Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development

In the paper

“Clinical, behavioral, and self-report measures of addiction, personality, cognition, behavior, and exposure to early life stress were collected as part of a screening and natural history study of AUD in 454 individuals who represented the spectrum of alcohol use and AUD.A three-factor model generally demonstrated a good fit with the assessment measures, and the factors closely aligned with the Add”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Kwako et al., 2019 source

In the paper

“The extended amygdala has long been hypothesized to play a key role in fear, anxiety, and stress (Le Doux, 2000;Shackman and Fox, 2016) and also in the emotional component of pain processing (Neugebauer et al., 2004).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Le Doux, 2000
• Supported

  In the section “The central extended amygdala responds to a broad spectrum of threats” (page unavailable), our copy describes the central extended amygdala as important for fear and anxiety and links its activity to the stress-sensitive hormone cortisol during threatening exposure. Shackman and Fox are cited for the fear, anxiety, and stress portion of the sentence; the pain-processing portion is attributed to Neugebauer et al. (LLM, conf=0.90)

  cites Shackman and Fox, 2016 source
• ?Not checked — no full text of the sourcecites Neugebauer et al., 2004 source

In the paper

“Mutant mice that lacked arrestin 3 (b-arrestin 2) exhibited greater analgesia but significantly less antinociceptive tolerance, physical dependence, constipation, and respiratory suppression in response to morphine (Raehal and Bohn, 2014).”

What the sources say

• Partly supported

  Section 7 states that mice lacking β-arrestin2 have enhanced morphine analgesia and less antinociceptive tolerance, physical dependence, constipation, and respiratory suppression. It qualifies the dependence finding: dependence is reduced at lower morphine doses, but at high doses it is indistinguishable from that in wild-type mice. The claim omits that dose limitation. (LLM, conf=0.87)

  cites Raehal and Bohn, 2014 sourceExperimental — accuracy not yet measured

In the paper

“In animal models, early studies showed that precipitated opioid withdrawal decreases extracellular dopamine levels in the NAc and mesolimbic dopamine system (Pothos et al., 1991;Rossetti et al., 1992) and decreases dopamine neuron firing in the VTA (Diana, 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites Pothos et al., 1991 source
• ?Not checked — no full text of the sourcecites Rossetti et al., 1992 source
• Partly supported

  In “Dopamine as a Possible Therapeutic Target” (page unavailable), the paper reports reduced dopamine-neuron activity after morphine withdrawal in rats. It does not specify that the opioid withdrawal was precipitated or explicitly locate that firing reduction in the VTA. The extracellular-dopamine portion of the citing sentence is attributed to other citations, not Diana (2011). (LLM, conf=0.82)

  cites Diana, 2011 sourceExperimental — accuracy not yet measured

In the paper

“Consistent with the hypothesis of blunted glucocorticoids in the HPA and sensitized CRF in the CeA, chronic glucocorticoid receptor blockade with mifepristone, when administered systemically during the course of alcohol vapor exposure, prevented the escalation of alcohol intake and blocked the increase in progressive-ratio responding for alcohol in dependent animals (Vendruscolo et al., 2012).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Vendruscolo et al., 2012 source

In the paper

“For alcohol, an increase in prodynorphin mRNA expression is observed in the CeA during acute withdrawal (Kissler et al., 2014) and in the NAc during withdrawal after 1 month of voluntary alcohol consumption (Przewłocka et al., 1997).”

What the sources say

• Partly supported

  The Results section reports increased DYN A-like immunoreactivity in the CeA of alcohol-dependent rats euthanized during acute withdrawal. It measured peptide immunoreactivity, not prodynorphin mRNA expression. The NAc finding is attached to a different citation in the citing sentence and is not attributed to Kissler et al. (LLM, conf=0.90)

  cites Kissler et al., 2014 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Przewłocka et al., 1997 source

In the paper

“Vasopressin is a neurohormone that is synthesized in the hypothalamus and transported to the posterior pituitary (Brownstein et al., 1980), where it is released into the bloodstream during dehydration to act via vasopressin V 2 receptors on the kidneys to produce water retention (Kaufmann et al., 2000).”

What the sources say

• ?Not checked — no full text of the sourcecites Brownstein et al., 1980 source
• Partly supported

  The Introduction (page unavailable) states that vasopressin activates V2 receptors in renal collecting ducts, causing water retention. It does not address release into the bloodstream during dehydration. The hypothalamus-to-posterior-pituitary portion is cited to Brownstein et al., not Kaufmann et al. (LLM, conf=0.87)

  cites Kaufmann et al., 2000 sourceExperimental — accuracy not yet measured

In the paper

“k-Opioid receptor antagonists do not block the acute rewarding (”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Schlosburg et al., 2013 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Zhou et al., 2013b

In the paper

“In dependent rats, the a 1 -adrenergic receptor antagonist prazosin selectively blocked the increase in drinking that was associated with acute withdrawal (Walker et al., 2008), and the b-adrenergic receptor antagonist propranolol blocked the increase in drinking that was associated with acute withdrawal in dependent rats at doses that did not block nondependent drinking (Gilpin and Koob, 2010).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Walker et al., 2008
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Gilpin and Koob, 2010 source

In the paper

“k-Opioid receptor agonists (administered systemically) and dynorphins (administered intracerebrally) produce aversive-like effects in both animals and humans (Shippenberg et al., 2007) and have been hypothesized to mediate negative emotional states that are associated with drug withdrawal (Chavkin and Koob, 2016), pain, and more specifically pain that is associated with acute withdrawal (see also”

What the sources say

• Partly supported

  The discussion before §3 (page unavailable) says κ-opioid receptor agonists produce dysphoria in humans and aversive effects in experimental animals; it also reports conditioned aversion after systemic administration in animals. It does not establish that intracerebrally administered dynorphins produce aversive effects in both animals and humans. The later claim about negative emotional states is attached to a different citation, so it is not judged here. (LLM, conf=0.84)

  cites Shippenberg et al., 2007 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Chavkin and Koob, 2016 source

In the paper

“For alcohol, intracerebroventricular nociceptin administration significantly reduced the expression of somatic withdrawal signs and reversed anxiety-like behaviors that were associated with both chronic and acute alcohol intoxication in Wistar rats (Economidou et al., 2011).”

What the sources say

• Supported

  The Results for Experiment 1 report significantly reduced somatic withdrawal scores after intracerebroventricular N/OFQ. The Discussion reports reduced anxiety-like responses following both chronic and acute ethanol intoxication, and Materials and Methods identifies the subjects as male Wistar rats. No page numbers are available in our copy. (LLM, conf=0.95)

  cites Economidou et al., 2011 source

In the paper

“Similar effects on dependenceinduced drinking in rats and binge-like drinking in mice were observed with injections of NPY in the amygdala, BNST, and NAc shell but not in the hypothalamus, suggesting a focus of the effects of NPY on alcohol drinking on the extended amygdala (Kelley et al., 2001;Gilpin et al., 2008;Pleil et al., 2015).”

What the sources say

• ?Not checked — no full text of the sourcecites Kelley et al., 2001 source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Gilpin et al., 2008 sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Pleil et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“The blockade of glial cell activation restored mesolimbic dopamine function using minocycline (Taylor et al., 2016), prevented withdrawal using various inhibitors of glial cell activation (Watkins et al., 2009), prevented the relapse of morphine-seeking behavior via the epigenetic reprogramming of interleukin-10 overexpression (Schwarz et al., 2011), and prevented incubation-induced heroin seeking”

What the sources say

• Supported

  Only the minocycline clause is attributed to Taylor et al. In the Results section, the paper reports that inhibiting microglial activation with minocycline restored cocaine place preference in opioid-dependent animals. The Introduction frames this restored reward processing as addressing disrupted mesolimbic dopamine function; the paper demonstrates it through reward behavior rather than a direct dopamine-function measure. (LLM, conf=0.88)

  cites Taylor et al., 2016 source
• Partly supported

  The Watkins et al. citation is attached only to the withdrawal claim, not the separately cited dopamine or morphine-seeking claims. The References (page unavailable) list a study reporting reduced opioid withdrawal with the glial modulator ibudilast, and the Concluding remarks predict suppression of opioid dependence. Neither establishes that glial-activation inhibitors prevent withdrawal altogether. (LLM, conf=0.85)

  cites Watkins et al., 2009 sourceExperimental — accuracy not yet measured
• Supported

  The Introduction reports that neonatal handling increased IL-10 expression, attenuated glial activation, and prevented reinstatement of morphine conditioned place preference; it attributes the lasting IL-10 increase to decreased methylation of the IL-10 gene in microglia. The Results also report that the glial modulator ibudilast blocked reinstatement of morphine-seeking behavior. The other effects in the citing sentence are attributed to other citations, not Schwarz et al. (LLM, conf=0.89)

  cites Schwarz et al., 2011 source

In the paper

“The acute administration of opioids exerts anti-inflammatory effects (Eisenstein, 2019), whereas chronic opioid exposure activates microglia and astrocytes in the spinal cord (Watkins et al., 2009;Cahill et al., 2016) and central nervous system, including the VTA, NAc, frontal cortex, and periaqueductal gray (Hao et al., 2011;Taylor et al., 2016).”

