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Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation - where stored memories become briefly labile upon retrieval - may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval + ketamine (RET + KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical ‘reconsolidation window’ predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptive memory and should be further pursued in alcohol and drug use disorders. Memories linking environmental cues to alcohol reward are involved in the development and maintenance of heavy drinking. Here, the authors show that a single dose of ketamine, given after retrieval of alcohol-reward memories, disrupts the reconsolidation of these memories and reduces drinking in humans.
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Ketamine can reduce harmful drinking by
pharmacologically rewriting drinking memories
Ravi K. Das 1*, Grace Gale1, Katie Walsh1, Vanessa E. Hennessy1, Georges Iskandar 2, Luke A. Mordecai3,
Brigitta Brandner3, Merel Kindt4, H. Valerie Curran1& Sunjeev K. Kamboj1
Maladaptive reward memories (MRMs) are involved in the development and maintenance of
acquired overconsumption disorders, such as harmful alcohol and drug use. The process of
memory reconsolidation - where stored memories become briey labile upon retrieval - may
offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharma-
cologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-
methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous
drinkers when administered immediately after their retrieval. MRM retrieval +ketamine
(RET +KET) effectively reduced the reinforcing effects of alcohol and long-term drinking
levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its
metabolites during the critical reconsolidation windowpredicted benecial changes only
following MRM reactivation. Pharmacological reconsolidation interference may provide a
means to rapidly rewrite maladaptive memory and should be further pursued in alcohol and
drug use disorders. OPEN
1Clinical Psychopharmacology Unit, University College London, London, UK. 2University College Hospital and University College Hospital at Westmoreland
Street, London, UK. 3Pain Management Centre, University College Hospital, London, UK. 4Experimental Clinical Psychology, University of Amsterdam,
Amsterdam, The Netherlands. *email:
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Overconsumption disorders such as harmful drinking,
alcohol and substance use disorders (AUDs, SUDs),
which represent leading causes of global preventable
mortality and morbidity, are fundamentally acquired or learned
behaviours1. Contemporary neuroscientic models posit that the
adaptive reward learning processes that control motivated beha-
vior can be usurped by addictive drugs2forging harmful drug-use
behaviors that are encoded by maladaptive reward memories
(MRMs)3. These MRMs are learned associations that encode the
contingencies between drug-predictive environmental stimuli
(e.g. the smell and taste of beer) and drug reward4. MRMs
underlie the tendency of environmental trigger cues and contexts
to grab attention and provoke motivated behavioral routines
including craving5, drug-seeking and excessive consumption.
They are thus a core mechanism underlying alcohol over-
consumption and long-term relapsing behavior that must be
unlearnedfor curative amelioration of problematic drinking.
However, effective, targeted memory rewriting currently
represents an unmet clinical challenge. Critically, once stabilized-
or consolidated - into long-term memory storage, MRMs were
thought to become long-lasting and essentially immutable, pro-
moting rebound/ relapse even long after successful reduction or
detoxication and abstinence6. Current treatments such as
cognitive-behavioral or cue exposure therapy do not involve
unlearning of MRMs7, but rather, suppression by alternative
learning. The continued latent existence of MRMs limits the long-
term efcacy of these interventions and underlies the high relapse
rates that typify AUD/SUDs8,9.
Recent insights into long-term memory persistence and mal-
leability may hold the key to directly rewriting maladaptive
memories. Reconsolidation is a memory maintenance process
whereby reactivated long-term memories temporarily destabilize
in order to incorporate newly available information, and hence
update their contents10. Preclinical research has shown
that memory destabilization requires the right retrieval condi-
tions. These are typically brief, cue-driven retrievals that incor-
porate novel information or prediction error11 regarding
outcomes. Once destabilized, memories rely upon an N-Methyl D-
Aspartate Receptor (NMDAR) mediatedMAPK/ERKprotein
synthesis cascade to reorganize the synaptic architecture encoding
memory traces and restabilize or reconsolidate memories in their
new form. By pharmacologically intervening with reconsolida-
tion, it is theoretically possible to selectively target and weaken
memories12,13. The temporary reconsolidation window of mem-
ory instability following reactivation therefore offers a unique and
novel mechanism to directly rewrite MRMs and strip them of
their relapsogenic potential at the source14.
Reliable pharmacological MRM rewriting remains elusive,
however, due to the relative difculty in reactivating/destabiliz-
ing inherently robust MRMs in human drug users and the
severely limited menu of well-tolerated reconsolidation block-
ers15. Indeed, most preclinical studies of reconsolidation involve
experimentally generated modelsof MRMs that are orders of
magnitude weaker than true human MRMs, and also employ
highly toxic compounds (with highly limited human translat-
ability) to block reconsolidation16. Thus, despite the great the-
oretical potential of reconsolidation as a therapeutic target and
promising emergent research17, in the absence of a gold standard
reconsolidation blocker, the translational feasibility and scope of
pharmacological memory rewriting remains relatively untested.
Ketamine is a dissociative anesthetic that may have unique
potential in this regard, since it is a high-afnity non-competitive
NMDAR antagonist that is relatively well tolerated and safe in
humans. Ketamine is currently experiencing a renaissance in
neuroscience and psychiatry due to its rapid and novel anti-
depressive action18. Further it has previously been used to
successfully treat alcoholism19 and heroin addiction, via unex-
plored, but not explicitly reconsolidation-based mechanisms20.It
thus carries potential therapeutic utility for addictive disorders in
its own right. Importantly, these antidepressant and anti-addictive
actions may not be independent, since depression and SUDs are
highly co-morbid21 and concomitant improvements in response to
an anti-depressant intervention may be seen to the extent that the
former is driving the latter. We therefore assessed for the rst time
whether intravenous ketamine during the reconsolidation win-
dowwould interfere with the reconsolidation of robust alcohol-
MRMs in harmful drinkers by blocking NMDAR activity. To
differentiate reconsolidation-dependent from non-specic affective
(e.g. anti-depressive) therapeutic mechanisms, ketamine was
administered following the retrieval/destabilization of maladaptive
alcohol memories (retrieval +ketamine; RET +KET) or control
(non-drinking) memories (No RET +KET), with placebo (saline;
PBO) controlling for the effects of MRM retrieval per se (RET +
PBO). We further assessed plasma ketamine and its metabolites
during the critical reconsolidation windowas potential predictive
biomarkers of response to the memory-rewriting manipulation.
In RET +KET, we hypothesized that ketamine would weaken
MRMs via reconsolidation interference, reducing the motiva-
tional effects of alcohol (alcohol/ cue reactivity) and drinking
levels in hazardous/harmful drinkers. These changes should be
negatively associated with levels of blood biomarkers of ketamine
metabolism during the critical reconsolidation window, indicative
of a reconsolidation-interference mechanism. We also predicted
(smaller magnitude) improvement in these measures in No
RET +KET, given the antidepressant and potential anti-AUD
properties of ketamine alone, but that these would not be related
to ketamine metabolite biomarkers following the memory
retrieval and drug manipulation. No improvement was expected
from MRM reactivation alone (RET +PBO). This three group
design allowed us to differentiate competing mechanistic inter-
pretations. If any effects of ketamine were purely due to anti-
depressive effects and independent of memory reconsolidation,
the retrieval manipulation should be inconsequential and no
differential improvement trajectory should be observed between
RET +KET and No RET +KET. We thus assessed reconsolida-
tion as a novel potential therapeutic mechanism and a means for
catalyzing the efcacy of ketamine in problematic drinking.
Here we report that MRM retrieval +ketamine produces a
rapid reduction in the reinforcing and motivational properties of
alcohol and substantial, lasting reductions in drinking levels
compared to retrieval or ketamine alone. Plasma levels of keta-
mine and its metabolites are predictive of these benecial effects
only following MRM retrieval. These ndings demonstrate MRM
reconsolidation interference by ketamine and rewriting of reward
structures surrounding alcohol. The subsequent, lasting clinical
benets observed suggest that this one-session intervention
approach should be pursued in the future treatment of alcohol
related disorders.
Sample characteristics. All in-text descriptive statistics repre-
(age 27.5 ± 8.1 yrs). Despite lacking formal diagnoses of AUD
nor seeking treatment, they had particularly high drinking
levels (74.09 ± 37.92 UK units (8 g alcohol)/week) and AUDIT
scores (22.13 ± 4.93), denoting physically harmful drinking and
moderate-high risk of developing AUD. Participant character-
istics for relevant variables are given in Table 1.
Reactivity to alcohol. Time (Day 1 vs. Day 10) × Group ANOVA
found signicant Time x Group interactions for urge to drink
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ratings [F(2, 87) 6.489, p0.007, n
20.1] (Fig. 1c, d and
Supplementary Note 1), indicating signicant reductions in
RET +KET in urge to drink a beer placed in front of them
[F(1,87) =19.703, p< 0.001, n
2=0.185] and post-consumption
urge to drink more of the beer [F(1,87) =24.46, p< .001, n
0.219] with no signicant reduction in the control groups [Fs <
0.5, ps > 0.48]. Pre-drink anticipated enjoyment of beer also
reduced in RET +KET [F(1,87) =20.273, p< .001, n
as did post-consumption actual enjoyment [F(1,87) =8.67, p=
0.004, n
2=0.091]. Enjoyment did not change in the control
groups [Time × Group interactions F(2,87) =8.234, p=0.001,
2=0.159 and F(2, 87) =3.298, p=0.042, n
2=0.07, respec-
tively] (Fig. 1a, b; Full detail and alcohol picture cue reactivity in
Supplementary Note 1).
