) |
| Income, Median (Q1–Q3), n | 100K | 80K | 117K | 100K |
| (60K–150K) | (39.5K–160K) | (75K–197.5K) | (60K–150K) | |
| 181 | 46 | 17 | 118 | |
| Treated Condition | ||||
| Mental Health | 143 (71.1%) | 42 (80.8%) | 14 (77.8%) | 87 (66.4%) |
| Pain | 19 (9.5%) | 2 (3.8%) | 1 (5.5%) | 16 (12.2%) |
| Mental Health and Pain | 38 (18.9%) | 8 (15.4%) | 3 (16.7%) | 27 (20.6%) |
| Other | 1 (0.5%) | - | - | 1 (0.8%) |
| Total number of treatments Median (Q1–Q3) | ||||
| 11 (6–20) | 12 (7–24) | 9.5 (6–19) | 10 (6–20) | |
| Psychotherapy, n (%) | 137 (68.2%) | 36 (69.2%) | 13 (72.2%) | 88 (67.2%) |
Note. Treated condition Mental Health includes psychiatric conditions (e.g., depression, anxiety, post-traumatic stress disorder, substance use disorders). Percentages refer to columns and may not add up to 100 due to rounding. Median was used as a measure of central tendency in variables with extreme values.
Change in Typical Substance Use Rating
Full Sample
The results of the rating of change in substance use are presented in Table 2. The mean change rating was 2.18 (SD = .84), indicating moderate to strong positive change that participants considered desirable on average. Of the full sample, 54.7% (n = 110) reported some positive change that was considered desirable in their typical substance use. Strong positive change was reported by 24.9% of the sample, moderate positive change by 14.9%, and slight positive change by another 14.9% of the sample. Additionally, 25.9% (n = 52) reported no change, two participants (1.0%) indicated slight negative change that was considered undesirable, and 18.4% (n = 37) chose N/A indicating they do not use substances at all. Of the 110 participants reporting some positive change in their substance use, 72.7% (n = 80) reported engaging in some form of psychotherapy.
Table 2.
Change in Substance Use Outcomes for Full Sample and Problematic Substance Use-Based Groups.
| Problematic Substance Use |
||||
|---|---|---|---|---|
| Full Sample N = 201 |
Past n = 52 |
Present n = 18 |
No n = 131 |
|
|
| ||||
| Change in substance use rating, n (%) | ||||
| Strong positive – desirable | 50 (24.9%) | 24 (46.2%) | 3 (16.7%) | 23 (17.6%) |
| Moderate positive - desirable | 30 (14.9%) | 12 (23.1%) | 3 (16.7%) | 15 (11.5%) |
| Slight positive – desirable | 30 (14.9%) | 5 (9.6%) | 6 (33.3%) | 19 (14.5%) |
| No change | 52 (25.9%) | 9 (17.3%) | 5 (27.8%) | 38 (29.0%) |
| Slight negative – undesirable | 2 (1.0%) | - | 1 (5.6%) | 1 (0.8%) |
| Moderate negative –undesirable | - | - | - | - |
| Strong negative – undesirable | - | - | - | - |
| N/A not using substances | 37 (18.4%) | 2 (3.8%) | - | 35 (26.7%) |
| Change in substance use rating, M (SD) | 1.45 (1.25) | 2.02 (1.15) | 1.11 (1.18) | 1.22 (1.23) |
| Other psychedelics use, n (%) | ||||
| No prior, No after | 112 (55.7%) | 27 (51.9%) | 6 (33.3%) | 79 (60.3%) |
| Yes prior, No after | 45 (22.4%) | 14 (26.9%) | 3 (16.7%) | 28 (21.4%) |
| Yes prior, Yes after | 29 (14.4%) | 9 (17.3%) | 6 (33.3%) | 14 (10.7%) |
| No prior, Yes after | 9 (4.5%) | 1 (1.9%) | 3 (16.7%) | 5 (3.8%) |
| Not sure prior (1 no post, 1 yes post) | 2 (1.0%) | 0 (0.0%) | 0 (0.0%) | 2 (1.5%) |
| Prefer not to say (3 at post, 1 at prior) | 4 (2.0%) | 1 (1.9%) | 0 (0.0%) | 3 (2.3%) |
Note. Percentages refer to columns and may not add up to 100 due to rounding.