What the sources say

• Supported

  Eisenstein (2019) is cited for the acute-administration clause, not the chronic-exposure clause, which has separate citations. In “Effect of Opioids on Macrophages, Microglia, and Macrophage/Microglial-Derived and T Cell-Derived Cytokines and Other Inflammatory Associated Mediators” (page unavailable), the review reports that acute morphine administration reduced pro-inflammatory cytokine responses in macrophages, supporting the attributed anti-inflammatory effect. (LLM, conf=0.90)

  cites Eisenstein, 2019 source
• Supported

  Watkins et al. are cited for the spinal-cord glial-activation clause, not the acute anti-inflammatory effect or the named brain regions, which have separate citations. In “Beyond pathological pain: glial modulation of opioid actions” (page not provided), the review reports opioid-induced glial activation and morphine-induced increases in microglial and astrocytic activation markers; its cited studies include spinal inflammatory responses associated with chronic morphine exposure. (LLM, conf=0.88)

  cites Watkins et al., 2009 source
• ?Could not verify

  Cahill et al. is cited for the spinal-cord portion of the sentence, not the acute anti-inflammatory effect or the other named brain regions. The 'Allostatic Processes in the VTA' section discusses activated microglia after prolonged morphine exposure, and the References list includes work on spinal astrocytes, but the passages found do not state that chronic opioid exposure activates both microglia and astrocytes in the spinal cord (searched: spinal cord, glial activation, microglia and astrocytes). (LLM, conf=0.72)

  cites Cahill et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Here, microglia via a BDNF-potassium-chloride transporter member 5 mechanism are hypothesized to be activated during opioid withdrawal and increase VTA GABAergic tone, which inhibits dopaminergic neurons (Cahill et al., 2016).”

What the sources say

• Supported

  In “Allostatic Processes in the VTA” (page unavailable), the paper proposes activated microglia as a source of BDNF during abstinence after prolonged morphine use and describes a BDNF–KCC2 pathway that makes VTA GABAergic neurons more excitable. The same section describes GABAergic input as inhibiting VTA dopamine neurons. The citing sentence presents this combined mechanism as a hypothesis, consistent with the paper’s wording. (LLM, conf=0.88)

  cites Cahill et al., 2016 source

In the paper

“Both stress and chronic pain activate microglia, increase Toll-like receptor 4 (TLR4) danger signals, increase the expression of nuclear factor kB target genes, and increase tumor necrosis factor a”

What the sources say

• Partly supported

  The discussion of neuron-to-glia signals (page not provided) says nerve injury is associated with CNS TLR4 upregulation and TNF production, and the discussion of glial activation says inflammation or injury activates spinal microglia. These passages support parts of the chronic-pain claim, but they do not establish that stress produces the same changes or that either condition increases NF-κB target-gene expression. The paper discusses danger signals detected by TLRs, not an increase in those signals under both conditions. (LLM, conf=0.86)

  cites Watkins et al., 2007 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Graeber, 2010 source

In the paper

“Furthermore, TLR4 knockdown in the amygdala reduced responding for alcohol in alcoholdependent rats (Liu et al., 2011), consistent with the hypothesis that the activation of innate immune danger signals within the amygdala may contribute to hyperkatifeia that drives dependence-induced alcohol drinking.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Liu et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“For alcohol, chronic alcohol exposure increases brain 2-AG (Caillé et al., 2007;Alvarez-Jaimes et al., 2009) and N-arachidonoylethanolamine (AEA), particularly in basal forebrain areas, in rodents (González et al., 2004;Vinod et al., 2006), but decreases in both 2-AG and AEA were observed in the CeA during withdrawal (Serrano et al., 2018).”

What the sources say

• Partly supported

  Caillé et al. is cited for the increase in 2-AG, not for the sentence’s AEA or withdrawal claims. The Results section, “Ethanol, heroin, and cocaine self-administration induce specific alterations in NAc shell eCB levels” (page not available), reports increased extracellular 2-AG during an ethanol self-administration session. But “Baseline dialysate AEA and 2-AG levels are unaltered as a function of previous drug self-administration history” (page not available) reports no baseline 2-AG increase after repeated exposure, so the paper does not establish a sustained increase from chronic alcohol exposure. (LLM, conf=0.88)

  cites Caillé et al., 2007 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report increased extracellular 2-AG in the nucleus accumbens during ethanol self-administration by Wistar rats. They do not establish that chronic alcohol exposure increases brain 2-AG. The AEA and CeA-withdrawal claims are attached to other citations, not this paper. (LLM, conf=0.85)

  cites Alvarez-Jaimes et al., 2009 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable) report that CeA 2-AG decreased during 12 hours of abstinence in alcohol-dependent rats. They report no effect of alcohol history or sampling time on CeA AEA levels, so the claim that AEA also decreased during withdrawal is not supported. The earlier increases elsewhere in the brain are attributed to other citations in the citing sentence. (LLM, conf=0.92)

  cites Serrano et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“Both FAAH inhibitors and MAGL inhibitors, which functionally increase endocannabinoids, decreased withdrawal-induced anxiety-like behavior and decreased alcohol consumption in alcoholdependent rats (Serrano et al., 2018).”

What the sources say

• Partly supported

  The results on anxiety-like behavior report improvement with the MAGL inhibitor MJN110 in alcohol-dependent rats, and the discussion says both MAGL and FAAH inhibitors ameliorated dependence-associated anxiety-like behavior. The alcohol-intake results report a significant reduction with MJN110, but the discussion states that FAAH inhibition did not consistently alter alcohol consumption in dependent rats or mice. Thus, the claim overstates the alcohol-consumption finding for FAAH inhibitors (sections on anxiety-like behavior, FAAH inhibition, and 2-AG clearance inhibition; page unavailable). (LLM, conf=0.92)

  cites Serrano et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“It has also been hypothesized to normalize stress function and attenuate hyperkatifeia in the context of addiction (Lee and Weerts, 2016).”

What the sources say

• Supported

  The ‘Oxytocin and stress’ section (page unavailable) proposes that oxytocin may normalize HPA-axis function and reduce anxiety and craving relevant to drug and alcohol use. The paper also summarizes evidence that it may attenuate withdrawal-associated negative mood and symptoms. Together, these support the citing sentence’s hypothesis, although the paper does not use the term ‘hyperkatifeia.’ (LLM, conf=0.88)

  cites Lee and Weerts, 2016 source

In the paper

“Oxytocin also reduced cue-induced reinstatement in dependent rats but not in nondependent rats (Hansson et al., 2018).”

