Entactogen Effects of Ketamine: A Reverse-Translational Study

Abstract

Objective: The authors sought to assess the prosocial, entactogen effects of ketamine.

Methods: Pleasure from social situations was assessed in a sample of participants with treatment-resistant depression from randomized, double-blind, placebo-controlled studies, using four items of the Snaith-Hamilton Pleasure Scale (SHAPS) at five time points over 1 week following treatment with ketamine (0.5 mg/kg intravenously) or placebo. The primary endpoint was postinfusion self-reported pleasure on the four SHAPS items pertaining to social situations, including the item on helping others, between the ketamine and placebo groups. In a rodent experiment, the impact of ketamine on helping behavior in rats was assessed using the harm aversion task. The primary endpoint was a reduction in lever response rate relative to baseline, which indicated the willingness of rats to forgo obtaining sucrose to help protect their cage mate from electric shock.

Results: Relative to placebo, ketamine increased ratings of feeling pleasure from being with family or close friends, seeing other people's smiling faces, helping others, and receiving praise, for 1 week following treatment. In the rodent experiment, during the harm aversion task, ketamine-treated rats maintained lower response rates relative to baseline to a greater extent than what was observed in vehicle-treated rats for 6 days posttreatment and delivered fewer shocks overall.

Conclusions: In patients with treatment-resistant depression, ketamine treatment was associated with increased pleasure from social situations, such as feeling pleasure from helping others. Ketamine-treated rats were more likely to protect their cage mate from harm, at the cost of obtaining sucrose. These findings suggest that ketamine has entactogen effects.

Keywords: Antidepressants; Depressive Disorders; Entactogens; Ketamine/Esketamine.

FIGURE 1.. Patients with treatment resistant depression (TRD) have an increased probability of self-reporting feeling pleasure from social interaction following single dose ketamine treatment ^a

^a Panels A-D illustrate the distribution of responses made by patients with treatment resistant depression (TRD), proportional to the total number of responses for each treatment group, on four items of the Snaith-Hamilton pleasure scale (SHAPS). Each plot is the cumulative distribution of responses across five different time points post-treatment (230 minutes, 1 day, 2 days, 3 days, 7 days). Each item has four responses (strongly agree, agree, disagree, and strongly disagree) which indicate the degree of pleasure or enjoyment the patient would feel in each of the social scenarios. This study utilized a cross-over design with each patient receiving both placebo (saline) and ketamine (0.5 mg/kg/i.v. over 40 minutes). In panel A, patients were more likely report feeling pleasure from receiving praise from other people after ketamine treatment relative to placebo (log odds ratio=1.5; 95% CI=1.1–2.0; p<0.001). In panel B, patients were more likely to report enjoying seeing other people’s smiling faces following ketamine treatment relative to placebo (log odds ratio=1.2; 95% CI=0.79–1.6; p<0.001). In panel C, patients were more likely to report enjoying being with their family or close friends following ketamine treatment relative to placebo (log odds ratio=1.4; 95% CI=0.97–1.7; p<0.001). In panel D, patients were more likely to report feeling pleasure from helping others following ketamine treatment relative to placebo (log odds ratio=1.2; 95% CI=0.79–1.6; p<0.001).

FIGURE 2.. Harm aversion task (HAT) workflow ^a

^a Panel A illustrates the experimental workflow for the harm aversion task (HAT). Panels B and C illustrate the operant chamber design and outcomes associated with a failed and successful HAT trail, respectively (Created with Biorender.com). The central plexiglass divider was clear with small perforations at the bottom to allow the rats to smell and hear each other. The observer rat’s chamber on the right side was equipped with a retractable lever with a cue light and a centrally located sucrose delivery tray. In panel B, a failed HAT trial resulted from the observer pressing the lever which immediately delivered a shock to the demonstrator followed by a sucrose pellet being delivered to the tray. A successful HAT trial resulted from the observer omitting a lever response, thus ensuring the safety of the demonstrator at the cost of the sucrose pellet being withheld.