Past, Present, No History of Problematic Substance Use Groups
Table 2 presents the results of the change in substance use rating in each group based on the history of problematic substance use. The group of participants indicating past problematic substance use had the highest mean change rating at 2.02 (SD = 1.15) and highest percentage of participants experiencing some positive change, at 78.8% (n = 41) and no reports of negative change. The group of participants indicating present problematic substance use had mean change rating at 1.11 (SD = 1.18), with 66.7% (n = 12) experiencing positive change, one participant (5.5%) experiencing slight negative change, and 27.8% (n = 5) experiencing no change. Lastly, the group of participants reporting no history of problematic substance use had a mean change rating at 1.22 (SD = 1.23) with most participants (55.7%, n = 73) reporting no change or not using substances, 43.5% (n = 57) reporting positive change, and one (0.8%) reporting slight negative change.
To assess differences in change in substance use rating between the three groups, a one-way ANOVA was conducted with the rating of change as the dependent variable. The ANOVA detected significant differences in change in substance use rating across the problematic substance use groups (i.e., past, present, no history of), F[2,161] = 8.10, p < .001, eta squared = .09. Post hoc comparisons showed that the group of participants with past problematic substance use had significantly higher rating of positive changes compared to the group of participants with present problematic substance use (p = .020), and the group of participants with no history of problematic substance use (p < .001). The two groups of present and no history of problematic substance use did not differ in the rating of change in substance use (p = 1.000).
Other Psychedelics Use
Of the full sample, 38 participants (18.9% ) used other psychedelics after the initiation of ketamine treatment, of whom nine participants (4.5% of the sample) did not have any experience with other psychedelics prior to the ketamine treatment. The group of participants with present problematic substance use had the highest percentage of participants using other psychedelics after the initiation of ketamine treatment (50.0%), compared to participants with past (19.2%), or no history of problematic substance use (14.5%). Results of other psychedelic use are presented in Table 2.
Type of Substances
Participants reported reductions or other positive outcomes related to substance use (i.e., reduced craving and tolerability, enhanced motivation to quit) indicating specific substances. Comments included change in the use of alcohol (n = 56), cannabis (n = 25), nicotine cigarettes/products (n = 15), opioids (n = 10) and other prescribed or over-the-counter medications (n = 10). Several participants reported reductions but did not specify the substance or specified some and mentioned “other drugs” or “illicit” substances (n = 8).
Change in Typical Substance Use Experiences
Overall, participants’ experiences (i.e., qualitative responses) aligned with the quantitative ratings of substance use change. We organized participant comments under three themes: (1) positive outcomes, aligning with positive outcomes in clinical trials (e.g., reduced use, Azhari et al., 2020; reduced craving, Dakwar et al., 2019; increased motivation to quit, Dakwar et al., 2014), (2) neutral outcomes (e.g., no change in use), and (3) negative outcomes (e.g., increases in use). Few discrepancies were noted, in which a change was perceived by the participant as positive and desirable, however, the qualitative information revealed a risky behavior or attitude. The subthemes and codes that were identified are presented below with example quotes from the participants. Themes, subthemes, codes, definitions, and whether the code appeared in each group (i.e., past, present, no history of problematic substance use) are presented in Table 3.
Table 3.
Coding Framework of Experiences of Change in Other Substance Use.