What the sources say

• Supported

  The Animal Studies section reports that oxytocin significantly decreased cue-induced reinstatement of alcohol seeking in dependent rats but had no effect on the reinstatement response in non-dependent rats. The Abstract states the same distinction. (LLM, conf=0.95)

  cites Hansson et al., 2018 source

In the paper

“Naloxone-precipitated morphine withdrawal in rats that were chronically treated with morphine increased Hcrt-1 gene expression and Hcrt neuron activation in the lateral hypothalamus, and an Hcrt-1 receptor antagonist attenuated the somatic expression of naloxone-precipitated morphine withdrawal (Laorden et al., 2012).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Laorden et al., 2012 source

In the paper

“For alcohol, NPY administration directly in the brain blocked the increase in self-administration in alcoholpreferring rats and in alcohol dependence, blocked the transition to excessive drinking with the development of dependence, and blocked the increase in GABA release in the CeA that was produced by alcohol”

What the sources say

• ?Not checked — no full text of the sourcecites Gilpin et al., 2003 source
• Partly supported

  The Discussion (page not supplied) reports that NPY infused into the CeA abolished dependence-induced increases in operant alcohol responding; it also describes prior findings of reduced drinking in alcohol-preferring rats. But NPY was given after dependence developed, so this study did not show that it blocked the transition to excessive drinking. The Discussion says the effect on CeA GABA transmission is a hypothesis, not a demonstrated block of alcohol-induced GABA release. (LLM, conf=0.91)

  cites Gilpin et al., 2008 sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Gilpin et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“In heroin users during abstinence in a double-blind placebocontrolled study, acute intranasal oxytocin administration reduced craving and withdrawal scores and decreased cortisol levels but did not significantly change anxiety (Moeini et al., 2019).”

What the sources say

• Supported

  The Abstract describes a randomized, double-blind, placebo-controlled trial of a single intranasal oxytocin dose in heroin-dependent men during abstinence. It reports reduced craving and withdrawal scores, decreased cortisol, and no significant change in anxiety; the Results section confirms the craving, withdrawal, and anxiety findings. (LLM, conf=0.95)

  cites Moeini et al., 2019 source

In the paper

“For alcohol, women are more likely to experience blackouts, liver inflammation, brain atrophy, cognitive deficits, certain cancers, negative affect during withdrawal, and stress-or anxiety-induced relapse (Becker and Koob, 2016).”

What the sources say

• Partly supported

  The Withdrawal/Negative Affect section (page not available) reports more rapid alcoholic liver disease and neurotoxicity in women, while the Preoccupation/Anticipation section reports greater stress-induced relapse risk for women with alcohol use. The copy does not establish the specific claims about blackouts, liver inflammation, brain atrophy, cognitive deficits, or cancers. Its evidence about longer-lasting negative affect concerns adolescent girls after heavy drinking, not specifically withdrawal; it also does not establish anxiety-induced relapse separately from stress-induced relapse. (LLM, conf=0.86)

  cites Becker and Koob, 2016 sourceExperimental — accuracy not yet measured

In the paper

“Chronic alcohol exposure and withdrawal result in modest elevations of alcohol intake in male High Alcohol Preferring 2 mice.In contrast, female High Alcohol Preferring 2 mice did not show changes in alcohol intake (Lopez et al., 2011).”

What the sources say

• Supported

  The Results section for Experiment 2 reports increased ethanol intake in male HAP-2 mice after chronic ethanol exposure and withdrawal, while HAP-2 females showed no change. The paper’s Abstract Results describes the male increase as modest, matching the claim. (LLM, conf=0.94)

  cites Lopez et al., 2011 source

In the paper

“Opioids are recognized as the most powerful and effective drugs for the relief of acute pain in humans, and a unifying common theme is their relief of pain and suffering, including negative emotional states (Lutz and Kieffer, 2013).”

What the sources say

• Partly supported

  The Introduction describes morphine as a highly potent, widely used painkiller and says opioid drugs have euphoric effects and influence mood. It does not establish that opioids are the most powerful and effective drugs specifically for acute pain in humans, or that opioids generally relieve negative emotional states; the paper describes distinct mood effects across opioid receptors. (LLM, conf=0.87)

  cites Lutz and Kieffer, 2013 sourceExperimental — accuracy not yet measured

In the paper

“A small study showed that intranasal oxytocin blocked alcohol withdrawal in humans, based on such measures as the Alcohol Withdrawal Symptom Checklist of the Clinical Institute Withdrawal Assessment for Alcohol, and reduced the amount of benzodiazepines that were required for treatment (Pedersen et al., 2013).”

What the sources say

• Supported

  The Abstract Methods describe a small randomized trial (7 oxytocin recipients and 4 placebo recipients) that used both CIWA scores and the Alcohol Withdrawal Symptom Checklist; these are separate measures. The Abstract Results report lower withdrawal scores and substantially less lorazepam required with oxytocin, while the Conclusions say the treatment may block alcohol withdrawal. (LLM, conf=0.92)

  cites Pedersen et al., 2013 source

In the paper

“However, opioids are significantly less effective against chronic pain, such as neuropathic pain, fibromyalgia, and low-back pain, and tolerance develops to the analgesic effects of opioids, thus necessitating the need for increasingly higher doses to sustain analgesia (McQuay, 1988;Dowell et al., 2016).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites McQuay, 1988
• Partly supported

  The Clinical Evidence Review (page not provided) says opioids provide moderate short-term pain relief and that tolerance can diminish response over time, while long-term benefit for chronic pain remains uncertain. It does not establish that opioids are significantly less effective for the three named conditions or that tolerance necessitates increasingly higher doses; the Recommendations instead advise reassessment when dose requirements escalate. (LLM, conf=0.85)

  cites Dowell et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“However, for alcohol, the gaps between women and men are narrowing with regard to the prevalence, frequency, and intensity of drinking, early onset drinking, having AUD, drunk driving, and self-reported consequences (White et al., 2015;Slade et al., 2016).”

What the sources say

• ?Not checked — no full text of the sourcecites White et al., 2015 source
• Partly supported

  The Methods (Data extraction) include drinking prevalence, frequency, amount consumed, age of onset, alcohol use disorder, and alcohol-related problems among the indicators examined. The Results (Pooled results from meta-analyses) find a narrowing male–female gap across the three broad indicator categories. Drink driving is mentioned as an example of a negative consequence, but the paper does not establish a narrowing gap for drink driving specifically. (LLM, conf=0.84)

  cites Slade et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Individuals who were in acute withdrawal (24-72 hours) from opioids or protracted abstinence (average of 30 months) exhibited lower pain thresholds and pain tolerance, measured by the ischemic pain submaximal tourniquet procedure, and these decreases in pain thresholds were exacerbated by negative emotional states (Carcoba et al., 2011).”

What the sources say

• Partly supported

  Methods §2.1 gives 24–72 hours since the last heroin dose and a mean 30.4 months of abstinence; §2.2 confirms the tourniquet procedure. Results §3.4 and the Discussion report reduced thresholds and tolerance during withdrawal, but the abstinent group’s heightened pain sensitivity appeared only on tolerance assessments. Negative pictures further reduced pain thresholds in the withdrawal group, not demonstrably in both groups. (LLM, conf=0.90)

  cites Carcoba et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“However, male rats also exhibit greater motivational signs of withdrawal, such as anxiety-like responses in the social interaction test (Varlinskaya and Spear, 2004) and elevated plus maze after one cycle of exposure to an alcohol liquid diet (Overstreet et al., 2004a), and greater increases in acoustic startle responses than female rats (Reilly et al., 2009).”

What the sources say

• ?Not checked — no full text of the sourcecites Varlinskaya and Spear, 2004 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Overstreet et al., 2004a
• Supported

  The Reilly et al. citation is attached to the comparison of acoustic startle responses, not the social interaction or elevated plus maze findings, which have separate citations. The Discussion reports a consistent increase in startle reactivity during ethanol withdrawal in males, versus small to no changes in females and ovariectomized females. (LLM, conf=0.94)

  cites Reilly et al., 2009 source

In the paper

“In animal models, female rodents generally acquire morphine and heroin self-administration faster than males and exhibit higher motivation to self-administer opioids (Lynch and Carroll, 1999;Cicero et al., 2003;Becker and Koob, 2016).”

What the sources say

• ?Not checked — no full text of the sourcecites Lynch and Carroll, 1999 source
• ?Not checked — no full text of the sourcecites Cicero et al., 2003 source
• Supported

  In the Opiates subsection of “Animal Models,” the review states that females acquire morphine and heroin self-administration faster than males and show higher motivation to self-administer both drugs. This directly supports the attributed paraphrase. (LLM, conf=0.95)

  cites Becker and Koob, 2016 source

In the paper

“For alcohol, males generally exhibit a greater withdrawal response and slower recovery from acute alcohol withdrawal (Becker and Koob, 2016).”