Drinking behavior. Subjective impressions of drinking changes
showed signicant Group effects for volume of drinking [F(2,87) =
3.164, p=0.047, η2=0.07], enjoyment of drinking [F(2, 87) =
3.929, p=0.028, η2=0.08] and general urge to drink [F(2,87) =
5.071, p=0.008, η2=0.1]. In all cases, this was driven by sig-
nicantly greater reductions in RET +KET than the other two
groups [independent samples ts >2.36,p<0.05,r> 0.29 (individual
tests in Supplementary Note 1)].
Linear mixed models on TLFB-rated number of drinking days/
week corroborated these ratings, with signicant reductions in
RET +KET [F(1,89.449) =10.986, p=0.001, n
2=0.084], and
no signicant reduction in the control groups [Group × Time
F(2,89.85) =3.802, p=0.026] (Fig. 2a). As participants may
compensate for more days abstinent by drinking more/bingeing
on drinking days, we assessed changes in total alcohol consump-
tion and bingeing.
The RET +KET group showed highly signicant reductions in
general alcohol consumption (beer, wine or spirits) from baseline
to post manipulation [F(1,89.17) =19.55, p< 0.001, n
equivalent to a reduction of 23.5 UK units/188 g ethanol over a
Table 1 Levels of drinking-related and demographic variables at baseline, with inferential tests
RET +PBO RET +KET No RET +KET Total Statistic p FDR α
Age 27.7 ± 8.33 26.5 ± 6.25 28.23 ± 9.57 27.48 ± 8.11 0.354 0.703 0.036
Gender (N F/M) 9 11 15 35 χ2
=0.27 0.319 0.022
N smokers 18 19 19 56 χ2
=0.095 0.954 0.047
AUDIT C 9.1 ± 1.03 9.2 ± 1.03 8.9 ± 1.18 9.07 ± 1.08 0.596 0.553 0.028
AUDIT total 22.17 ± 4.86 23.77 ± 5.15 20.47 ± 4.33 22.13 ± 4.93 3.559 0.033 0.003
SCID 0.93 ± 0.83 1.1 ± 0.92 0.77 ± 0.57 0.93 ± 0.79 1.344 0.266 0.019
Motivation to reduce 3.17 ± 0.59 3.13 ± 0.35 3.17 ± 0.38 3.16 ± 0.45 0.054 0.947 0.046
OCDS obsession 6.6 ± 3.31 6.57 ± 3.38 5.53 ± 3.45 6.23 ± 3.38 0.966 0.385 0.024
OCDS compulsion 11 ± 2.24 10.47 ± 2.66 10.93 ± 2.89 10.8 ± 2.59 0.371 0.691 0.033
OCDS total 17.6 ± 5.13 17.03 ± 5.52 16.47 ± 5.91 17.03 ± 5.49 0.315 0.731 0.038
TLFB total units (last
14 days)
135.2 ± 60.17 164.05 ± 86.82 130.04 ± 57.06 143.1 ± 70.16 2.098 0.129 0.008
TLFB daily units (last
14 days)
9.74 ± 4.28 11.76 ± 6.22 9.29 ± 4.08 10.26 ± 5.01 2.11 0.127 0.006
TLFB total units (last 7 days) 69.35 ± 32.21 86.73 ± 45.75 66.19 ± 32.08 74.09 ± 37.92 2.645 0.077 0.005
N drinking days (last
14 days)
11.07 ± 2.72 11.07 ± 2.78 11.2 ± 2.44 11.11 ± 2.62 0.025 0.975 0.050
N drinking days (last 7 days) 5.6 ± 1.33 5.63 ± 1.27 5.7 ± 1.47 5.64 ± 1.34 0.042 0.959 0.049
N binge days (last 14 days) 3.3 ± 3.31 4.73 ± 3.65 2.83 ± 2.32 3.62 ± 3.21 2.974 0.056 0.004
N binge days (last 7 days) 1.83 ± 1.79 2.6 ± 1.87 1.4 ± 1.35 1.94 ± 1.74 3.983 0.022 0.001
SOCRATES Recognition 24.87 ± 3.14 23.83 ± 3.42 23.33 ± 4.21 24.01 ± 3.64 1.4 0.252 0.017
SOCRATES Ambivalence 11.3 ± 2.9 10.97 ± 3.79 9.9 ± 3.45 10.72 ± 3.42 1.388 0.255 0.018
SOCRATES taking steps 21.77 ± 4.04 21.33 ± 4.04 20.87 ± 4.52 21.32 ± 4.18 0.343 0.71 0.037
BAS drive 11.1 ± 2.71 11.53 ± 2.98 10.57 ± 2.45 11.07 ± 2.72 0.951 0.39 0.027
BAS fun 13.27 ± 2.75 14.33 ± 1.6 13.77 ± 1.72 13.79 ± 2.11 1.957 0.147 0.009
BAS reward 16.63 ± 1.65 16.53 ± 2.62 16.3 ± 1.88 16.49 ± 2.07 0.201 0.819 0.041
BIS 20.87 ± 2.69 19.57 ± 2.81 19.97 ± 2.57 20.13 ± 2.72 1.837 0.165 0.013
BDI 15.47 ± 9.69 14.03 ± 8.58 11.3 ± 8.7 13.6 ± 9.07 1.657 0.197 0.014
CEOA sociability 25.77 ± 3.43 26.3 ± 4.16 24.43 ± 3.82 25.5 ± 3.86 1.904 0.155 0.012
CEOA tension reduction 7.3 ± 2.28 6.57 ± 1.81 7.03 ± 2.11 6.97 ± 2.07 0.96 0.387 0.026
CEOA liquid courage 12.93 ± 2.48 12.63 ± 2.98 12.23 ± 3.08 12.6 ± 2.84 0.453 0.637 0.031
CEOA sexuality 9.07 ± 2.8 8.3 ± 2.67 8.07 ± 2.43 8.48 ± 2.65 1.179 0.313 0.021
CEOA impairment 20.97 ± 5.24 21.3 ± 5.49 20.7 ± 3.98 20.99 ± 4.9 0.111 0.895 0.044
CEOA Risk/aggression 11.27 ± 3.04 12.03 ± 3.74 11.43 ± 3.46 11.58 ± 3.4 0.416 0.661 0.032
CEOA self perception 7.17 ± 2.37 6.77 ± 2.92 6 ± 2.23 6.64 ± 2.54 1.657 0.197 0.015
DTS TOLERANCE 2.92 ± 0.88 3.02 ± 1.01 2.93 ± 1.08 2.96 ± 0.98 0.091 0.913 0.045
DTS ABSORBANCE 2.79 ± 1.08 3.01 ± 1.12 2.92 ± 1.31 2.91 ± 1.16 0.273 0.762 0.040
DTS APPRAISAL 3.12 ± 0.96 3.55 ± 0.83 3.13 ± 1.09 3.27 ± 0.97 1.944 0.149 0.010
DTS REGULATION 3.1 ± 1.02 2.7 ± 1.08 2.88 ± 1.02 2.89 ± 1.04 1.115 0.332 0.023
DTS TOTAL 2.98 ± 0.81 3.07 ± 0.84 2.97 ± 0.98 3.01 ± 0.87 0.122 0.885 0.042
PANAS +VE 32.07 ± 7.91 33.47 ± 7.25 31.93 ± 8.11 32.49 ± 7.71 0.359 0.699 0.035
PANAS VE 20.9 ± 6.38 21.1 ± 7.44 19.47 ± 6.91 20.49 ± 6.88 0.497 0.61 0.029
For continuous measures, the statistics given are mean ±SD, along with corresponding Fvalues (DF 2, 87). For binary measures, Ns are given along with chi-square degrees of freedom and test values
(denoted by χ2). RET=Retrieval, KET=Ketamine, PBO=Placebo. FDR α=False Discovery Rate alpha, calculated according to Benjamini and Hochberg36.P-values represent One-way ANOVA on
group differences. Signicant uncorrected p-values at p< 0.05 are highlighted in bold. Only p-values lower than the associated FDR αare signicant at FDR- corrected p< 0.05. The groups did not differ
on any baseline variables according to FDR criteria
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week. A signicant, although smaller, reduction was also seen in
the No RET +KET group [F(1,89.17) =6.527, p=0.012, n
0.052], equivalent to a reduction of 13.6 UK units/109 g ethanol.
No signicant reduction in alcohol consumption was observed in
RET +PBO [F(1,89.95) =0.726 p=0.396, n
2=0.006]; 4.9 UK
units/39 g ethanol (Fig. 2b). The Group × Time interaction was
marginally signicant [F(2,89.432 =3.123, p=0.049]. When
achieved ketamine plasma concentration was taken into account
(see Table 2, and predictive biomarkerssection below) this
interaction was further strengthened.
RET +KET also showed a highly signicant reduction in
binges (>6 drinks/week from baseline to post manipulation
[F(1,88.953) =15.821, p<0.001, n
2=0.116], with no signicant
reductions in the control groups (ps.22, n
20.014: trend-level
Group × Time interaction F(2,89.324) =2.682, p=0.074]. Thus
the RET +KET group were not compensating for reduced
drinking frequency with greater drinking density.
Long-term maintenance. Reversion to heavy drinking typies
drinking interventions. We assessed this by comparing drinking
levels post manipulation (Day 10) across follow-up to 9 months.
Due to response attrition and missing data at each follow-up time
point, linear mixed models were used to analyze follow-up data
owing to better handling of missing data. Intercepts and slopes
for Time (post manipulation, 2 week, 3, 6, 9 months) were
modelled as random effects with an unstructured covariance
matrix, due to improved t over a xed Time effect model
(Δ2LL =χ2(2) =11.87, p=0.002). Group was included as a
xed effect and baseline alcohol unit consumption as a covariate.