| Theme and Subtheme | Code | Definition | Appearance |
||
|---|---|---|---|---|---|
| Past | Present | No | |||
|
| |||||
| Positive Outcomes | |||||
| Reduced substance use (no elaboration) | Reductions, no elaboration | Short comments on reduced substance use without elaborating on the experiences | X | X | X |
| Temporary reductions | Temporary reduction in substance use in proximity to treatment after which use returns to regular levels | X | - | X | |
| Improved health and well-being | Coping with mental health | Reduced use due to reduced need to self-medicate to cope with poor mental health | X | - | X |
| Coping with pain | Reduced use due to reduced need to self-medicate to cope with pain | X | - | X | |
| Overall better health | Reduced use to improve health or due to improved health | X | X | X | |
| Maintaining abstinence | Ketamine helps maintain long-term alcohol abstinence | X | - | - | |
| Reduced craving, desire, or tolerability | Craving | Reduced use due to reduced craving, desire, or interest in substances | X | X | X |
| Tolerability | Reduced use due to reduced physical tolerability to alcohol (e.g., can’t tolerate the smell or taste) | X | - | X | |
| A sudden change | Sudden quitting/ self-insight | Ketamine led to quitting use overnight, experiencing a “switch” flipping or new insight on substance use. | X | X | - |
| Decision not to use substances | Informed decision | Decision not to use or reduce use to avoid problems with ketamine | X | X | X |
| Increased motivation to change | Motivation/ intention | Ketamine led to increased motivation to quit smoking, although still smoke | - | X | - |
| Neutral Outcomes | |||||
| No change in substance use | No change | Regular substance use did not change. | X | X | X |
| Change before ketamine | Use of a specific substance was stopped before initiation of ketamine treatments (e.g., quit smoking years before) | X | X | - | |
| Change in attitude | Peace with substance use | A new internal peace accepting some substance use (e.g., less guilt on cannabis use for sleep) | X | - | X |
| Negative Outcomes | |||||
| Increase in use | Ketamine not accessible | Increased use due to ketamine not being accessible at that time. When ketamine was accessible, reductions in use were experienced. | - | X | X |
| Ketamine didn’t help | Increased use due to ketamine not helping, leading to hopelessness and worsened mental health | - | - | X | |
| Increased use, unharmful, unrelated to ketamine | Increased substance use which is related to changes in life circumstances (e.g., starting college), unrelated to the ketamine treatment | X | - | X | |
| Intentions to use other drugs | Openness to use other drugs | Ketamine led to openness to using psychedelics, purchased from nonmedical sources. | - | X | - |
| Recreational ketamine substitutes other substance use | Ketamine substitutes alcohol | Ketamine used recreationally substituting alcohol at parties. | - | - | X |
Note. Themes, subthemes, codes, definitions, and whether the theme appeared in the substance-use based groups (i.e., past, present, no history of - problematic substance use). X reflects appearance of theme by participants of the group.
Positive Outcomes
Results yielded 105 comments, across 87 participants, describing positive outcomes related to substance use which were summarized into subthemes: (a) reduced substance use without additional elaboration, (b) positive outcomes in substance use related to improved health and well-being, (c) reduced craving, desire, or tolerability, (d) decision not to use substances (when treated with ketamine to avoid problems), (e) a sudden change, and (f) increased motivation to change substance use (i.e., quit smoking).
Reduced Substance Use (No Elaboration).
Across 38 participants, 40 comments described some reduced use of substances/medications. Thirty-seven comments described reductions in use of substances (n = 23), opioids (n = 5), and other medications (n = 9) without elaborating further. For example, “I quit cigarettes and marijuana and use alcohol occasionally” (50-year, female, mental health patient, past problematic substance use [substance not detailed], booster treatment stage, strong positive change in substance use). “I am off opioids, which is life changing” (62-year, female, pain patient, present problematic substance use [substance not detailed], long term booster treatment stage, strong positive change in substance use). Three additional comments described reductions in substance use that were temporary, either following the initial series of treatments or following each single treatment. For example, “Initially there was a decrease in alcohol consumption. That occurred during the first six infusions. About a month afterward I crave beer like I did before ketamine” (49-year, female, mental health patient, past problematic alcohol use, booster treatments, slight positive change in substance use). “After my sessions my cannabis use falls tremendously” (36-year, male, mental health patient, past problematic alcohol use, booster treatment stage, strong positive change in substance use).
Improved Health and Well-being.
Twenty-five participants reported reduced substance use related to improved health and well-being. Comments described reduced need to self-medicate in order to cope with poor mental health (n = 11) or pain (n = 8), reduced use in order to improve, or due to improved, health and well-being (n = 6), and ketamine supporting long-term maintenance of alcohol abstinence (n = 1).
I definitely drink less alcohol. I was drinking quite a lot before I started ketamine treatments and now I rarely drink. I do feel it is at least partly due to the ketamine treatments. This is because I’m less depressed and anxious, and depression and anxiety were two major reasons why I was drinking so much (48-year, male, mental health patient, past problematic alcohol use, booster treatment stage, strong positive change in substance use).
I used to drink a lot and smoke pot or do edibles. Mostly it was to escape the mental and physical pain I live in daily. Since starting ketamine treatment I have no longer wanted or needed to do that (41-year, gender neutral, mental health and pain patient, past problematic alcohol, cannabis, nicotine use, booster treatment stage, strong positive change in substance use).
I have noted a slight decrease in alcohol use. It is probably due to better sleep and lower stress (36-year, male, mental health patient, no history of problematic substance use, completed the initial series of treatments, slight positive change in substance use).