What the sources say

• Supported

  In “Sex Differences in the Withdrawal/Negative Affect Stage,” the review states that males generally show a greater withdrawal response and slower recovery from acute alcohol withdrawal. Its examples concern animal models, including male and female rats. (LLM, conf=0.95)

  cites Becker and Koob, 2016 source

In the paper

“The type of pain is likely important, as well as the dependent variable that is used to measure negative affective effects of pain, the time course of dynorphin mediation, and the opposing actions of dynorphin neuron subcircuits (Cahill et al., 2014;Massaly et al., 2016).”

What the sources say

• Partly supported

  The sections “DO KORs CONTRIBUTE TO PAIN AVERSIVENESS?” and “OPIOID RECEPTORS MODULATE PAIN AND REWARD” distinguish acute from chronic pain and discuss sustained dynorphin release, supporting the importance of pain type and time course. The paper also discusses measures of pain aversion, but its “KOR REGULATION OF MESOLIMBIC CIRCUITRY” section describes differing KOR effects across neural projections, not opposing actions of dynorphin-neuron subcircuits. The indexed passages provide no page numbers. (LLM, conf=0.83)

  cites Cahill et al., 2014 sourceExperimental — accuracy not yet measured
• Partly supported

  In “Pain and stress dysregulate the mesolimbic reward pathway” (page unavailable), the review says responses vary with the type of pain and pain paradigm. In “Dopamine and kappa opioid system in chronic pain and stress disorders” (page unavailable), it discusses differing behavioral measures and opposing effects of KOR activation in distinct nucleus accumbens regions. It does not specifically establish a time course for dynorphin’s mediation of pain-related negative affect or attribute those opposing effects to dynorphin neuron subcircuits. (LLM, conf=0.86)

  cites Massaly et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Indeed, in a study of chronic inflammatory pain that was induced by a hindpaw injection of Complete Freund's Adjuvant, dynorphin expression increased in dynorphin-containing neurons in a discrete subregion of the NAc shell through a disinhibition mechanism, and pain increased k-opioid receptor function (Massaly et al., 2019).”

What the sources say

• Supported

  The Discussion (page not provided) states that pain increases dynorphin expression and recruits dynorphin-containing neurons in a discrete NAc shell subregion through disinhibition, and increases KOR function. The Methods (page not provided) confirm that the inflammatory-pain model used a hindpaw injection of Complete Freund’s Adjuvant. (LLM, conf=0.95)

  cites Massaly et al., 2019 source

In the paper

“Alcohol withdrawal-induced hyperalgesia was also attenuated by a histone deacetylase inhibitor, suggesting possible epigenetic mechanisms (Pradhan et al., 2019).”

What the sources say

• Supported

  The Discussion reports that an HDAC inhibitor prevented withdrawal-induced mechanical hyperalgesia in rats and says this suggests epigenetic regulation. That supports the citing sentence’s hedged interpretation; the study does not establish a specific epigenetic mechanism. (LLM, conf=0.94)

  cites Pradhan et al., 2019 source

In the paper

“The local infusion of microgram amounts of the k-opioid receptor antagonist nor-BNI into the ventral NAc shell blocked conditioned place aversion and the lower motivation to self-administer sucrose that was produced by inflammation (Massaly et al., 2019).”

What the sources say

• Partly supported

  The Results section on KORs and pain-induced negative affect reports that local norBNI prevented or reversed the inflammation-induced decrease in motivation to self-administer sucrose. The Results section on dynorphin-containing neurons reports that 4 μg of norBNI in the ventral NAc shell blocked real-time place aversion during inflammatory pain. That aversion was induced by photo-stimulation, not shown to be conditioned place aversion produced by inflammation; 2 μg did not prevent it after inflammation. (LLM, conf=0.89)

  cites Massaly et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Thus, individuals with comorbid pain and AUD may drink to alleviate pain-related negative affect, and behavioral treatments that improve pain-coping skills may enhance pain-management abilities, subsequently reducing coping-motivated drinking (Moskal et al., 2018).”

What the sources say

• Supported

  The Discussion’s Conclusions state that people with co-occurring pain may drink to alleviate pain-related negative affect. They also propose that interventions improving pain-coping skills may enhance pain management and reduce coping-motivated drinking. The cited paper presents this as a possibility, matching the claim’s cautious wording; page numbers were not provided in our copy. (LLM, conf=0.94)

  cites Moskal et al., 2018 source

In the paper

“The lateral habenula projects to the VTA, and its activation is known to decrease activity in VTA dopamine neurons (Hikosaka, 2010; see the Within-System Neuroadaptations section above).”

What the sources say

• Supported

  The Abstract states that lateral habenula neurons project to the VTA. The Reward-based decision-making section reports that electrical stimulation of the lateral habenula inhibits dopamine-neuron activity in the VTA; it describes the connection to those neurons as indirect. (LLM, conf=0.94)

  cites Hikosaka, 2010 source

In the paper

“Moderate alcohol use was associated with positive painrelated outcomes (e.g., greater quality of life), but excessive drinking and AUD were associated with deleterious pain-related outcomes (e.g., greater pain severity; Zale et al., 2015).”

What the sources say

• Supported

  The review’s Summary and Conclusions describes a possible curvilinear association: moderate consumption may be associated with positive chronic-pain outcomes, while excessive use and AUD may be associated with worse outcomes. The Effects of Pain on Alcohol Use section specifically names greater quality of life among people with chronic pain, and the Effects of Alcohol on Pain section reports greater pain severity among trauma patients with a history of AUD. The citing sentence presents these as associations, not causal effects. (LLM, conf=0.94)

  cites Zale et al., 2015 source

In the paper

“Intraventricular and intranasal administration of melanocortin-4 receptor antagonists reduced thermal hyperalgesia in alcohol-dependent rats during withdrawal (Roltsch Hellard et al., 2017), and this effect appeared to be mediated by melanocortin-4 receptor signaling in the CeA (Avegno et al., 2018).”

What the sources say

• ?Not checked — no full text of the sourcecites Roltsch Hellard et al., 2017 source
• Supported

  The MC4Rs in CeA results section reports that an MC4R antagonist infused into the CeA rescued thermal hyperalgesia in alcohol-dependent rats during withdrawal. The Discussion likewise states that MC4R blockade in the CeA rescues alcohol withdrawal hyperalgesia, supporting the clause attributed to Avegno et al. (LLM, conf=0.93)

  cites Avegno et al., 2018 source

In the paper

“Alcohol withdrawal-induced hyperalgesia and relapse-like alcohol consumption were reversed by the chemogenetic inhibition of lateral habenula neurons, the pharmacological activation of M-channels, and the overexpression of the M-channel subunit potassium voltage-gated channel subfamily KQT member 3 (Kang et al., 2019).”

What the sources say

• Supported

  The Abstract states that chemogenetic inhibition of lateral habenula neurons, pharmacological activation of M-channels, and KCNQ3 overexpression relieved hyperalgesia and decreased relapse-like alcohol consumption in alcohol-withdrawn rats. The Results section on KCNQ3 overexpression also reports increased paw-withdrawal latency and reduced ethanol intake. (LLM, conf=0.94)

  cites Kang et al., 2019 source

In the paper

“Polymorphisms of the CRF binding protein (CRHBP) gene have also been associated with the risk of both heroin addiction in African Americans (Levran et al., 2014) and a higher risk of drinking and/or anxiety in subjects with AUD (Haass-Koffler et al., 2016).”

What the sources say

• Supported

  The Discussion reports that CRHBP rs1875999 was associated with heroin addiction in the study’s African American sample. The association was nominal and did not survive correction for multiple testing. The drinking and anxiety clause is attributed to Haass-Koffler et al., not to Levran et al. (LLM, conf=0.91)

  cites Levran et al., 2014 source
• Supported

  The Results section reports that CRHBP variants were associated with drinks per drinking day and anxiety measures in alcohol-dependent patients, and concludes that variation might alter the risk of drinking and/or anxiety. The heroin-addiction clause is attributed to Levran et al., not to this source. (LLM, conf=0.92)

  cites Haass-Koffler et al., 2016 source

In the paper

“Associations were found between SNPs of the NPY Y2 receptor (NPY2R) gene and alcohol dependence, alcohol withdrawal symptoms, tobacco addiction, comorbid alcohol and cocaine dependence, and cocaine dependence (Wetherill et al., 2008;Okahisa et al., 2009;Mutschler et al., 2012;Bhaskar et al., 2013).”