This revealed further reductions in weekly alcohol consumption
in all groups [Time main effect: F(1,81.684) =12.677, p=0.001],
with no evidence of rebound to baseline levels (Fig. 2c), no further
signicant Group × Time effect was observed [F(2, 81.54) =
0.091, p=0.913], indicating that the differential drinking
reduction observed in RET +KET occurred rapidly following
manipulation (by Day 10), with subsequent uniform reduction in
all groups; consistent with a reconsolidation blockade effect. By
9 months, RET +KET had halved their average weekly con-
sumption from ~84 to ~41 UK units. Figure 3gives individual-
level unit drinking data and distribution across all time points as
pirate plots.
Predictive blood biomarkers of response. There is considerable
inter-individual variation in the metabolism of ketamine, parti-
cularly in heavy drinkers where glutamatergic homeostasis is
perturbed by chronic alcohol use. Table 2shows Spearman rank
correlations of post-infusion plasma ketamine levels and its
metabolites norketamine (NK) and dehydroxynorketamine
(dhNK) with primary outcomes. To the extent that reconsolida-
tion blockade was the mechanism responsible for the observed
reductions in drinking and that blood markers are a proxy for
central ketamine availability, achieved plasma ketamine &
metabolite levels during the reconsolidation windowshould
predict subsequent drinking in RET +KET, but not No RET +
KET. This is precisely what was observed, with moderate to large
negative associations between ketamine levels and subsequent
Anticipated enjoyment
Enjoyment of beer
Urge to drink beer
p < 0.001
Urge to drink more beer
p = 0.004
p < 0.001 p = 0.001
Fig. 1 Reductions in motivational and reinforcing properties of beer in RET +KET from Day 1 (baseline) to Day 10 (post manipulation). aAnticipated
enjoyment of beer. bPost consumption actual enjoyment, cUrge to drink beer, dPost consumption urge to drink more beer. In all cases, signicant
reductions were observed only in RET +KET. Boxes represent mean ± IQR, whiskers represent range. Dots are individual data points. Pvalues represent
Ftests on multivariate simple-effects of Time within. Source data are provided as a Source Data le
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drinking in RET +KET only. Intriguingly, the metabolites NK
and dhNK better predicted craving and overall AUDIT scores,
with dhNK uniquely predicting craving at 9 months.
Accounting for this variability in central ketamine concentra-
tions by including achieved plasma ketamine levels as a covariate
in the primary mixed-model analysis of unit alcohol consumption
explained further variance in drinking, strengthening the Group ×
Day interaction [F(2, 85.42) =3.719, p=0.037, η
This study found that intravenous ketamine following the brief
retrieval of maladaptive cue-alcohol memories produced a com-
prehensive reduction in the reinforcing effects of alcohol among
harmful drinkers. A rapid and lasting reduction in number of
drinking days per week and volume of alcohol consumed was
observed when ketamine followed MRM retrieval/destabilization,
with no rebound to baseline observed for at least 9 months
following manipulation. Control groups receiving retrieval or
ketamine alone did not show such changes in reward-related
responses to alcohol, although the latter group did show some
reduction in drinking.
This pattern of results is aligned with a therapeutic mechanism
grounded in reconsolidation interference. Successful interference
with the MRMs that putatively underlie excessive drinking should
theoretically allow rapid and lasting dampening of reward
responsivity to alcohol cues, reducing motivation to drink and
drinking levels. The reductions in drinking attributable to keta-
mine per se (i.e. without MRM retrieval) are aligned with pre-
vious research indicating a potential therapeutic effect of
ketamine in heavy drinking and addictive disorders, potentially
via modication of glutamatergic dysregulation or mTOR-
mediated downstream effects on neural plasticity20. Notably
however, the effect of ketamine alone was considerably smaller
than when combined with MRM retrieval. We therefore posit that
prior MRM reactivation can be a potential catalyst for ketamines
N drinking days
Baseline Post-manipulation
80 †† †† ††
1 month
3 months
6 months
9 months
p < 0.001
p < 0.001
p = 0.004
Time Baseline Post-manipulation
Alcohol consumption in UK units (8g EtOH)
Total UK units (8g EtOH) per week
Fig. 2 Changes in drinking outcomes. aReduction in number of drinking days from Day 1 (baseline) to Day 10 (post manipulation) in RET +KET only. Dots
are individual data points, boxes and lines represent mean ± IQR, whiskers represent range. bReductions in total alcohol consumption per week (UK units)
across the same period bars are mean ± SEM and dots individual data. cChanges in alcohol consumption across all measured time points. Data points and
bars represent mean/SD using all participant data available at each time point. Signicant reductions from baseline are denoted by for No RET +KET, *
for RET +KET and # for RET +PBO. One symbol =p<.05, two symbols =p< .01, three symbols =p< .001. In all panels, p-values are from F tests of
simple contrasts against baseline within-group. Individual data points for b,care given by group in Fig. 3. Source data are provided as a Source Data le
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efcacy in this scenario. Given the negligible additional time
investment, discomfort, or clinical burden required to incorporate
MRM reactivation, we recommend that this strategy is pursued to
develop ketamine-based pharmacotherapies for AUD. This may
further prove a fruitful approach in other disorders for which
ketamine is currently under investigation and where maladaptive
memory is implicated (e.g. depression and PTSD).
The moderate/large associations between blood ketamine and
ketamine metabolite levels during the critical reconsolidation
windowin RET +KET are noteworthy, as they represent a
potential biomarker for treatment response in a reconsolidation
paradigm. That these associations were only seen in the active
group strongly suggests that reconsolidation blockade was
responsible for the remedial effects of the manipulation. Without
prior destabilization of MRMs (No RET +KET), acute plasma
levels of ketamine, norketamine and dehydroxynorketamine were
relatively inconsequential to long term drinking levels. Since
responding appeared dose-dependent and given that ketamine is
relatively safe even at fully anesthetic doses, future studies may
wish to consider using higher doses of ketamine (up to full
anaesthesia) to maximize NMDAR saturation and subsequent
memory interference.
These results are the rst (to our knowledge) to demonstrate
that reconsolidation of naturally acquired maladaptive alcohol
memories in humans is dependent on NMDAR signaling, and
that weakening of alcohol MRMs can be achieved with ketamine
following MRM reactivation. The resultant, comprehensive
reductions in cue reactivity and meaningful, lasting reductions in
alcohol consumption outside of the lab after a single brief
manipulation are unprecedented in alcohol research. This speaks
to the potential scope of the reconsolidation-interference
approach. Current top-down(psychosocial) treatment mod-
alities that rely upon incremental learning of new, adaptive cog-
nitive and behavioral patterns to suppress MRMs typically require
prolonged treatment over multiple sessions. This presents issues
both in terms of therapist burden and service user disengagement
and recidivism.
The reconsolidation interference approach instead tackles this
issue from the bottom-up, theoretically allowing direct weakening
of pathogenic memory mechanisms and more rapid therapeutic
gains. This is not to say the two approached need be mutually
exclusive. Indeed the greatest treatment benets may be seen
through combination of an initial reconsolidation-based inter-
vention to weaken relapsogenic memories, followed by cognitive-
behavioral methods designed to instill more adaptive behaviors
and cognitions.
Despite these promising results, several key issues remain that
must be addressed through further study and renement of this
approach. Firstly, although ketamine is widely used and safe,
particularly at the sub-anesthetic concentrations used here, its
dissociative and psychotogenic properties and typical adminis-
tration route (IV) mean specialist supervision is required and that
it may be contraindicated for certain individuals with high schi-
zotypal or dissociative traits. Contemporary advances in drug
delivery technologies (e.g. intranasal) and the discovery of less
dissociative analogs, spurred by ketamines burgeoning use in
depression, may be critical in improving the tolerability and
acceptability of this approach in substance use disorders. Clearly,
the tolerability and potential harms from single-dose ketamine
(which we argue are minimal) must be weighed against the health
benets of reduced drinking. Drugs that act as antagonists/inhi-
bitors of other pathways implicated in reconsolidation, such as
noradrenergic antagonists may also hold promise for the weak-
ening of maladaptive memories22. Although these remain rela-
tively untested in the context of heavy drinking, meta-analysis
suggests that these may be less generally effective in weakening
reward memories than NMDAergic compounds16.
Relatedly, although we suggest, based on preclinical research,
that NMDAR antagonism is a likely potential mechanism
underlying the observed effects, we cannot say with certainty that
this is the only system involved in the current study. Ketamine
has several targets, including other classes of glutamate receptor
and opioid receptors which may have contributed to the observed
effects. Although the NMDAR is thought to be the primary
gatekeeperof memory reconsolidation23, non-NMDA receptors
may also represent potential therapeutic targets for reconsolida-
tion going forward.