I’ve been able to quit smoking although I still smoke socially. I quit drinking years before the ketamine infusions but I believe that ketamine helps to keep me from returning to alcohol (42-year, gender neutral, mental health and pain patient, past problematic alcohol use, long-term booster treatment stage, strong positive change in substance use).
Reduced Craving, Desire, or Tolerability.
Across 25 participants, comments described reductions in use due to reduced craving for or interest in using substances (n = 21) and reduced tolerability of alcohol (n = 6).
I used to drink daily before ketamine. I would drink 3–4 beers per night or a bottle of wine. I no longer drink, not even socially. I have no desire. I don’t like the taste or smell anymore. This is completely ket[amine] related. I drank heavily for 20 years (46-year, female, mental health patient, past problematic alcohol use, booster treatment stage, strong positive change in substance use).
A Sudden Change.
Four participants reported a sudden change following a self-insight during the ketamine treatment that led to a sudden reduction or abstinence.
...I have never abused any substances other than cannabis and after my first ketamine experience I saw that it was a waste of time, harmful, and caused shame. Why would I want to substitute another drug when I understand substance abuse on a very “cellular” level and know it is a waste of time, money and potential (71-year, male, mental health patient, present problematic cannabis use, booster treatment stage, strong positive change in substance use).
Decision Not to Use Substances.
Six participants reported an informed decision to reduce or stop the use of any substance that might be interfering with ketamine. Some were told by their provider to stop use.
I’ve stopped drinking alcohol. I was told alcohol didn’t mix well with ketamine, so I stopped drinking it and I just never started again. I only drank socially before, but now for example at happy hour at work I just have sparkling water (38-year, female, mental health patient, no history of problematic substance use, long-term booster treatment stage, experiencing no change in substance use).
Increased Motivation to Change.
Although no change in use was experienced, two participants wrote about increased motivation to quit cigarette smoking.
I still smoke cigarettes, the same amount that I did before ketamine. I was hoping it would be easier to quit now but it has not proven to be easier. But I don’t smoke more than before, it’s the same amount. I have more of desire to quit now however (37-year, female, mental health patient, present cigarette user, long-term booster treatment stage, slight positive change in substance use).
Neutral Outcomes
Outcomes that were categorized as neutral included no change in regular use, or change in attitude related to the regular use.
No Change in Substance Use.
Comments describing no change in substance use from pre-ketamine treatment (n = 41) were mostly (78.0%) provided by participants who reported no history of problematic substance use. The typical substance use of these participants ranged from regular use, to occasional, minimal, or non-existent before or after the ketamine treatment. For example: “I felt no change but I also do not drink alcohol or smoke. I do enjoy cannabis on the weekends but haven’t noticed any changes to that” (52-year, male, mental health patient, no history of problematic substance use, completed the initial series of treatments, no change in substance use). Fifteen participants explicitly commented they did not use any substance before or after ketamine. Three participants reported that some substance use was stopped before the initiation of the medical ketamine treatment.
Change in Attitude.
Four participants reported change in their attitude towards substances such as increased peace with some use, for example, “I DO use cannabis before bed now… I beat myself up about it a lot less than I would have before the ketamine (60-year, male, past problematic alcohol use, completed the initial series of treatments, slight positive change in substance use). Others reported peace with using substances in moderation.
...ketamine helped me find my way out of an unhealthy religious situation that forbade their [substances] use. I am a conservative user of both alcohol and cannabis now, but I believe I do it in a healthy, positive manner (38-year, male, mental health patient, no history of problematic substance use, long-term booster treatment stage, strong positive change in substance use).
Negative Outcomes
Outcomes that were categorized as negative included increases in substance use, openness to using other drugs, or ketamine used recreationally substituting other substances.
Increase in Use.
Nine participants indicated increases in substance use compared to prior to ketamine treatment. Of the nine, four indicated that the increase in use was not harmful, relatively light, and in social contexts. For example, “There has been an increase (from never to rarely) due to changes in life circumstances, being in college, and being with friends.” (19-year, male, mental health patient, no history of problematic substance use, long-term booster treatment stage, no change in substance use). In contrast, four participants indicated that their use increased due to ketamine not being accessible to them at that time and that they were using less when they had better access to the treatment.
Since not being able to keep up with ketamine, I’m suffering extreme depression that includes SI [suicidal ideation]. Also anxiety. So I definitely have used (legal) marijuana to self medicate. I was doing much less of that when I had better access to ketamine (34-year, female, mental health patient, no history of problematic substance use, booster treatment stage, slight negative change in substance use).