What the sources say

• Partly supported

  The Abstract Results and Results > Association results report NPY2R SNP associations with alcohol dependence, withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence. The paper does not report an NPY2R association with tobacco addiction; that part of the sentence is not supported by this source. (LLM, conf=0.91)

  cites Wetherill et al., 2008 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Okahisa et al., 2009 source
• ?Not checked — no full text of the sourcecites Mutschler et al., 2012 source

In the paper

“Exposure to childhood trauma is a major risk factor for the development and maintenance of AUD (De Bellis, 2002) and predicts an earlier onset of heavy drinking (Waldrop et al., 2007;Enoch, 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites De Bellis, 2002 source
• ?Not checked — no full text of the sourcecites Waldrop et al., 2007 source
• Supported

  The section on early-onset problem drinking reports that childhood stressors predict earlier drinking onset and that childhood maltreatment increases the risk of adolescent binge drinking. The Conclusion describes a pathway from early-life stress through adolescent problem drinking to alcohol dependence. Although the citing sentence attaches De Bellis (2002) to the separate ‘major risk factor’ clause, Enoch (2011) supports the earlier-drinking point attributed to it. (LLM, conf=0.90)

  cites Enoch, 2011 source

In the paper

“However, using this choice model, a study in rhesus monkeys failed to show positive effects with a CRF 1 receptor antagonist (although one of three monkeys did respond) and a k-opioid receptor antagonist, but it did show positive results with opioid substitution drugs (Negus and Rice, 2009).”

What the sources say

• Supported

  The Discussion’s “Effects of Antalarmin and GNTI” section reports that the kappa-opioid antagonist failed to suppress increased heroin choice in any monkey and the CRF1 antagonist was ineffective in two of three. The Results confirm a response to the CRF1 antagonist in the third monkey. The “Effects of morphine” section reports that morphine suppressed the withdrawal-associated increase in heroin choice and describes positive findings for other mu-opioid agonists from prior studies. (LLM, conf=0.91)

  cites Negus and Rice, 2009 source

In the paper

“A recent epidemiological study showed particularly high comorbidity between AUD and major depressive disorder and bipolar disorder and comorbidity with personality disorders and anxiety disorders (Grant et al., 2015).”

What the sources say

• Supported

  The Results (Comorbidity) report associations between AUD and major depressive disorder, bipolar I disorder, antisocial and borderline personality disorders, and several anxiety disorders. The Abstract (Results) describes the anxiety-disorder associations as modest, consistent with the citing sentence’s distinction between particularly high comorbidity with mood disorders and comorbidity with anxiety disorders. (LLM, conf=0.92)

  cites Grant et al., 2015 source

In the paper

“In rodent studies, choice procedures are notoriously resistant to disruption, and a large proportion of rats continue to select a sweet solution (e.g., saccharin) rather than the drug even after the clear establishment of dependence (Lenoir et al., 2013;Ahmed, 2018).”

What the sources say

• Partly supported

  The Results (page unavailable) show that 8 of 20 rats with extended heroin access still preferred saccharin, and the Discussion describes markers of dependence in that group. But extended access also increased heroin preference from 25% to 60%, so describing the choice procedure as resistant to disruption without that qualification overstates this paper's finding. (LLM, conf=0.86)

  cites Lenoir et al., 2013 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Ahmed, 2018 source

In the paper

“In human studies, gabapentin blocked craving in a human laboratory study in non-treatment-seeking AUD subjects (Mason et al., 2009) and was shown to be an effective treatment of AUD in a double-blind placebo-controlled clinical trial (Mason et al., 2014).”

What the sources say

• Partly supported

  The Abstract identifies a human laboratory study of non-treatment-seeking, alcohol-dependent participants, and the Discussion reports that gabapentin significantly attenuated several measures of cue-induced craving. “Blocked craving” overstates that result: the Results report no significant difference in general craving. The clinical-trial claim is attributed to Mason et al. (2014), not this source. (LLM, conf=0.84)

  cites Mason et al., 2009 sourceExperimental — accuracy not yet measured
• Supported

  The Mason et al. (2014) citation is attached to the treatment-trial finding, not the preceding claim about the 2009 laboratory study. The Introduction describes a double-blind, placebo-controlled trial, and the Abstract Results report improved abstinence and no-heavy-drinking rates; the Discussion concludes that gabapentin, particularly at 1800 mg, effectively treated alcohol dependence. (LLM, conf=0.94)

  cites Mason et al., 2014 source

In the paper

“Both Hcrt-1 and Hcrt-2 receptor blockade decreased alcohol self-administration in alcohol-preferring rats(Lawrence et al., 2006;Brown et al., 2013).”

What the sources say

• ?Not checked — no full text of the sourcecites Lawrence et al., 2006 source
• Supported

  The Introduction reports that selective OX1R blockade attenuated ethanol self-administration in ethanol-preferring rats. The section “Central OX2R antagonism reduces ethanol, but not sucrose self-administration” reports that both tested doses of the OX2R antagonist significantly reduced responding for ethanol. No page numbers are available in our copy. (LLM, conf=0.92)

  cites Brown et al., 2013 source

In the paper

“A recent overall-negative study with a gabapentin prodrug has been reported, but the consensus was that the dose was low, and secondary analyses showed some efficacy in some subgroups of subjects in the study (Falk et al., 2019;Laska et al., 2020).”

What the sources say

• Partly supported

  The Results report no significant overall benefit and identify statistically significant effects in some subgroups; the Discussion cautions that these subgroup findings could be spurious. The Discussion says a higher dose might have been needed, but also says the tested dose was within the range previously found efficacious for alcohol use disorder. It does not establish a consensus that the dose was low. (LLM, conf=0.88)

  cites Falk et al., 2019 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction reports that the original gabapentin enacarbil trial found no significant difference from placebo, and the Discussion reports better outcomes for some subgroups in this reanalysis. The paper gives the dose as 600 mg twice daily but does not say there was a consensus that it was low. (LLM, conf=0.88)

  cites Laska et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“For alcohol in animal models, alcohol self-administration in dependent rats prevented the manifestation of a withdrawal syndrome (Roberts et al., 1996) and reversed the hypodopaminergic effects of alcohol withdrawal (Weiss et al., 1996).”

What the sources say

• ?Not checked — no full text of the sourcecites Roberts et al., 1996 source
• Supported

  The Weiss et al. citation is attached to the claim that self-administration reversed withdrawal-related hypodopaminergia, not to the separate withdrawal-syndrome claim attributed to Roberts et al. In Weiss et al.'s Discussion (Figure 5), ethanol self-administration in dependent rats restored accumbal dopamine to prewithdrawal levels. (LLM, conf=0.94)

  cites Weiss et al., 1996 source

In the paper

“Indeed, opioid addiction has been hypothesized to be sustained by a learned association between opioids and relief from an existing dysphoric state, and this learned association is formed through negative reinforcement (Evans and Cahill, 2016).”

What the sources say

• Supported

  In “Learned association of relief from aversion” (page not provided), the authors hypothesize that relief of dysphoric withdrawal states creates a learned association with opioid use. They explicitly describe that relief as negative reinforcement and propose that the association can later drive craving and relapse. (LLM, conf=0.94)

  cites Evans and Cahill, 2016 source

In the paper

“For alcohol, prepro-Hcrt mRNA increased in the lateral hypothalamus in inbred alcohol-preferring rats after chronic alcohol consumption(Lawrence et al., 2006) but decreased in the perifornical area in Sprague-Dawley rats(Morganstern et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Lawrence et al., 2006 source
• Partly supported

  The Results (Experiment 1; page not available) report that chronic ethanol consumption reduced OX mRNA in Sprague-Dawley rats. The measurement was in the perifornical lateral hypothalamus (PFLH), however, not the perifornical (PF) area separately; the paper’s separate LH-versus-PF analysis concerned acute ethanol. The claim about alcohol-preferring rats is attributed to a different citation and is not judged here. (LLM, conf=0.85)

  cites Morganstern et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“With regard to non-alcohol-like drugs, acamprosate is one of three Food and Drug Administration-approved medications for the treatment of AUD that is widely prescribed worldwide, and it has an effect size (Mason, 2003;Maisel et al., 2013;Jonas et al., 2014) that is similar to selective serotonin reuptake inhibitors for depression (Schalkwijk et al., 2014).”