FIGURE 3.. Lever response training among observer rats was consistent prior to treatment ^a

^a In panel A, lever response rate during observer rats’ lever training to obtain sucrose pellets consistently increased across sessions independent of sex or their eventual treatment pairing (sex, p=0.2868; treatment, p=0.8156; session, p<0.0001; F_{session×treatment}=0.2974, df=2, 100, p=0.7434). In panel B, latency to press the lever (response latency) during rats’ lever training consistently decreased across sessions independent of sex or their eventual treatment pairing (sex, p=0.8892; treatment, p=0.7706; session, p<0.0001; F_{session×treatment}=0.6021, df=2, 99, p=0.5496). In panel C, the total number of rewards earned during lever training was not significantly different among eventual treatment pairing groups, but male rats earned more rewards relative to females overall (sex, p=0.0411, mean difference=14.89; treatment, p=0.2743; F_{sex×treatment}=0.7730, df=1, 50, p=0.3835). In panel D, the total amount of tray activity during lever training did not differ significantly across eventual treatment groups or sex (sex, p=0.1687; treatment, p=0.2640; F_{sex×treatment}=0.3356, df=1, 50, p=0.5650). These data demonstrate rats’ rapidly associate lever presses with reward delivery. Three-way analysis of variance with Dunnett’s post hoc test for panel A and a mixed-effects analysis with Dunnett’s post hoc test for panel B, ****p<0.0001 effect of session relative to session 1. Two-way analysis of variance for panels C and D, *p<0.05 effect of sex.

FIGURE 4.. A single dose of ketamine reduces response rate during the harm aversion task (HAT)^a

^a Panel A illustrates lever response rate of the observer rats during a baseline session, in which lever presses delivered a sucrose pellet, and during the harm aversion task (HAT), in which lever presses delivered a shock to the demonstrator rat in addition to delivering a sucrose pellet to the observer rat. Independent of sex, rats treated with saline after HAT session 1 maintained response rates significantly lower than baseline during HAT sessions 2–4 whereas rats treated with ketamine (10 mg/kg/s.c.) after HAT session 1 maintained response rates significantly lower than baseline during HAT sessions 2–7. Within HAT session 3 specifically, ketamine treated rats had significantly lower response rates relative to saline treated rats (sex, p=0.0637; treatment, p=0.0290; session, p<0.0001; F_{treatment×session}=2.711, df=7, 350, p=0.0095; F_{treatment×sex}=2.519e⁻⁵, df=1, 50, p=0.9960; F_sex×session=1.334, df=7, 350, p=0.2329). In panel B, total shocks delivered during HAT sessions 2–7 (post-treatment sessions) were significantly lower in rats treated with ketamine relative to rats treated with saline. Three-way analysis of variance with Dunnett’s post hoc test for panel A, ^#p<0.05, ^###p<0.001, ^####p<0.0001 effect of session within treatment compared to baseline; *p<0.05 effect of treatment within session. Two-tailed, unpaired t-test for panel B, *p<0.05.

FIGURE 5.. Ketamine increases the likelihood of rats omitting responding and entering the reward tray during the harm aversion task (HAT) ^a

^a In panel A, latency to press the lever (response latency) during harm aversion task (HAT) sessions 1–7 was significantly increased independent of sex and treatment relative to baseline (sex, p=0.6876; treatment, p=0.2753; session, p<0.0001; F_{treatment×session}=0.4890, df=7, 322, p=0.8425; F_{treatment×sex}=0.6645, df=1, 50, p=0.4188; F_sex×session=0.5953, df=7, 322, p=0.7910). Panel B illustrates how rats treated with ketamine were more likely to omit pressing the lever during a HAT session relative to saline treated rats (relative risk=1.106; p=0.0030; 95% CI=1.037–1.193). In panel C, latency to enter the reward tray (tray entry latency) was significantly increased relative to baseline on HAT session 1 in both saline and ketamine treated rats. Saline treated rats maintained heightened tray entry latency relative to baseline during HAT session 2 whereas ketamine treated rats maintained heightened tray entry latency relative to baseline during HAT session 3 (sex, p=0.4386; treatment, p=0.0337; session, p<0.0001; F_{treatment×session}=1.548, df=7, 321, p=0.1502; F_{treatment×sex}=0.0579, df=1, 50, p=0.8108; F_sex×session=0.6677, df=7, 321, p=0.6994). Panel D illustrates how rats treated with ketamine were more likely to omit entering the tray during a HAT session relative to saline treated rats (relative risk=1.114; p=0.0029; 95% CI=1.044–1.203). Three-way analysis of variance with Dunnett’s post hoc test for panels A and C, ^#p<0.05, ^###p<0.001, ^####p<0.0001 effect of session compared to baseline (session within treatment for panel C). Two-sided Fisher’s exact test for panels B and D, *p<0.05.