Another participant reported an increase in use because ketamine didn’t help, which increased sense of hopelessness and worsened mental health.
I do consume more alcohol than I did before, but I don’t think it’s related to the ketamine. If anything, it’s more from a heavy-embedded sadness that it didn’t work and a feeling of overall helplessness. Trying to embrace that even ketamine (even after transcranial magnetic stimulation) can’t help my ‘treatment resistant’ depression. (31-year, female, mental health and pain patient, no history of problematic substance use, booster treatment stage, no change in substance use)
Although rare, and regardless of the participant’s perception, two other comments warrant attention.
Openness to Use Other Psychedelics.
One participant commented on openness to try psychedelics, possibly accessed from nonmedical sources: “It honestly hasn’t changed my use of other drugs with the exception of being open to trying psychedelics. I have tried psilocybin once therapeutically since as it’s much cheaper and I can access a reliable source” (47-year, male, mental health patient, present problematic cannabis use, booster treatment stage, no change in substance use).
Recreational Ketamine Substitutes Other Substance Use.
Although it was not self-perceived as risky or problematic, one participant reported that ketamine became a substitute for alcohol in certain recreational contexts.
I do not drink alcohol much anymore for a combination of reasons; primarily my body doesn’t metabolize alcohol well. Recreational ketamine gives me a more enjoyable way to connect to a party or rave, while still enabling me to leverage recreational use for mental health. I do not believe in the full separation of recreational and therapeutic ketamine usage (28-year, female, mental health patient, booster treatment stage with additional at-home ketamine, no history of problematic substance use, slight positive change in substance use).
Other Responses
Sixty-nine participants indicated the question was not applicable to them, provided unrelated responses (e.g., reported change in eating behaviors), or did not respond at all to the question. Most of these (73.9%) were provided by participants reporting no history of problematic substance use.
Discussion
The present exploratory secondary analysis study, based on self-reported ratings and experiences, found that many real-world ketamine patients in our sample experienced reductions or other positive outcomes in substance use following medical ketamine, with several themes emerging in the individual’s experiences. Many participants (54.7%) reported some positive change in substance use that was perceived as desirable. Positive changes included reductions in use related to better health and well-being and reduced need for coping with substances, reduced craving, abstinence maintenance, and increased motivation to stop nicotine use. Positive changes were mostly related to reductions in alcohol use, but also to cannabis, cigarette smoking, and among some pain patients, opioid use. Reductions in use of other prescribed and over-the-counter medications were also reported. Almost half of the sample (44.3%) were participants with non-problematic substance use who reported no change in substance use, or indicated not using substances at all. Our findings of positive outcomes in other substance use complement findings from targeted clinical studies investigating the use of ketamine as treatment for SUDs (Walsh et al., 2022, Goldfine et al., 2023). Raising some concerns, almost 19% of the participants used other psychedelics after the initiation of ketamine, with 4.5% reporting not having prior experience with other psychedelics. Unique characteristics emerged from the quantitative and qualitative findings for the three groups based on the status of problematic substance use (i.e., past, present, no history of).
The group of participants reporting past problematic substance use reported more subjective experiences of positive changes in substance use and significantly higher rating of positive changes compared to the other two groups. This may have resulted from several reasons. These participants may have responded better to the treatment. It is also possible that these participants had more severe, or perceived their basic substance use more negatively and thus had more room for change since the initiation of medical ketamine, as well as had an enhanced awareness of these outcomes and experiences. Unless specified in the qualitative responses, it was unclear whether the change occurred following the initiation of the medical ketamine, or long before the treatment and ketamine was helping with maintenance due to continued well-being. Together, for some individuals, ketamine may lead to positive outcomes related to other substance use, or a supporting treatment to maintain positive outcomes related to problematic substance use while treating comorbid poor mental health or pain.