What the sources say

• ?Not checked — no full text of the sourcecites Mason, 2003 source
• Partly supported

  The Results (End-of-Treatment Outcomes; page unavailable) report effect sizes for acamprosate in treating alcohol use disorders, supporting the part of the sentence for which Maisel et al. is cited. The copy does not establish that acamprosate is one of three FDA-approved medications; the Discussion (Concluding Comments; page unavailable) says its effects are somewhat smaller than those of medications for depression, rather than establishing similarity to SSRIs. The SSRI comparison is separately cited to Schalkwijk et al. (LLM, conf=0.87)

  cites Maisel et al., 2013 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Jonas et al., 2014 source

In the paper

“In a human laboratory study of non-treatment-seeking subjects with AUD, mifepristone decreased alcoholcued craving in the laboratory and reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase (Vendruscolo et al., 2015).”

What the sources say

• Supported

  The paper describes a human laboratory study of nontreatment-seeking, alcohol-dependent volunteers (Number 8 August 2015; page not specified). It reports significantly lower alcohol-cued craving after one week of mifepristone and fewer drinks per week during treatment and post-treatment follow-up than with placebo. (LLM, conf=0.94)

  cites Vendruscolo et al., 2015 source

In the paper

“It also blocked hyperkatifeia-like responses in alcoholdependent rats and blocked dependence-induced drinking in rodents (Roberto et al., 2008).”

What the sources say

• Partly supported

  The Discussion reports that gabapentin blocked anxiety-like behavior after withdrawal from a single high ethanol dose, but that experiment did not test chronically alcohol-dependent rats. The Discussion also reports that gabapentin blocked dependence-induced increases in ethanol drinking in rats. Thus, the drinking finding is supported, while the claimed dependence status for the anxiety finding is not. (LLM, conf=0.88)

  cites Roberto et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“consistent with the argument that stressful events during protracted abstinence can generalize to such a dysphoric state and produce recall that opioid drugs can relieve such a negative state (Koob, 2008;Evans and Cahill, 2016).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Koob, 2008
• Supported

  In “Learned association of relief from aversion,” the paper argues that opioid use becomes associated with relief of dysphoria and that a later negative life event—even after years of abstinence—can reactivate that association. It also describes stress-induced relapse as a generalization from drug relief of withdrawal-induced dysphoria. (LLM, conf=0.93)

  cites Evans and Cahill, 2016 source

In the paper

“A heuristic framework for addiction includes a threestage cycle-binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation-that provides a starting point for exploring the relatively new construct of hyperkatifeia in the context of drug withdrawal (Koob and Le Moal, 1997;Koob, 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Le Moal, 1997 source
• ?Not checked — no full text of the sourcecites Koob, 2019 source

In the paper

“Here, negative reinforcement becomes the source of motivation for drug seeking as the individual works to reduce, terminate, or prevent the negative emotional state or hyperkatifeia of drug withdrawal.”

In the paper

“From a nosology perspective, substance use disorders are now considered spectrum disorders as described by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5; American Psychiatric Association, 2013), which provides a framework for the intensity of symptoms with regard to the number of symptoms that are presented by the individual.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites American Psychiatric Association, 2013

In the paper

“In opioid addiction or OUD, drug use includes intense initial intoxication that is associated with intravenous or smoked drug intake, followed by the development of profound tolerance and the consequent escalation of intake.”

In the paper

“Under this addiction framework, stage-related dysregulation occurs in three functional domains (incentive salience/ habits, negative emotional states, and executive function) that are mediated by three major neurocircuitry elements (basal ganglia, extended amygdala, and prefrontal cortex, respectively; Koob and Le Moal, 1997).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Le Moal, 1997 source

In the paper

“Although all drugs of abuse have positive reinforcing properties, the termination of drug taking inevitably leads to negative emotional states of acute and protracted withdrawal in the withdrawal/negative affect stage, which generates a second motivational drive from negative reinforcement.”

In the paper

“These three stages feed into each other, become more intense, and ultimately lead to the pathologic state of addiction or substance use disorder (Koob and Le Moal, 1997; Fig. 1).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Le Moal, 1997 source

In the paper

“The classic drugs of addiction are opioids and alcohol.The pattern of misuse for each encompasses most of the patterns that are observed with other drugs of abuse.”

In the paper

“An inability to obtain the drug and the resulting abstinence results in physical discomfort, somatic signs of withdrawal, and profound hyperkatifeia.”

In the paper

“Hyperkatifeia, which often precedes somatic signs of withdrawal, signals pronounced preoccupation with obtaining opioids (craving).”

In the paper

“Under this framework in the withdrawal/negative affect stage, the manifestation of a withdrawal syndrome after the cessation of chronic drug administration can be defined not only in terms of the classic”

In the paper

“The two opposing responses are temporally linked (a triggers b), with the b-process subtracting the impact of the already existing a-process.”

In the paper

“In fact, opponent process theory was not only argued to be a counteraction to the hedonic actions of drugs of abuse; it was also argued to be a general phenomenon that is associated with hedonic breaks with homeostasis, including fear conditioning, tonic immobility, ulcer formation, eating disorders, jogging, peer separation, glucose preference, and even skydiving (Solomon andCorbit, 1973, 1974;H”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1973 source
• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source
• ?Not checked — no full text of the sourcecites Hoffman and Solomon, 1974 source

In the paper

“Under this framework, the first, initial use of a drug triggers a primary affective process (a positive hedonic process), termed the”

In the paper

“From the perspective of self-regulation theory, opponent process-driven hyperkatifeia sets up misregulation in which subjects take more drug to alleviate hyperkatifeia, which paradoxically drives more hyperkatifeia.”

In the paper

“This resulting tolerance produces more drug taking to remove the b-process and thus engages the addictive cycle (Solomon and Corbit, 1974).”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source

In the paper

“Little work has explored the neurobiological basis of opponent processes.”

In the paper

“Early theorists argued that counteradaptations can explain the physiological (physical, somatic) effects of opioid withdrawal in the domain of body temperature (Himmelsbach, 1943;Martin, 1968).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Himmelsbach, 1943
• ?Not checked — no full text of the sourcecites Martin, 1968

In the paper

“Withdrawal from drugs of abuse is one symptom of what is defined symptomatically as substance use disorder in the DSM-5 and Drug Dependence in the International Statistical Classification of Diseases and Related Health Problems, 10th revision (World Health Organization, 1992).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites World Health Organization, 1992

In the paper

“However, from the perspective of negative reinforcement, drug seeking and craving that are associated with acute and protracted abstinence are key to the thesis outlined herein, in which somatic measures of withdrawal can be an index of dependence but do not always reflect the more motivational measures of withdrawal or hyperkatifeia.”

In the paper

“With repeated stimulation (e.g., drug taking), the b-process is strengthened so that it has a faster onset and greater intensity and takes longer to decay (Solomon and Corbit, 1974).”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source

In the paper

“Notably, however, hyperkatifeiaassociated symptoms of withdrawal generally have an earlier onset and are manifested at lower doses of chronic drug intake.”

In the paper

“Withdrawal from an alcohol binge or chronic high alcohol intake is characterized by a severe emotional and somatic withdrawal syndrome and intense craving for alcohol that is often driven by both negative emotional states and positive emotional states, similar to opioids.”

In the paper

“As discussed by Solomon and Corbit (1974), the quickest and possibly most effective way of removing the b-process is to produce the a-process by taking the drug again.”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source

In the paper

“The notion of dependence on a drug, object, role, activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence.The degree of dependence can be equated with the amount of this negative affect, which may range from mild discomfort to extreme distress, or it may be equated with the amount of difficulty or effort required to do without the drug, obj”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Russell, 1976

In the paper

“However, both somatic and psychologic symptoms are mediated by physiological changes in the body and brain, but the argument here is that the symptoms that are associated with hyperkatifeia have significantly more motivational significance than somatic signs of withdrawal (Koob, 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob, 2019 source

In the paper

“Later, counteradaptations were invoked to explain how the initial acute hedonic effects of a drug are opposed or counteracted by homeostatic changes in systems that mediate the primary effects of the drug (Solomon and Corbit, 1974;Siegel, 1975;Poulos and Cappell, 1991).”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source
• ?Not checked — no full text of the sourcecites Siegel, 1975 source
• ?Not checked — no full text of the sourcecites Poulos and Cappell, 1991 source

In the paper

“The hypothesis in this review is that neural substrates of hyperkatifeia are a driving force of addiction, are multidetermined components of key motivational neurocircuits, and have been largely neglected in the search for pharmacotherapies for addiction.”