A primary obstacle to the valid assessment of potential ther-
apeutic reconsolidation-blockers is the lack of standardization in
retrieval procedures designed to destabilize MRMs. Indeed,
inconsistency in retrieval procedures is the norm in the eld and
may explain the inconsistency in studies attempting to interfere
with memory reconsolidation17,2427. We have attempted to
address this issue through consistent use and detailed description
of our MRM destabilization protocol28. However although
effective, our procedure was not necessarily optimal. Indeed,
what constitutes optimalretrieval parameters for destabilization
of different memory types remains an empirical unknown that
must be identied to realize the full potential of reconsolidation
as a therapeutic strategy. Currently, when confronted with null
results, we are unable to infer whether a failure to block memory
reconsolidation, or a failure to destabilize memories a priori was
responsible. This is due to the fact that memory destabilization
and interference is currently a silentprocess, lacking a valid
biomarker. It must thus currently be inferred from successful
reductions in behavioral readoutsof MRM strength, as in the
Table 2 Spearmans rank correlations between ketamine metabolism and primary drinking outcomes post manipulation (Day 10)
and at nal follow-up (9 months) time-points
Drinking Days Units consumed Craving (ACQ) AUDIT Drinking Days Units consumed Craving (ACQ) AUDIT
N=28 N=19
RET Ketamine 0.465* 0.543** 0.257 0.175 0.261 0.449 0.149 0.44
+Norketamine .197 0.288 0.173 0.422* 0.29 0.481* 0.008 0.627**
KET dhNK 0.028 0.082 0.518** 0.457* 0.458* 0.436 0.572* 0.573**
N=29 N=21
No Ketamine 0.06 0.177 0.062 0.184 0.07 0.02 0.178 0.09
+Norketamine 0.015 0.119 0.109 0.096 0.022 0.01 0.122 0.01
KET dhNK 0.152 0.018 0.08 0.033 0.03 0.051 0.172 0.022
Signicant correlations are highlighted in bold
ACQ alcohol craving questionnaire, dhNK dehydroxynorketamine
*p< 0.05, **p< 0.01, ***p< 0.001
6NATURE COMMUNICATIONS | (2019)10:5187 | /s41467-019-13162-w |
Content courtesy of Springer Nature, terms of use apply. Rights reserved
Baseline Post-manipulation 1 month 3 months 6 months 9 months
Baseline Post-manipulation 1 month 3 months 6 months 9 months
Baseline Post-manipulation 1 month 3 months 6 months 9 months
Weekly UK units (8g EtOH)
Weekly UK units (8g EtOH)
Weekly UK units (8g EtOH)
Fig. 3 Individual-level total unit drinking data across all time-points. Top Panel =RET +PBO, Middle Panel =RET +KET, Bottom panel =No RET +KET.
Dots represent individual data points and the violinsthe relative kernel density across the entire range of values. Diamonds and whiskers represent mean
± SD of each time point. Source data are provided as a Source Data le
NATURE COMMUNICATIONS | (2019)10:5187 | 2-w | 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved
current study. Thus despite the convergent evidence supporting
this mechanism, we cannot say for certain that MRM weakening
produced the benecial effects observed here. Future research
must tackle this issue directly, with the aim of developing inde-
pendent biomarkers of memory destabilization. Having estab-
lished ketamine as a robust, dose-dependent reconsolidation
blocker in the current study marks a key step forward in
achieving this aim and bringing this therapeutic approach to the
The participants in the current study showed a clearly harmful
and problematic pattern of drinking, equivalent to that seen in
clinical AUD, but had not received a formal diagnosis of AUD
from a healthcare professional and were not treatment-seeking.
There is signicant variability in cut-point thresholds for diag-
nosing AUD from AUDIT scores in a UK drinking population.
According to Foxcroft et als29 ndings, based on mean AUDIT
scores many of the sample might be expected to meet criteria for
AUD. That the sample did not meet SCID criteria for severe
alcohol dependence at screening is therefore noteworthy. This is
because the sample scored very highly on measures of heaviness
of consumption and effects of bingeing (which contributed
greatly to AUDIT scores), but did not display physical sympto-
matology, extreme distress, inability to perform daily tasks nor
morning drinking (which contribute highly to SCID criteria).
These discrepancies raise important questions around exactly
what is being assessed by alcohol use screening tools and potential
response biases (see supplementary discussion). Given the novelty
of the experimental manipulation assessed here, immediate
assessment in a treatment-seeking sample would have been pre-
mature and carried greater potential for iatrogenic harm follow-
ing a relatively untested intervention. Hazardous/harmful and
non-treatment-seeking disordered drinkers are a key target group
in their own right, however and the reductions observed here,
could have enormous public health implications. Given the high
levels of problematic drinking in the current sample, one may
reasonably expect similar effects to be observed in a more severely
dependent/ treatment-seeking population and there is now a
strong rationale to conduct such clinical trials in formally diag-
nosed populations.
It is worth noting that baseline levels of alcohol consumption
in RET +KET tended to be higher than the other two groups.
While this difference was not statistically signicant, we cannot
rule out regression to the mean as a contributing factor to the
observed reduction in alcohol consumption. Based on the pattern
of results in their entirety, however, this explanation is highly
unlikely. The clear and striking complementary reductions in the
hedonic and motivational properties of alcohol, drinking fre-
quency (which did not differ at baseline) and the association of
these with objective ketamine biomarkers seen in RET +KET, are
commensurate with the comprehensive dampening of alcohol
reward memory structures that might be expected from successful
MRM reconsolidation interference.
Owing to response attrition, power, and sample representa-
tiveness decreased throughout follow-up. Follow-up data showed
that a self-selecting group of responsive participants. This may
explain why the drinking data converge at the 9 month time
point, with all groups reporting very similar (albeit much lower
than baseline) levels of drinking. Despite this, intention-to-treat
analyses did not show any appreciable difference to analyses
performed on the available data.
This is the rst study to demonstrate interference with the
reconsolidation of maladaptive alcohol memories in humans
using ketamine. These ndings highlight the promise of recon-
solidation interference as a therapeutic mechanism in harmful
drinking, alcohol and substance use disorders and offers key
insights into the therapeutic targets of ketamine, while adding to
the burgeoning list of its potential psychiatric indications. The
striking apparent dampening of reward structures surrounding
alcohol and substantial, lasting reductions in drinking levels
highlight that reconsolidation interference may form a key part
utility of the next generation of more effective long-term treat-
ments for addictive disorders.
Participants. Participants were 90 beer-preferring men (n=55) and women (n=
35) with hazardous/harmful drinking patterns, recruited via open internet adver-
tisements. Despite a problematic pattern of drinking, participants did not have a
formal diagnosis of AUD and were non-treatment seeking. Primary inclusion
criteria were: scoring > 8 on the Alcohol Use Disorders Identication Test
(AUDIT)30; not meeting SCID criteria for AUD at screening; Consuming > 40
(men) or > 30 (women) UK units/week (1 unit =8 g ethanol), primarily drinking
beer, non-treatment seeking (see Supplementary Methods).
Design and procedure. Ketamine infusion followed retrieval of alcohol-MRMs
(RET +KET) or control (orange juice) reward memories (No RET +KET). A
third group retrieved alcohol-MRMs prior to IV placebo (RET +PBO). Random
allocation to the activegroup (RET +KET) and two control conditions (N =30
per group) allowed us to assess effects of ketamine via reconsolidation, above those
of ketamine per se. Drug manipulations were single-blind and placebo controlled.
All participants completed a 3-day testing protocol at University College London
(UCL) and the attached hospital (UCLH). Follow-up reassessment was performed
up to 9 months. Attrition during remote follow-up left 9 month respondent Ns at:
Ret +PBO =20/RET +KET =17/No RET +KET =19. Participants were reim-
bursed for their participation. Written, informed consent was obtained prior to
participation and all procedures were approved by the UCL Research Ethics
Committee and UK Medicines and Healthcare Regulatory Authority, in line with
the Declaration of Helsinki (2013).
We assessed clinically-relevant MRM weakening via (1) reactivity to sampled
alcohol (beer) and alcohol cues (2) perceived changes in drinking levels, plus
quantitative drinking days/week, binges/week and total alcohol consumption via
the Timeline Follow-Back31. A three-day protocol was used. The rst (Day 1) and
nal (Day 10) days provided baselineand post manipulationassessments of
primary outcomes and questionnaire-based variables. Memory retrieval/ dug
manipulation took place on Day 3. Procedure are registered under ISRCTN registry
(No. 10138262,
Tasks and apparatus. For cue reactivity assessment (Day 1 and Day 10), parti-
cipants were given a 150 ml glass of beer and told they would consume this after
rating a series of images. They then rated their induced urge to drink and liking of
four orange juice images and four beer images (subsequently used as retrieval cues
in RET/No RET procedures), plus three wine and two soft drink images (not used
as retrieval cues), followed by their urge to drink the beer given to them and their
predicted enjoyment of the beer. These were all on 11-point (5to+5) scales.
They then consumed the beer according to timed prompts and rated their post-
consumption actual enjoyment of the drink and urge to drink more. These scales
thus assessed the hedonic and motivational properties of alcohol, which are central
to excess consumption. These Day 1 procedures both allowed assessment of
changes in cue reactivity and reinforcing properties of alcohol, and set the
expectation of beer consumption to maximize PE when beer was withheld during
reactivation on Day 3.
The MRM retrieval/destabilization procedure (Day 3) was one we have
previously used to reactivate alcohol MRMs32 and was identical to the cue
reactivity task except (1) the beer was replaced with orange juice in the No RET +
KET group (2) only four condition-approp riate cue images were rated (4 × orange
juice images in No RET, 4 × beer images in RET groups) (3) in all groups, the drink
was unexpectedly withheld at the appropriate timed prompt, generating negative
prediction error, which has been shown to be a necessary condition for memory
destabilization.33. Ketamine hydrochloride or saline placebo infusion (I.V.) began
5 min after RET/No RET, procedures following a brief set of distractor tasks.
Ketamine and placebo concentrations were maintained at 350 ng/ml for 30 min
using a pharmacokinetic (domino) infusion model. Blood draws were taken 15 min
pre and post infusion and gas chromatography was used to assay achieved plasma
levels of ketamine, norketamine (NK) and dehydroxynorketamine (dhNK) and
explore whether these, as a proxy for central concentrations during the
reconsolidation window, were predictive of responses to the manipulation.
On Day 10, participants repeated the cue reactivity task and reported perceived
changes in their drinking behavior (volume, enjoyment and craving) since Day 1
using three ve-point scales (+2=greatly increased, 2=greatly decreased).
Drinking was quantied over the previous week on Day 1 (baseline) and Day 10
(post manipulation) via the Timeline Follow-Back31. Remote follow-up
assessments of drinking (TLFB) were performed 2 weeks, 3, 6, and 9 months
following Day 10 (see Supplementary Methods for full list of measures).