The group of participants reporting present problematic substance use was the smallest, and caution should be applied with the interpretation of the findings. Participants in this group had lower mean ratings of change in substance use compared to participants who reported past problematic use, and did not differ in ratings of change compared to the group of participants reporting no history of problematic substance use (although the subjective experiences were different). While there were no reports of reduced use due to reduced need to cope with poor mental health or pain, as in the other two groups, some participants reported general reductions in use and craving, experiences of insight into the self, and increased motivation to change (e.g., quit smoking). Additionally, the present problematic substance use group had the highest percentage of participants (50.0%) using other psychedelics after the initiation of ketamine treatment. This population with the complexity of comorbid problematic substance use appears to experience only slight changes in other substance use, however, may further legitimize/increase use of other psychedelic substances. This group of patients may need additional support and monitoring. The literature suggests that adjunct psychotherapy might enhance and/or prolong ketamine effects in general (Drozdz et al., 2022), and in treating alcohol use disorder specifically (Grabski et al., 2022). Grabski et al. (2022) investigated the ketamine-psychotherapy interaction utilizing a four-arm design (ketamine/placebo with psychotherapy/alcohol education). While the ketamine with psychotherapy group showed the greatest mean percentage of days of alcohol abstinence, the results were not statistically significant. In our sample, although most of the participants with present problematic substance use reported engaging in some type of psychotherapy, almost a third reported they did not, which may be a possible explanation for the modest mean magnitude of change in this group. Nevertheless, our findings suggest that ketamine appears to not increase the use of most other substances for many participants, however, for some, may increase perceived safety and/or use of other psychedelics. Still, more targeted research with a larger sample is needed to fully understand whether psychotherapy is needed to optimize and/or prolong the ketamine therapeutic effect among patients with comorbid SUD.
Participants who reported no history of problematic substance use reported reducing or stopping use of other medications (e.g., opioids), reducing substance use intentionally (e.g., to avoid problems), or experiencing reduced craving and tolerability for substances. Similar to the group of past problematic substance use, some participants reported reductions in use because there was no longer a need to cope with poor mental health or pain. These participants perceived a beneficial effect of the treatment on other substance use, even if they did not perceive (or report) their substance use as problematic. Some reported low or no substance use even before initiating ketamine, suggesting that therapeutic ketamine may not increase risk of initiating, using, or misusing other substances overall for this sample. These findings align with and add to past research (Phillips et al., 2019, Wan et al., 2014) investigating the antidepressant effect of ketamine among patients who reported no history of drug use (Phillips et al., 2019), or current substance use or dependence (Wan et al., 2014). These studies reported no incidents of increased craving or drug-seeking behaviors during or in follow-up assessments (among those participants who could be reached at follow-up). Our findings extend this research to real-world patients with different comorbidities and health conditions, across different providers and clinics that utilize different treatment protocols.
Although medical ketamine appeared to be overall beneficial to most participants in our sample (regarding other substance use), a few alarming comments warrant more research on the scope and consequences of such experiences. First, five participants who reported increases in substance use also reported current worsened mental health because ketamine either did not help or was not accessible at that time. These experiences raise important issues of insurance coverage and accessibility, as well as patient education. Ketamine, like other treatments, might not be effective for all, and other alternatives should be discussed and expectations managed. Second, two comments suggested ketamine may lead to openness to using psychedelic drugs purchased from nonmedical sources (which aligns with 18.9% of the participants reporting using other psychedelics after the initiation of ketamine treatment), or ketamine used as a substitute for other recreational substances, implying an exaggerated sense of safety with psychoactive substances and/or legitimizing substance use. Together, these comments highlight alarming issues warranting additional research to inform regulation efforts on risks and safety, patient and provider education, patient monitoring, and insurance coverage.
Combining the quantitative and qualitative results highlighted important considerations relevant to community ketamine practitioners. Some patients may not acknowledge that their substance use is harmful or problematic. For example, some participants in our sample who self-reported no history of problematic substance use also reported they had used substances to cope with poor mental health or pain. Given that coping motives are associated with substance use problems (e.g., Bresin & Mekawi, 2020), even patients who do not perceive their substance use as problematic, may be at some risk. Others may think their regular substance use is not relevant or maybe even contraindicative to the treatment. In our sample, only 2.5% of the participants explicitly indicated being treated for SUD, however, another 32.3% indicated having a current or past history of problematic substance use. Together, patients may not inform their providers about their substance use, unless they are explicitly asked or assessed for severity of use. Moreover, for some participants, ketamine led to a change in attitude such as reducing feelings of guilt and self-blame that are related to substance use or increased social use. Especially because the treatment could be long-term for many, it is important to educate and monitor all patients so that any substance use that exists or develops remains unharmful. Lastly, clinicians should be aware that the patient’s perception of a change as positive or negative may not be sufficient to assess the risk of misusing ketamine or other substances. Such is the case in our sample of a female participant who rated her change as slight positive and desirable, however reported that ketamine was a favorable substitute for alcohol in recreational contexts. Taken together, ketamine practitioners should thoroughly evaluate substance use-related comorbidities and behaviors, continuously monitor nonmedical substance use with patients in short and long-term treatment, and prioritize patient education in all stages.