In the paper

“However, this leads to further strengthening of the b-process and the necessity to increase the amount of drug that is needed to remove the b-process.”

In the paper

“Several medications that target hyperkatifeia have been approved by the U.S. Food and Drug administration for the treatment of AUD and OUD.”

In the paper

“Physical symptoms of withdrawal are reflected by signs and symptoms of a physical nature that are usually opposite to the acute effects of the drug itself.”

In the paper

“This hypernegative emotional state, termed hyperkatifeia, is hypothesized to sensitize with repeated drug exposure and withdrawal.”

In the paper

“Here, the b-process presents as a negative emotional state and is described as intensely aversive (Solomon and Corbit, 1974).”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source

In the paper

“Many individuals with AUD continue with a binge/withdrawal pattern for extended periods; for others, the pattern evolves into an opioid-like substance use disorder, in which they must have alcohol available at all times to avoid the consequences of abstinence (Koob et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob et al., 2019 source

In the paper

“The unexpected delivery of rewards caused inhibition of the lateral habenula, consistent with an aversive role for activation of the habenula (Matsumoto and Hikosaka, 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Matsumoto and Hikosaka, 2007 source

In the paper

“Chronic alcohol is well known to upregulate N-methyl-D-aspartate (NMDA) receptor function in the brain (Chandler et al., 1993;Snell et al., 1993;Roberto et al., 2004), including the upregulation of different NMDA receptor subunits with chronic alcohol and withdrawal in some brain regions (Trevisan et al., 1994;Follesa and Ticku, 1995).”

What the sources say

• ?Not checked — no full text of the sourcecites Chandler et al., 1993 source
• ?Not checked — no full text of the sourcecites Snell et al., 1993 source
• ?Not checked — no full text of the sourcecites Roberto et al., 2004 source

In the paper

“In addition to the above within-system neuroadaptations, other neurocircuits appear to be activated by excessive drug intake that act in hedonic opposition to reward neurotransmitter circuits [corticotropinreleasing factor (CRF), norepinephrine, glucocorticoids, dynorphin, hypocretin, and neuroimmune factors] or act to protect against the development of hyperkatifeia (NPY, nociceptin, endocannabin”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Bloom, 1988 source
• ?Not checked — no full text of the sourcecites Koob and Le Moal, 1997 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Koob, 2008

In the paper

“Key components of hyperkatifeia are dysphoria and malaise, reflected by a decrease in brain reward function and an increase in brain and hormonal stress responses.”

In the paper

“However, chronic alcohol decreases GABA receptor function, with multiple effects on GABA receptor subunits, including downregulation of the a1 subunit and upregulation of the a4 subunit (Mhatre et al., 1993;Devaud et al., 1997).”

What the sources say

• ?Not checked — no full text of the sourcecites Mhatre et al., 1993 source
• ?Not checked — no full text of the sourcecites Devaud et al., 1997 source

In the paper

“Much of the work on within-system neuroadaptations has focused on the mesolimbic dopamine system that projects from the VTA to the nucleus accumbens (NAc; Fig. 4).”

In the paper

“For opioids, the noncompetitive glutamate receptor antagonist MK-801 blocked the expression of withdrawal signs that were precipitated by naloxone in opioid-dependent animals (Tanganelli et al., 1991;Tokuyama et al., 1996), suggesting a hyperglutamatergic contribution to opioid withdrawal.”

What the sources say

• ?Not checked — no full text of the sourcecites Tanganelli et al., 1991 source
• ?Not checked — no full text of the sourcecites Tokuyama et al., 1996 source

In the paper

“Acute alcohol potentiates receptor-activated cAMP production, but chronic exposure to alcohol decreases cAMPprotein kinase A activity and a decrease in cAMP response element binding protein (CREB) phosphorylation (Gordon et al., 1986).”

What the sources say

• ?Not checked — no full text of the sourcecites Gordon et al., 1986 source

In the paper

“Finally, a local dynorphin circuit in the NAc has been hypothesized to be activated and ultimately contribute to the hypodopaminergic state of opioid and alcohol withdrawal (Carlezon et al., 2000).”

What the sources say

• ?Not checked — no full text of the sourcecites Carlezon et al., 2000 source

In the paper

“For opioids at the neurocircuitry level, a prominent neuroadaptation is the loss of dopaminergic function in the mesolimbic dopamine pathway, which is hypothesized to contribute to hedonic tolerance and the hypohedonia that is associated with opioid withdrawal (see Fig. 4).”

In the paper

“The k-opioid receptor agonist U50,488H suppressed dopamine release in the NAc in rats that self-administered heroin, resulting in an increase in immediate heroin intake (Xi et al., 1998).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Xi et al., 1998

In the paper

“The vasopressin V 1B receptor antagonist SSR149415 blocked the heroin-and foot shock-induced reinstatement of heroin-seeking behavior, suggesting that vasopressin systems in the amygdala may be a key component of the aversive emotional consequences of opioid withdrawal (Zhou et al., 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Zhou et al., 2008 source

In the paper

“Altogether, converging data from studies of CRF and norepinephrine suggest that both CRF and noradrenergic neurotransmission are enhanced during opioid and alcohol withdrawal, and CRF and noradrenergic functional receptor antagonists can block motivational aspects of opioid and alcohol withdrawal.”

In the paper

“Whereas, acutely, opioid receptor agonists inhibit the HPA axis, opioid withdrawal potently activates it (Culpepper-Morgan and Kreek, 1997;Bearn et al., 2001).”

What the sources say

• ?Not checked — no full text of the sourcecites Culpepper-Morgan and Kreek, 1997 source
• ?Not checked — no full text of the sourcecites Bearn et al., 2001 source

In the paper

“Dynorphin is an opioid peptide that binds k-opioid receptors.”

In the paper

“The V 1b receptor antagonist SSR149415 dose-dependently reduced the higher levels of alcohol self-administration that were observed in dependent animals, without affecting alcohol drinking in nondependent animals (Edwards et al., 2012a).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Edwards et al., 2012a

In the paper

“The selective blockade of k-opioid receptor by 20 mg/kg nor-binaltorphimine (nor-BNI) administration (i.p.) 5 hours before naltrexone-precipitated withdrawal in morphine-dependent rats decreased some signs of opioid withdrawal during a 30-minute withdrawal session and, more relevant for the present thesis, decreased the subsequent conditioned place aversion for the withdrawal chamber 2 days later”

What the sources say

• ?Not checked — no full text of the sourcecites Kelsey et al., 2015 source

In the paper

“For opioids, individuals with OUD, when subjected to acute withdrawal from heroin and methadone, exhibited persistent elevations of cortisol levels (Culpepper-Morgan and Kreek, 1997;Bearn et al., 2001), and cortisol levels correlated with withdrawal severity (Bearn et al., 2001).”

What the sources say

• ?Not checked — no full text of the sourcecites Culpepper-Morgan and Kreek, 1997 source
• ?Not checked — no full text of the sourcecites Bearn et al., 2001 source

In the paper

“High corticosterone decreases CRF mRNA in the PVN but increases CRF mRNA in the CeA and lateral BNST (Makino et al., 1994a,b;Albeck et al., 1997;Schulkin et al., 1998;Shepard et al., 2000).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Makino et al., 1994a,b
• ?Not checked — no full text of the sourcecites Albeck et al., 1997 source
• ?Not checked — no full text of the sourcecites Schulkin et al., 1998 source

In the paper

“Injections of TNFa in the amygdala in rats increased anxiety-like behavior and mimicked the amplification of anxiety-like behavior that was observed with repeated cycles of alcohol drinking (Breese et al., 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Breese et al., 2008 source

In the paper

“Altogether, the data suggest that, at least in rats, the modulation of endogenous endocannabinoids can reverse hyperkatifeia that is associated with opioid withdrawal, but the nature of such modulation may be circuitspecific.”