8NATURE COMMUNICATIONS | (2019)10:5187 | /s41467-019-13162-w |
Content courtesy of Springer Nature, terms of use apply. Rights reserved
Statistical approach. Sample size was calculated in G*Power for 1-β=0.95
to detect a minimum effect size of n
2=0.05 at α=0.05 for the interaction in 2
(baseline, post manipulation) × 3 (Group) mixed ANOVA, assuming ρof 0.5. This
yielded a total required sample size of N=78 (26 per group). Anticipating minimal
attrition and technical error, we randomized N=30/group.
Data analysis was performed using IBM SPSS 25 for Windows. Where
sphericity was violated in repeated measures, the Greenhouse Geisser correction or
multivariate terms were used, depending on εvalues and according to the
recommendations of Stevens34. Primary drinking-related dependent variables (cue
reactivity, alcohol consumption), were assessed with 2 × 3 mixed ANOVA: within-
subjects factor =Time (Baseline vs. post manipulation), between-subjects factor =
Group (RET +PBO, RET +KET, No RET +KET). Signicant k> 2 main effects
and interactions in omnibus ANOVAs were investigated with multivariate simple
effects analyses and paired tests on marginal means, where appropriate. Due to
technical error, one participants (male, RET +PBO) TLFB data were lost for the
post manipulation time point. As such, these data and longer-term follow-up data
on TLFB were analyzed using linear mixed models, including random intercepts
per-participant, Group as a xed factor and including participant-level random
slopes across time if they improved model t (assessed via Akaikes Information
Criterion and chi-square tests on Δ2LL) and did not hinder convergence. For
ANOVA, effect size is (partial) eta squared (η2/η
2), was calculated by SPSS. For
xed effects in mixed models, pseudoη
2was calculated using the formulae from
Westfall et al35 Alpha for all a priori tests was set at 0.05, with p-values Bonferroni
corrected for post hoc tests. False discovery rate in analysis of baseline
demographic variables was controlled with the BenjaminiHochberg procedure36.
All tests are two-sided. For full data handling, see Supplementary Methods.
Data availability
The data that support the ndings of this study are available from the corresponding
author upon reasonable request. The source data underlying Figs. 1ad, 2ac, 3 and
Supplementary Fig. 1 are provided as a Source Data le
Received: 11 March 2019; Accepted: 18 October 2019;
Published online: 26 November 2019
1. Torregrossa, M. M., Corlett, P. R. & Taylor, J. R. Aberrant learning and
memory in addiction. Neurobiol. Learn. Mem. 96, 609623 (2011).
2. Koob, G. F. & Volkow, N. D. Neurocircuitry of addiction.
Neuropsychopharmacology 35, 217238 (2010).
3. Milton, A. L. & Everitt, B. J. The persistence of maladaptive memory:
Addiction, drug memories and anti-relapse treatments. Neurosci. Biobehav.
Rev. 36, 11191139 (2012).
4. Hyman, S. E. Addiction: a disease of learning and memory. Am. J. Psychiatry
162, 14141422 (2005).
5. Litt, M. D., Cooney, N. L. & Morse, P. Reactivity to alcohol-related stimuli in
the laboratory and in the eld: predictors of craving in treated alcoholics.
Addiction 95, 889900 (2000).
6. Kalivas, P. W. & OBrien, C. Drug addiction as a pathology of staged
neuroplasticity. Neuropsychopharmacology 33, 166180 (2007).
7. Bouton, M. E. Context, ambiguity, and unlearning: sources of relapse after
behavioral extinction. Biol. Psychiatry 52, 976986 (2002).
8. Conklin, C. A. & Tiffany, S. T. Applying extinction research and theory to cue
exposure addiction treatments. Addiction 97, 155167 (2002).
9. Vervliet, B., Craske, M. G. & Hermans, D. Fear extinction and relapse: state of
the art. Annu. Rev. Clin. Psychol. 9, 215248 (2013).
10. Lee, J. L. C. Reconsolidation: maintaining memory relevance. Trends Neurosci.
32, 413420 (2009).
11. Pedreira, M. E., Pérez-Cuesta, L. M. & Maldonado, H. Mismatch between
what is expected and what actually occurs triggers memory reconsolidation or
extinction. Learn. Mem. 11, 579585 (2004).
12. Milton, A. L., Lee, J. L. C., Butler, V. J., Gardner, R. & Everitt, B. J. Intra-
amygdala and systemic antagonism of NMDA receptors prevents the
reconsolidation of drug-associated memory and impairs subsequently both
novel and previously acquired drug-seeking behaviors. J. Neurosci. 28,
82308237 (2008).
13. Milton, A. et al. Antagonism at NMDA receptors, but not β-adrenergic
receptors, disrupts the reconsolidation of pavlovian conditioned approach and
instrumental transfer for ethanol-associated conditioned stimuli.
Psychopharmacol. (Berl.). 219, 751761 (2012).
14. Torregrossa, M. M. & Taylor, J. R. Learning to forget: manipulating extinction
and reconsolidation processes to treat addiction. Psychopharmacol. (Berl.).
226, 659672 (2013).
15. Walsh, K. H., Das, R. K., Saladin, M. E. & Kamboj, S. K. Modulation of
naturalistic maladaptive memories using behavioural and pharmacological
reconsolidation-interfering strategies: a systematic review and meta-analysis of
clinical and sub-clinicalstudies. Psychopharmacol. (Berl.). 235, 25072527
16. Das, R. K., Freeman, T. P. & Kamboj, S. K. The effects of N-methyl d-aspartate
and B-adrenergic receptor antagonists on the reconsolidation of reward
memory: a meta-analysis. Neurosci. Biobehav. Rev. 37, 240255 (2013).
17. Germeroth, L. J. et al. Effect of a brief memory updating intervention on
smoking behavior: a randomized clinical trial. JAMA Psychiatry 74, 214223
18. Lapidus, K. A. B. et al. A randomized controlled trial of intranasal ketamine in
major depressive disorder. Biol. Psychiatry 76, 970976 (2014).
19. Kolp, E., Friedman, H. L., Young, M. S. & Krupitsky, E. Ketamine enhanced
psychotherapy: preliminary clinical observations on its effectiveness in
treating alcoholism. Humanist. Psychol. 34, 399422 (2006).
20. Ivan Ezquerra-Romano, I., Lawn, W., Krupitsky, E. & Morgan, C. J. A.
Ketamine for the treatment of addiction: evidence and potential mechanisms.
Neuropharmacology 142,7282 (2018).
21. Swendsen, J. D. & Merikangas, K. R. The comorbidity of depression and
substance use disorders. Clin. Psychol. Rev. 20, 173189 (2000).
22. Xue, Y.-X. et al. Effect of selective inhibition of reactivated nicotine-associated
memories with propranolol on nicotine craving. JAMA Psychiatry 74, 224232
23. Mamou, C. Ben, Gamache, K. & Nader, K. NMDA receptors are critical for
unleashing consolidated auditory fear memories. Nat. Neurosci. 9, 12371239
24. Millan, E. Z., Milligan-Saville, J. & McNally, G. P. Memory retrieval,
extinction, and reinstatement of alcohol seeking. Neurobiol. Learn Mem. 101,
2632 (2013).
25. Zhang, J. J., Haubrich, J., Bernabo, M., Finnie, P. S. B. & Nader, K. Limits on
lability: Boundaries of reconsolidation and the relationship to metaplasticity.
Neurobiol. Learn. Mem. 154,7886 (2018).
26. Soeter, M. & Kindt, M. Disrupting reconsolidation: Pharmacological and
behavioral manipulations. Learn. Mem. 18, 357366 (2011).
27. Xue, Y.-X. et al. A memory retrieval-extinction procedure to prevent drug
craving and relapse. Science 336, 241245 (2012).
28. Das, R. K., Gale, G., Hennessy, V. & Kamboj, S. K. A prediction error-driven
retrieval procedure for destabilizing and rewriting maladaptive reward
memories in hazardous drinkers. J. Vis. Exp. e56097e56097.
10.3791/56097 (2018)
29. Foxcroft, D. R., Smith, L. A., Thomas, H. & Howcutt, S. accuracy of alcohol
use disorders identication test for detecting problem drinking in 1835 year-
olds in England: method comparison study. Alcohol. Alcohol. 50, 244250
30. Saunders, J. B., Aasland, O. G., Babor, T. F., De La Fuente, J. R. & Grant, M.
Development of the alcohol use disorders identication test (AUDIT): WHO
collaborative project on early detection of persons with harmful alcohol
consumption-II. Addiction 88, 791804 (1993).
31. Sobell, L. C. & Sobell, M. B. Timeline follow-back. in Measuring alcohol
consumption 4172 (Springer, 1992).
32. Das, R. K. K., Lawn, W. & Kamboj, S. K. K. Rewriting the valuation and
salience of alcohol-related stimuli via memory reconsolidation. Transl.
Psychiatry 5, e645e645 (2015).
33. Sevenster, D., Beckers, T. & Kindt, M. Prediction error governs
pharmacologically induced amnesia for learned fear. Science 339, 830833
34. Stevens, J. P. Applied multivariate statistics for the social sciences. (Routledge,
35. Westfall, J., Kenny, D. A. & Judd, C. M. Statistical power and optimal design
in experiments in which samples of participants respond to samples of stimuli.
J. Exp. Psychol. Gen.143, 20202045 (2014).
36. Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical
and powerful approach to multiple testing. J. R. Stat. Soc. Ser.57, 289300
We would like to thank Professor Tony Absalom for his insights on ketamine infusion
models and Dr. Kristian Warnes for his ongoing help formulating and dispensing the
study drugs. This work was supported by the Medical Research Council (grant number:
MR/M007006/1) to Drs. Das, Kamboj & Curran.
Author contributions
R.K.D. designed the study, collected the data, analyzed the data, and wrote the paper.
G.G., K.W., and V.E.H. collected and pre-processed the data. G.I., L.A.M., and B.B.
provided medical oversight and performed drug infusions. M.K. and H.V.C. helped
design and secure funding for the research. S.K.K. managed the research and edited
the paper, helped design the study and secured funding.