The present study has several limitations. First, this study is a secondary analysis of a small pilot study that used self-rated measures of problematic substance use and perceptions of change in substance use collected with an open-ended question embedded in the survey (rather than in-depth interviews). As this was not the main aim of the parent study, to minimize participant burden, we did not assess present SUD or change in substance use with validated measures of SUD diagnosis, or severity of nonmedical substance use (i.e., frequency and quantity) pre-ketamine and current. Although the single open-ended qualitative question provides initial evidence to further investigate, the understanding of the experiences within and across the different groups was not exhausted. For example, the group of participants who self-identified as having past problematic substance use probably included individuals who had SUDs in the past and recovered before the initiation of the ketamine treatment, as well as those who feel their recovery is related to the treatment. Targeted research should aim to distinguish between these two populations, as each may have further unique experiences, needs, and clinical considerations. Nevertheless, combining the quantitative rating of change and qualitative experiences strengthened the findings and highlighted important issues. Future research should extend this investigation to collect data with validated quantitative and qualitative tools, for example, applying the DSM-5 SUD symptom checklist and conducting in-depth interviews.
Second, our findings cannot be generalized. Our participants were not monetarily compensated. The self-selected sample may be biased by including mostly individuals who experienced positive effects from the treatment and who are interested in helping advance the science, practice, and regulation efforts. Additionally, our sample was small, mostly white and educated. All these prevent the generalization of the findings to other populations. As off-label ketamine is currently not covered by insurance plans, most patients in real-world clinical centers are individuals who can afford the expensive out-of-pocket treatment. Therefore, more research with diverse populations in more or less medically supervised settings (e.g., clinics, telehealth) is needed to better characterize the different groups of patients (or different sources of recruitment e.g., clinics/social media), before generalizations can be made. Lastly, our sample of ketamine patients with present problematic substance use was relatively small. More systematic and targeted research with larger and more diverse samples is needed (especially with the heterogeneity of ketamine treatment protocols across clinics and web-based providers) to investigate different groups of patients with or without SUDs, as well as other possible predictors (e.g., polysubstance use, other comorbidities) as different experiences, considerations, and needs emerged in our sample for the different subgroups.
In conclusion, although understudied, many individuals who use or misuse substances currently or did so in the past, are being treated with medical ketamine in real-world clinics. For many in our sample, the treatment appeared to indirectly lead to beneficial outcomes in nonmedical use of other substances (e.g., reductions). Additionally, among participants who did not use or misuse other substances, medical ketamine appeared to not induce drug-seeking behaviors. Nevertheless, for some, the treatment may lead to using other psychedelic drugs, or even using ketamine recreationally or substituting for other substances. More research (quantitative and qualitative) is needed to fully understand the relationship between medical ketamine and other substance use and better characterize patients at risk of increased nonmedical substance use. Such data will help inform patient and provider education, regulation efforts, coverage, standardization of screening, and individualized treatment protocols to enhance safety and access to effective healthcare for all patients who may benefit from medical ketamine.
Public Significance Statement.
Medical ketamine appeared to reduce other substance use for most real-world patients in our sample, including those with past or present problematic use, and not induce/increase use among patients reporting no/low substance use. However, several participants reported risky behaviors such as using ketamine as a substitute for alcohol. This initial analysis calls for larger studies to characterize patients at risk to inform regulation efforts and enhance safety in clinical practice.
Acknowledgments
SA and MSB would like to thank the Source Research Foundation for supporting this research. This research was also supported in part by the National Institute on Drug Abuse (NIDA) grant R21DA056813 (MSB). MSB gratefully acknowledges that her time was also supported in part by NIDA grant K01DA052673. All authors contributed in a significant way to the manuscript and all authors have read and approved the final manuscript. SA, MRP, DSV, ANO, JC, and MSB have no conflict of interest to report. MW is the founder and medical director of NeuroPain Health. This study was not preregistered. ANO is now at Oregon State University, Department of Psychological Science. The authors would like to thank the Ketamine Taskforce (https://www.ketaminetaskforce.org/) for advertising the parent study.
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