In the paper

“Given that the activation of NPY in the CeA has opposite effects to CRF, one hypothesis is that NPY may act as a buffer to the stress-driving effects of CRF; by extrapolation, low functional activity of NPY may contribute to the etiology and vulnerability to hyperkatifeia.”

In the paper

“Neuropeptide Y has powerful orexigenic and anxiolytic-like effects in animal models and has been hypothesized to act in opposition to the actions of CRF in AUD and substance use disorders (Heilig and Koob, 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Heilig and Koob, 2007 source

In the paper

“Here, withdrawal from chronic drug exposure amplifies neuroimmune gene expression, impacting stress and fear circuits, and as a result is hypothesized to contribute to hyperkatifeia.”

In the paper

“Nociceptin can block both opioid and alcohol withdrawal and attenuate the increase in alcohol and opioid self-administration in dependent animals.”

In the paper

“Altogether, one hypothesis is that repeated alcohol intake may downregulate the endogenous nociceptin system, resulting in the activation of alcohol consumption through the release of stress modulation.”

In the paper

“Endocannabinoids are hypothesized to have stressbuffering actions that may be involved not only in the response to repeated withdrawal from alcohol but also in the vulnerability to negative emotional dysregulation that drives excessive drinking.”

In the paper

“Thus, the hypothesis is that repeated cycles of binge/withdrawal sensitize neuroimmune systems that interact with brain stress systems to facilitate negative emotional states during withdrawal and drive compulsive-like drinking under a negative-reinforcement framework.”

In the paper

“Mice that lacked TLR4 were protected from alcohol-induced glial activation, anxiety-like behavior, and cognitive impairments (Pascual et al., 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites Pascual et al., 2011 source

In the paper

“In a double-blind crossover study of non-treatment-seeking individuals with alcohol abuse, oxytocin did not produce an overall decrease in craving, but further analysis revealed that the effects on craving were moderated by attachment anxiety, with oxytocin reducing craving in more anxiously attached individuals and increasing craving in less anxiously attached individuals (Mitchell et al., 2016).”

What the sources say

• ?Not checked — no full text of the sourcecites Mitchell et al., 2016 source

In the paper

“Dynorphin knockout mice exhibited a facilitated return to normal nociceptive baselines after a peripheral nerve lesion (Wang et al., 2001), suggesting a pronociceptive role for dynorphin in chronic pain, in contrast to the antinociceptive effects of acute k-opioid receptor agonist administration.”

What the sources say

• ?Not checked — no full text of the sourcecites Wang et al., 2001 source

In the paper

“Hyperalgesia in the tail flick test that was associated with morphine withdrawal was blocked by microinjections of a CRF 1 /CRF 2 peptide receptor antagonist in the CeA, without affecting plasma corticosterone responses (McNally and Akil, 2002).”

What the sources say

• ?Not checked — no full text of the sourcecites McNally and Akil, 2002 source

In the paper

“Interwoven into this framework is that chronic opioids lose their effectiveness for chronic emotional pain.One could argue that chronic opioids actually drive chronic emotional pain via withdrawal.”

In the paper

“Particularly important for the present thesis, opioids also relieve emotional pain, which is a key component of hyperkatifeia, as noted above, and the driving force for the withdrawal/negative affect stage of the addiction cycle.”

In the paper

“More men use and are addicted to opioids and alcohol (National Survey on Drug Use and Health, Substance Abuse and Mental Health Services Administration, 2007).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites National Survey on Drug Use and Health, Substance Abuse and Mental Health Services Administration, 2007

In the paper

“Finally, individual differences beg the question of selective vulnerability in individuals who enter the addiction cycle via the withdrawal/negative affect stage (Fig. 6).”

In the paper

“Indeed, negative affect, measured by the Beck Depression Inventory, increased thermal and electrical sensation pain sensitivity in alcohol withdrawal, and depressed mood in patients was associated with lower pain tolerance (Jochum et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Jochum et al., 2010 source

In the paper

“Hyperalgesia that is associated with alcohol withdrawal can be blunted by the blockade of CRF 1 receptors (Edwards et al., 2012b), and CRF receptor antagonists can blunt nociceptive hypersensitivity in a wide variety of pain assays in animals (Hummel et al., 2010).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Edwards et al., 2012b
• ?Not checked — no full text of the sourcecites Hummel et al., 2010 source

In the paper

“Much evidence shows that the activation of k-opioid receptor agonists elevates intracranial self-stimulation reward thresholds and decreases the function of the mesolimbic dopamine system (Todtenkopf et al., 2004;Chefer et al., 2013).”

What the sources say

• ?Not checked — no full text of the sourcecites Todtenkopf et al., 2004 source
• ?Not checked — no full text of the sourcecites Chefer et al., 2013 source

In the paper

“The threshold appeared to be a mean BAL of ;0.08% (i.e., the legal driving limit) for producing a small elevation of pain thresholds, and a significant reduction of pain intensity with a higher BAL was associated with greater pain insensitivity.”

In the paper

“Theorists have long hypothesized that a negativereinforcement model of drug use assumes that individuals frequently consume alcohol (or opioids) to alleviate aversive physical or emotional states (Cappell and Herman, 1972;Sher and Levenson, 1982;Khantzian, 1985;Koob and Bloom, 1988;Baker et al., 2004;Ahmed and Koob, 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Cappell and Herman, 1972 source
• ?Not checked — no full text of the sourcecites Sher and Levenson, 1982 source
• ?Not checked — no full text of the sourcecites Khantzian, 1985 source

In the paper

“Melanocortin receptors also modulate nociceptin, opioid-induced analgesia, the development of tolerance to this effect, and opioid withdrawal-induced hyperalgesia (Kalange et al., 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Kalange et al., 2007 source

In the paper

“With excessive use, these systems undergo neuroadaptations with chronic drug exposure that lower reward function, increase stress function, and increase the negative affect component of pain, all of which contribute to the construct of hyperkatifeia.”

In the paper

“The opioid substitution drug methadone transiently blocks opioid self-administration in rats and dogs but not in monkeys (Jones and Prada, 1977;Mello et al., 1983;Leri et al., 2004;Alizadeh et al., 2018), and buprenorphine decreases opioid self-administration in dependent rats and monkeys (Mello et al., 1983;Chen et al., 2006).”

What the sources say

• ?Not checked — no full text of the sourcecites Jones and Prada, 1977 source
• ?Not checked — no full text of the sourcecites Mello et al., 1983 source
• ?Not checked — no full text of the sourcecites Leri et al., 2004 source

In the paper

“A polymorphism of the oxytocin gene, rs6133010, was associated with alcohol dependence in a northern Chinese Han population (Yang et al., 2017).”

What the sources say

• ?Not checked — no full text of the sourcecites Yang et al., 2017 source

In the paper

“However, with chronic alcohol exposure and subsequent withdrawal, all of these epigenetic activities are reversed, with decreases in histone acetylation through an increase in histone deacetylase activity and decreases in the expression of BDNF, activity-related cytoskeleton-associated protein, and NPY in CeA circuitry that produce anxiety-like responses (Pandey et al., 2008a,b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Pandey et al., 2008a
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Pandey et al., 2008b

In the paper

“Altogether, these observations suggest that some measures of hyperkatifeia, such as the expression of stress-like responses in specific contexts and the escalation of drug taking in rodents, are sensitive to treatment with anti-hyperkatifeia agents, whereas other measures, such as choice procedures, may not be sensitive.”

In the paper

“The lifetime prevalence of DSM-IV substance dependence among people who began using drugs under the age of 14 was 34% and dropped to 14% for those who began using at age 21 or older (Grant and Dawson, 1998).”

What the sources say

• ?Not checked — no full text of the sourcecites Grant and Dawson, 1998 source

In the paper

“From a negative-reinforcement perspective, in a study cited above, rats showed avoidance of the cues that were paired with a hypothesized negative emotional state of precipitated opioid withdrawal, and this conditioned avoidance was blocked by a direct intracerebral injection of a peptide CRF antagonist in the CeA (Heinrichs et al., 1995).”

What the sources say

• ?Not checked — no full text of the sourcecites Heinrichs et al., 1995 source