NATURE COMMUNICATIONS | (2019)10:5187 | 2-w | 9
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Competing interests
The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at
Correspondence and requests for materials should be addressed to R.K.D.
Peer review information Nature Communications thanks Amy Milton, Reinout Wiers
and the other, anonymous, reviewers for their contribution to the peer review of this
work. Peer reviewer reports are available.
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... Binge memory retrieval and no-retrieval control. Participants in the BMR + RIT and BMR + sham groups underwent Binge Memory Retrieval (BMR) which followed a procedure parallel to those we have used successfully in previous studies on maladaptive reward memory reconsolidation 48,64 . The BMR procedure was introduced to the participants as a repeat of the session one 'taste test' (i.e. ...
... After repeating the biological and state measures from session 1, participants then completed the BMR or NR procedure as appropriate to their random group allocation. As with our previous studies 48,49 , following the BMR or NR procedure, participants completed high-load working memory tasks (prose recall from the Rivermead battery and digit span forwards and backwards), to ensure cognitive disen-Ethical approval. The authors assert that all procedures contributing to this work were approved by and comply with University College London Research Ethics Committee's ethical standards on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. ...
... Limitations. The aim of this study was to assess whether RIT efficacy could be catalysed by conducting retraining following 'reactivation' of maladaptive food reward memory, as we have shown for behavioural and drug interventions 48,50 . We did not find evidence of such effects, aside from in short-lived Go/No-Go task performance interpreting this as a reconsolidation-update effect would be tenuous. ...
Full-text available
Binge eating is increasingly prevalent among adolescents and young adults and can have a lasting harmful impact on mental and physical health. Mechanistic insights suggest that aberrant reward-learning and biased cognitive processing may be involved in the aetiology of binge eating. We therefore investigated whether recently developed approaches to catalyse brief interventions by putatively updating maladaptive memory could also boost the effects of cognitive bias modification training on binge eating behaviour. A non-treatment-seeking sample of 90 binge eating young adults were evenly randomised to undergo either selective food response inhibition training, or sham training following binge memory reactivation. A third group received training without binge memory reactivation. Laboratory measures of reactivity and biased responses to food cues were assessed pre-post intervention and bingeing behaviour and disordered eating assessed up to 9 months post-intervention. The protocol was pre-registered at We found limited evidence of premorbid biased processing in lab-assessed measures of cognitive biases to self-selected images of typical binge foods. Accordingly, there was little evidence of CBM reducing these biases and this was not boosted by prior ‘reactivation’ of binge food reward memories. No group differences were observed on long-term bingeing behaviour, caloric consumption or disordered eating symptomatology. These findings align with recent studies showing limited impact of selective inhibition training on binge eating and do not permit conclusions regarding the utility of retrieval-dependent memory ‘update’ mechanisms as a treatment catalyst for response inhibition training.
... Emerging data also suggest that ketamine interventions can decrease alcohol use and help control withdrawal symptoms (Das et al., 2019;Wong et al., 2015). These preliminary findings have generated significant academic and public interest and controversy, driven in part by ketamine"s diverse therapeutic applications and its status as a drug of abuse (Zhang et al., 2016). ...
... Four of these studies were undertaken in the United States (Dakwar et al., 2020;Pizon et al., 2018;Shah et al., 2018;Yoon et al., 2019), one in the United Kingdom (Das et al., 2019), two in Russia (Krupitsky et al., 1992;Krupitsky and Grinenko, 1997), and one in J o u r n a l P r e -p r o o f 9 France (Condi et al., 1972). Three studies utilized a RCT design (Dakwar et al., 2020;Das et al., 2019;Krupitsky et al., 1992) and three studies employed a cohort design (Krupitsky and Grinenko, 1997;Pizon et al., 2018;Shah et al., 2018), two of which included control groups (Krupitsky and Grinenko, 1997;Pizon et al., 2018). ...
... Four of these studies were undertaken in the United States (Dakwar et al., 2020;Pizon et al., 2018;Shah et al., 2018;Yoon et al., 2019), one in the United Kingdom (Das et al., 2019), two in Russia (Krupitsky et al., 1992;Krupitsky and Grinenko, 1997), and one in J o u r n a l P r e -p r o o f 9 France (Condi et al., 1972). Three studies utilized a RCT design (Dakwar et al., 2020;Das et al., 2019;Krupitsky et al., 1992) and three studies employed a cohort design (Krupitsky and Grinenko, 1997;Pizon et al., 2018;Shah et al., 2018), two of which included control groups (Krupitsky and Grinenko, 1997;Pizon et al., 2018). The other two studies were a retrospective case series (Condi et al., 1972) and a small open-label pilot study (Yoon et al., 2019), both without control groups. ...
Background Alcohol use disorder is highly prevalent and has important economical, societal, psychiatric, and medical consequences. All currently approved therapeutic approaches targeting alcohol dependence have relatively modest effects and high relapse rates. Recent evidence suggests that ketamine may be an effective intervention to treat alcohol use disorder and alcoholic withdrawal. This systematic review aimed to assess the current level of evidence for this intervention. Methods This systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered on the international database of systematic reviews PROSPERO. Medline(Ovid), CINAHL Complete(EBSCOhost), PsycINFO(Ovid), EBM Reviews(Ovid), EMBASE(Ovid), and Google Scholar were searched for studies using ketamine to treat harmful alcohol use, craving, or withdrawal states in humans. Studies of any methodology that evaluated ketamine in isolation or combination with other interventions were included. The risk of bias was assessed using specific Cochrane critical appraisal tools. Results Of 1922 abstracts identified, 8 full-text articles were eligible for inclusion, yielding a total sample size of 634 participants. Five studies investigated the impact of ketamine on alcohol use and/or cravings and/or withdrawal in outpatient settings. Three studies looked at the effect of adding ketamine to conventional treatment of withdrawal symptoms in participants admitted to intensive care unit for severe alcohol withdrawal. Results on primary outcomes were mixed within and across trials. Conclusions Despite promising results, the current evidence does not permit definitive conclusions about the efficacy of ketamine in alcohol use disorders or withdrawal. Future studies are warranted.
... In chronic alcohol consumption, NMDA receptors are upregulated, and changes in synaptic plasticity occur in key brain regions involved in addiction [16]. Ketamine's anti-NMDA activity may disrupt these pathologic changes [15] and rapidly attenuate associations and memories [17] that reinforce drinking behavior. ...
... While limited in generalizability, these data on ketamine are consistent with recent pre-clinical and clinical literature on ketamine's use for AUD. In a human laboratory setting with non-treatment seeking, non-depressed adults with problematic drinking [17], ketamine reduced craving and drinking quantity at 10 days post-infusion to a greater extent than placebo. In a pilot randomized trial (n = 40) by Dakwar et al., non-depressed patients with AUD who received a single ketamine infusion (0.71 mg/ kg over 52 min) showed a higher rate of no heavy drinking days (82% vs 59%) and attendance at a 21-day counseling visit (100% vs 75%) compared to the active control (midazolam) arm [42], suggesting the anti-craving effect of ketamine persists well beyond its detectable presence in circulation. ...
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Background Alcohol use disorder (AUD) accounts for millions of acute care encounters annually in the United States. Hospitalization represents a vital opportunity to intervene pharmacologically, but low medication adherence is a significant barrier. Two single-dose, adherence-independent interventions are well suited for pre-discharge administration: intravenous (IV) ketamine and intramuscular (IM) naltrexone. Their feasibility and readmission-reducing efficacy in hospital settings are not well-established. Methods A 3-arm, open-label randomized trial was conducted at our safety-net medical hospital among high-utilization inpatients with severe AUD. Consented adults (age 18–65) were randomized to (1) IV ketamine (KET) 0.5 mg/kg over 40 min, (2) IM naltrexone (NTX) 380 mg once, or (3) linkage alone (LA). The primary clinical outcome was 30-day all-cause hospital readmission rate. All were provided enhanced linkage to outpatient addiction clinic. Results We consented and randomized 44 participants (n = 13, 14, 17 for KET, NTX, LA, respectively), with a mean of 3.2 past-year hospitalizations. Compared to the LA arm, both the KET arm (RR 0.37, p = 0.17) and NTX arm (RR 0.52, p = 0.27) had a lower 30-day readmission rate, though the differences were nonsignificant. Immediate acceptability ratings of KET and NTX were 9.50 and 9.17 out of 10, respectively. No serious adverse events or illicit ketamine use was reported. Conclusions Both interventions are feasible and showed promise in reducing readmissions for high-utilization AUD inpatients. Despite randomization, baseline characteristics may have differed in ways that biased against the control arm. Additional pragmatic studies—with larger sample size, blinding, and robust follow-up data collection—are needed to verify findings and better understand mediating factors. Identifier NCT04562779. Registered 24 September 2020.
... Das et al. [176] investigated whether intravenous ketamine given during the so-called "reconsolidation window " would interfere with the reconsolidation of maladaptive reward memories in harmful drinkers (people with high use of alcohol, but who do not have a formal diagnosis of AUD). Ketamine infusion (350 ng/mL for 30 min) following the retrieval/destabilization of maladaptive alcohol memories induced a rapid reduction in the reinforcing and motivational properties of alcohol and substantially lasting reductions in drinking levels compared to the other groups (see details of the protocol in Das et al. [176] ). ...
... Das et al. [176] investigated whether intravenous ketamine given during the so-called "reconsolidation window " would interfere with the reconsolidation of maladaptive reward memories in harmful drinkers (people with high use of alcohol, but who do not have a formal diagnosis of AUD). Ketamine infusion (350 ng/mL for 30 min) following the retrieval/destabilization of maladaptive alcohol memories induced a rapid reduction in the reinforcing and motivational properties of alcohol and substantially lasting reductions in drinking levels compared to the other groups (see details of the protocol in Das et al. [176] ). This result indirectly supports the idea that psychotherapeutic interventions are necessary to obtain the therapeutic effect of ketamine in the treatment of AUD/SUD. ...
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Substance use disorder (SUD) is a global public health concern that affects millions of people worldwide. Considering current research, addiction has been noted as the last stage of a chronic disease that may impair brain reward circuit responses and affects personal and social life. Treatments for SUD face challenges including availability and limited pharmacological response, often resulting in low retention of patients. A growing number of studies from the 'psychedelic renaissance' have highlighted the therapeutic potential of psychedelics for several psychiatric disorders, including SUD. In this non-systematic review we discuss past and current clinical and observational studies with classic (LSD, DMT, psilocybin and mescaline) and non-classic (ibogaine, ketamine, MDMA, salvinorin A and THC) psychedelics for the treatment of SUD published until December 2021. Although results are still inconclusive for LSD, DMT, mescaline, MDMA and Salvinorin A, in general, the literature presents moderate evidence on the controlled use of psilocybin and ketamine for Alcohol Use Disorder, ketamine for management of opiate and alcohol withdrawal, and THC preparations for reducing withdrawal symptoms in Cannabis and possibly in Opioid Use Disorder. Importantly, studies suggest that psychedelics should be more effective when employed as an adjunct therapy. Extensive research is warranted to further elucidate the role of psychedelics in the treatment of SUD.
... So far, only isolated studies investigated alternative reconsolidation blocker other than propranolol in subjects with SUD. However, first promising evidence suggests that post-retrieval intravenous ketamine -an NMDA receptor antagonist -can reduce alcohol craving and consumption in at-risk drinkers up to 9-month follow-up, compared to ketamine alone or placebo infusion postretrieval [149]. Apart from that, combining memory retrieval with memantine [150], nitrous oxide gas [151], or lidocaine [152] revealed null results. ...
... Although based on a small number of studies published thus far (n = 8), a meta-analysis across retrieval interference strategies in (sub)clinical SUD [131] identified interference type (behavioral vs. pharmacological) as a significant moderator, as only behavioral post-retrieval interventions were associated with a significant moderate effect size (g = 0.6), in contrast to pharmacological interference strategies (g = −0.03). However, post-retrieval ketamine infusion has been associated with long-lasting reductions in alcohol consumption [149] and is therefore a promising new candidate worth investigating further. This also matches preclinical evidence showing that NMDA receptor antagonists are more effective reconsolidation blocker than β-adrenergic antagonists [153]. ...
Substance-related disorders are complex psychiatric disorders that are characterized by continued consumption in spite of harmful consequences. Addiction affects various brain networks critically involved in learning, reward, and motivation, as well as inhibitory control. Currently applied therapeutic approaches aim at modification of behavior that ultimately leads to decrease of consumption or abstinence in individuals with substance use disorders. However, traditional treatment methods might benefit from recent neurobiological and cognitive neuroscientific research findings. Novel cognitive-behavioral approaches in the treatment of addictive behavior aim at enhancement of strategies to cope with stressful conditions as well as craving-inducing cues and target erroneous learning mechanisms, including cognitive bias modification, reconsolidation-based interventions, mindfulness-based interventions, virtual-reality-based cue exposure therapy as well as pharmacological augmentation strategies. This review discusses therapeutic strategies that target dysregulated neurocognitive processes associated with the development and maintenance of disordered substance use and may hold promise as effective treatments for substance-related disorders.
... For example, experimental trails indicate that MDMA may enhance the effects of self-compassion practice (Kamboj et al., 2018), and in a psychotherapeutic setting, has passed preliminary trials for safe and effective treatment of post-traumatic stress disorder (PTSD) (Mithoefer et al., 2018). Experimental trials have also provided preliminary evidence that ketamine may help treat harmful drinking behaviours (Das et al., 2019). ...
Background: Mindfulness protocols, though beneficial for a range of indications, often involve long-term commitment and may not be accessible for those naturally low in trait mindfulness (e.g. attention-/ anxiety-related disorders). It remains unclear which ‘dose’ of mindfulness is necessary to produce beneficial effects, and broadly, how drugs such as nootropics and psychedelics may interact with mindfulness meditation. / Aims: The aims of this thesis are (1) to explore what dose of mindfulness is necessary to enhance state mindfulness (among other outcomes) and whether a drug can modulate, or add to the effects of a mindfulness strategy, (2) to explore how psychedelics may affect a meditation experience, and (3) to examine what role changes in mindfulness play in regards to beneficial psychological health outcomes shown after ceremonial psychedelic use. / Methods: A mixture of methodologies were applied to answer the above questions. Specifically, single-session mindfulness literature was systematically reviewed, and a double-placebo controlled study was designed and conducted to explore the potential for pharmacological enhancement of a single mindfulness strategy. A thematic analysis was conducted to explore user accounts of combined psychedelic and meditation experiences. Finally, linear multilevel models and longitudinal mediation models were used to explore the associations between changes in mindfulness capacity and psychological health over the course of a naturalistic ayahuasca study. / Results: Single-session mindfulness studies are capable of producing a variety of beneficial effects, and adjunctive modafinil appears to enhance some effects of behavioural strategies as well as participant engagement in subsequent practice. Psychedelics may also prove to be useful counterparts to meditations, and conversely, while psychedelics appear to enhance mindfulness, meditation practice can assist also in the navigation of, and potentially enhance effects of the psychedelic process.
... Similarly, Duclot and collaborators showed that NMDAR antagonist, ketamine, disrupted contextual fear reconsolidation (Duclot, et al., 2016). In a pilot clinical study, ketamine was recently shown to reduce harmful drinking by disrupting the reconsolidation of appetitive memories (Das, et al., 2019). It would be interesting to see if ketamine has similar effects on fear memory reconsolidation in PTSD patients. ...
Post-traumatic stress disorder (PTSD), characterized by abnormally persistent and distressing memories, is a chronic debilitating condition in need of new treatment options. Current treatment guidelines recommend psychotherapy as first line management with only two drugs, sertraline and paroxetine, approved by U.S. Food and Drug Administration (FDA) for treatment of PTSD. These drugs have limited efficacy as they only reduce symptoms related to depression and anxiety without producing permanent remission. PTSD remains a significant public health problem with high morbidity and mortality requiring major advances in therapeutics. Early evidence has emerged for the beneficial effects of psychedelics particularly in combination with psychotherapy for management of PTSD, including psilocybin, MDMA, LSD, cannabinoids, ayahuasca and ketamine. MDMA and psilocybin reduce barrier to therapy by increasing trust between therapist and patient, thus allowing for modification of trauma related memories. Furthermore, research into the memory reconsolidation mechanisms has allowed for identification of various pharmacological targets to disrupt abnormally persistent memories. A number of pre-clinical and clinical studies have investigated novel and re-purposed pharmacological agents to disrupt fear memory in PTSD. Novel therapeutic approaches like neuropeptide Y, oxytocin, cannabinoids and neuroactive steroids have also shown potential for PTSD treatment. Here, we focus on the role of fear memory in the pathophysiology of PTSD and propose that many of these new therapeutic strategies produce benefits through the effect on fear memory. Evaluation of recent research findings suggests that while a number of drugs have shown promising results in preclinical studies and pilot clinical trials, the evidence from large scale clinical trials would be needed for these drugs to be incorporated in clinical practice.
The role of glutamate system in the etiology and pathophysiology of psychiatric disorders has gained considerable attention in the past two decades, including dysregulation of the metabotropic glutamatergic receptor subtype 5 (mGlu5). Thus, mGlu5 may represent a promising therapeutic target for psychiatric conditions, particularly stress-related disorders. Here, we describe mGlu5 findings in mood disorders, anxiety, and trauma disorders, as well as substance use (specifically nicotine, cannabis, and alcohol use). We highlight insights gained from positron emission tomography (PET) studies, where possible, and discuss findings from treatment trials, when available, to explore the role of mGlu5 in these psychiatric disorders. Through the research evidence reviewed in this chapter, we make the argument that, not only is dysregulation of mGlu5 evident in numerous psychiatric disorders, potentially functioning as a disease “biomarker,” the normalization of glutamate neurotransmission via changes in mGlu5 expression and/or modulation of mGlu5 signaling may be a needed component in treating some psychiatric disorders or symptoms. Finally, we hope to demonstrate the utility of PET as an important tool for investigating mGlu5 in disease mechanisms and treatment response.
Existential, neurobiological and cognitive models of addictive behavior are considered as a theoretical basis for transformational therapy of addictive disorders. The NMDA receptor antagonist ketamine, which has neurotrophic, modulatory and psychedelic effects, demonstrates the universal properties of a transforming agent for any of the presented concepts of addictive behavior. Since persistent mental and behavioral changes essentially are psychobiological changes, the substrate that determines the effectiveness of the intervention is synaptic plasticity and neural network remodeling.
To date few medications are approved for treatment of alcohol use disorders. Medications for treatment of alcoholism should either increase abstinence rates resp reduce relapse rates or reduce alcohol intake (number of drinks per day) in affected individuals. Disulfiram has been used for decades. The drug blocks the enzyme alcohol dehydrogenase and causes unpleasant or toxic effects after alcohol intake but failed to find widespread use. The level of evidence for efficacy is limited, and disulfiram may be most useful in a supervised treatment setting. The putative glutamate modulator acamprosate has been studied extensively and has modest but significant effects on abstinence rates in alcoholics, while the opioid antagonist naltrexone antagonizes rewarding effects of alcohol and reduces alcohol intake or the risk of relapse to heavy drinking. Another opioid antagonist nalmefene has been approved in recent years and was reported to reduce alcohol intake in moderate drinkers while its effect on abstinence rates is unclear. Nalmefene was used as an as-needed medication and its use is still somehow controversial. No magic bullet for treatment of alcoholism is at the horizon. To date some medications targeting multiple neurotransmitters and used for other medical indications are studied for use in alcoholism including topiramate, varenicline, ondansteron, gabapentin, and others.
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Background Consolidated memories can undergo enduring modification through retrieval-dependent treatments that modulate reconsolidation. This represents a potentially transformative strategy for weakening or overwriting the maladaptive memories that underlie substance use and anxiety/trauma-related disorders. However, modulation of naturalistic maladaptive memories may be limited by ‘boundary conditions’ imposed on the reconsolidation process by the nature of these memories. Methods We conducted a systematic review and meta-analyses of behavioural and pharmacological studies examining retrieval-dependent modulation of reward- and threat-related memories in (sub) clinical substance use and anxiety/trauma, respectively. Results Of 4938 publications assessed for eligibility, 8 studies of substance use and 10 of anxiety (phobia)- and trauma-related symptoms were included in the meta-analyses. Overall, the findings were in the predicted direction, with most studies favouring the ‘retrieval + treatment’ condition. However, the magnitude of effects was dependent upon the nature of treatment, with pharmacological interventions showing a medium-sized effect (g = 0.59, p = 0.03) and behavioural treatments, a relatively small effect (g = 0.32, p = 0.10) in studies of phobia/trauma. Among studies of substance use, post-retrieval behavioural interventions yielded a larger effect (g = 0.60, p < 0.001) relative to pharmacological treatments (g = − 0.03, p = 0.91), with treatment type being a statistically significant moderator (χ²(1) = 4.20, p = 0.04). Conclusion Modification of naturalistic maladaptive memories during reconsolidation appears to be a viable treatment strategy for substance use and phobias/trauma disorders. However, high levels of heterogeneity and methodological variation limit the strength of conclusions that can be drawn from the reviewed studies at this stage.
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Maladaptive reward memories (MRMs) can become unstable following retrieval under certain conditions, allowing their modification by subsequent new learning. However, robust (well-rehearsed) and chronologically old MRMs, such as those underlying substance use disorders, do not destabilize easily when retrieved. A key determinate of memory destabilization during retrieval is prediction error (PE). We describe a retrieval procedure for alcohol MRMs in hazardous drinkers that specifically aims to maximize the generation of PE and therefore the likelihood of MRM destabilization. The procedure requires explicitly generating the expectancy of alcohol consumption and then violating this expectancy (withholding alcohol) following the presentation of a brief set of prototypical alcohol cue images (retrieval + PE). Control procedures involve presenting the same cue images, but allow alcohol to be consumed, generating minimal PE (retrieval-no PE) or generate PE without retrieval of alcohol MRMs, by presenting orange juice cues (no retrieval + PE). Subsequently, we describe a multisensory disgust-based counterconditioning procedure to probe MRM destabilization by re-writing alcohol cue-reward associations prior to reconsolidation. This procedure pairs alcohol cues with images invoking pathogen disgust and an extremely bitter-tasting solution (denatonium benzoate), generating gustatory disgust. Following retrieval + PE, but not no retrieval + PE or retrieval-no PE, counterconditioning produces evidence of MRM rewriting as indexed by lasting reductions in alcohol cue valuation, attentional capture, and alcohol craving. © 2018, Journal of Visualized Experiments. All rights reserved.
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Addiction is a chronic, relapsing disorder, characterised by the long-term propensity of addicted individuals to relapse. A major factor that obstructs the attainment of abstinence is the persistence of maladaptive drug-associated memories, which can maintain drug-seeking and taking behaviour and promote unconscious relapse of these habits. Thus, addiction can be conceptualised as a disorder of aberrant learning of the formation of strong instrumental memories linking actions to drug-seeking and taking outcomes that ultimately are expressed as persistent stimulus-response habits; of previously neutral environmental stimuli that become associated with drug highs (and/or withdrawal states) through pavlovian conditioning, and of the subsequent interactions between pavlovian and instrumental memories to influence relapse behaviour. Understanding the psychological, neurobiological and molecular basis of these drug memories may produce new methods of pro-abstinence, anti-relapse treatments for addiction.
The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses — the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.
Reconsolidation, a process by which long-term memories are rendered malleable following retrieval, has been shown to occur across many different species and types of memory. However, there are conditions under which memories do not reconsolidate, and the reasons for this are poorly understood. One emerging theory is that these boundary conditions are mediated by a form of metaplasticity: cellular changes through which experience can affect future synaptic plasticity. We review evidence that N-methyl-D-aspartate receptors (NMDARs) might contribute to this phenomenon, and hypothesize that resistance to memory destabilization may be mediated by the ratio of GluN2A/GluN2B subunits that make up these receptors. Qualities such as memory strength and the age of the memory may increase the GluN2A/GluN2B ratio, reducing the ability of reactivation cues to induce destabilization, thereby preventing reconsolidation. Other examples of experience-dependent learning and evolutionary perspectives of reconsolidation are also discussed.
Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine's ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed.
Importance: A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results. Objective: To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke. Design, setting, and participants: A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke. Intervention: The study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma.). Main outcomes and measures: Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke. Results: 69 male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d = 0.57, 95% CI, -0.02-1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d = 0.64, 95% CI, 0.05-1.22), and nicotine priming (d = 1.15, 95% CI, 0.52-1.76). Conclusions and relevance: In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.
Importance: Recent research on addiction-related memory processes suggests that protracted extinction training following brief cue-elicited memory retrieval (ie, retrieval-extinction [R-E] training) can attenuate/eradicate the ability of cues to elicit learned behaviors. One study reported that cue-elicited craving among detoxified heroin addicts was substantially attenuated following R-E training and through 6-month follow-up. Objective: To build on these impressive findings by examining whether R-E training could attenuate smoking-related craving and behavior. Design, setting, and participants: This prospective, mixed-design, human laboratory randomized clinical trial took place between December 2013 and September 2015. Participants were recruited in Charleston, South Carolina. Study sessions took place at the Medical University of South Carolina. The participants were 168 screened volunteer smokers, of whom 88 were randomized; 72 of these 88 participants (81.8%) attended all the follow-up sessions through 1 month. The primary eligibility criteria were current nicotine dependence (DSM criteria), smoking 10 or more cigarettes per day, and a willingness to attempt smoking cessation. Interventions: Participants were randomly assigned to receive either smoking-related memory retrieval followed by extinction training (the R-E group) or nonsmoking-related retrieval followed by extinction training (the NR-E group). Main outcomes and measures: Primary outcomes were cue-elicited craving and physiological responding to familiar and novel cues in the R-E group vs the NR-E group over a 1-month follow-up period. Secondary outcomes were smoking-related behaviors. Results: A total of 44 participants were randomly assigned to the R-E group (mean age, 48.3 years; 72.7% male); a total of 44 participants were randomly assigned to the NR-E group, with 43 attending at least 1 training session (mean age, 46.7 years; 55.8% male). The mean craving response to both familiar and novel smoking cues was significantly lower for participants in the R-E group than for participants in the NR-E group at 1-month follow-up (for both cue types: t1225 = 2.1, P = .04, d = 0.44, and Δ = 0.47 [95% CI, 0.04-0.90]). The mean numbers of cigarettes smoked per day at 2 weeks and 1-month were significantly lower for the R-E group than for the NR-E group (treatment main effect: F1,68 = 5.4, P = .02, d = 0.50, and Δ = 2.4 [95% CI, 0.4-4.5]). Significant differences in physiological responses, urine cotinine level, number of days abstinent, lapse, and relapse were not observed between groups (all between P = .06 and .75). Conclusions and relevance: Retrieval-extinction training substantially attenuated craving to both familiar and novel smoking cues and reduced the number of cigarettes smoked per day by participants 1 month after treatment relative to extinction training alone. Between-group differences were not observed for physiological responses, cotinine level, number of days abstinent, relapse, or lapse. In summary, R-E training is a brief behavioral treatment that targets smoking-related memories and has the potential to enhance relapse prevention. Trial registration: Identifier: NCT02154685.
RATIONALE: Reconsolidation is the process by which memories require restabilisation following destabilisation at retrieval. Since even old, well-established memories become susceptible to disruption following reactivation, treatments based upon disrupting reconsolidation could provide a novel form of therapy for neuropsychiatric disorders based upon maladaptive memories, such as drug addiction. Pavlovian cues are potent precipitators of relapse to drug-seeking behaviour and influence instrumental drug seeking through at least three psychologically and neurobiologically distinct processes: conditioned reinforcement, conditioned approach (autoshaping) and conditioned motivation (pavlovian-instrumental transfer or PIT). We have previously demonstrated that the reconsolidation of memories underlying the conditioned reinforcing properties of drug cues depends upon NMDA receptor (NMDAR)- and β-adrenergic receptor (βAR)-mediated signalling. However, it is unknown whether the drug cue memory representations underlying conditioned approach and PIT depend upon the same mechanisms. OBJECTIVES: Using orally self-administered ethanol as a reinforcer in two separate experiments, we investigated whether the reconsolidation of the memories underlying conditioned approach and PIT requires βAR- and NMDAR-dependent neurotransmission. RESULTS: For ethanol self-administering but non-dependent rats, the memories underlying conditioned approach and PIT for a pavlovian drug cue were disrupted by the administration of the NMDAR antagonist MK-801, but not the administration of the βAR antagonist propranolol, when given in conjunction with memory reactivation. CONCLUSIONS: As for natural reinforcers, NMDARs are required for the reconsolidation of all aspects of pavlovian drug memories, but βARs are only required for the memory representation underlying conditioned reinforcement. These results indicate the potential utility of treatments based upon disrupting cue-drug memory reconsolidation in preventing relapse.