1. THE SCIENCE OF RECOVERY: AN ADVANCED SEMINAR CARDWELL C. NUCKOLS, PhD cnuckols@elitecorp1.com WWW.CNUCKOLS.COM

2. THE SCIENCE OF RECOVERY “…this business of resentment is infinitely grave. We found that it is fatal. For when harboring such feeling we shut ourselves off from the sunlight of the Spirit. The insanity of alcohol returns and we drink again. And with us, to drink is to die.” Big Book page 66

3. THE SCIENCE OF RECOVERY GRATITUDE (LOVE) A CHANGE IN WORLDVIEW GRANDIOSITY(CHARACTER DEFECTS)

4. WHAT DO YOU SEE?

6. NOVELTY The study revealed three major findings. First, as expected, when people were highly curious to find out the answer to a question, they were better at learning that information. More surprising, however, was that once their curiosity was aroused, they showed better learning of entirely unrelated information (face recognition) that they encountered but were not necessarily curious about. People were also better able to retain the information learned during a curious state across a 24-hour delay. Curiosity may put the brain in a state that allows it to learn and retain any kind of information.

7. NOVELTY When curiosity is stimulated, there is increased activity in the brain circuit related to reward When curiosity motivated learning, there was increased activity in the hippocampus, a brain region that is important for forming new memories, as well as increased interactions between the hippocampus and the reward circuit. "So curiosity recruits the reward system, and interactions between the reward system and the hippocampus seem to put the brain in a state in which you are more likely to learn and retain information, even if that information is not of particular interest or importance Matthias J. Gruber, Bernard D. Gelman, Charan Ranganath. States of Curiosity Modulate Hippocampus-Dependent Learning via the Dopaminergic Circuit.Neuron, 2014 DOI: 10.1016/j.neuron.2014.08.06010.1016/j.neuron.2014.08.060

8. NUCLEUS BASALIS

9. THE SCIENCE OF RECOVERY: NEUROPLASTICITY THE NUCLEUS BASALIS IS… THE MODULATORY CONTROL CENTER FOR PLASTICITY

10. THE SCIENCE OF RECOVERY: NEUROPLASTICITY YOU ARE NEUROPLASTICIANS! WHAT ENHANCES PLASTICITY? NOVELTY THERAPEUTIC RELATIONSHIPS PHYSICAL EXERCISE MINDFULNESS

11. NEUROPLASTICITY BRAIN AT ALL AGES IS RESPONSIVE TO ENVIRONMENTAL STIMULI SYNAPSES CAN CHANGE IN MINUTES WHEN STIMULATED NEUROPLASTICITY IS MODULATED BY –GENETIC FORCES –EPIGENETIC FORCES THESE FACTORS INFLUENCE THE EXPRESSION OF GENES WITHOUT CHANGING THE DNA SEQUENCE

12. NEUROPLASTICITY BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) –WHEN AN ACTIVITY REQUIRES SPECIFIC CONNECTIONS BETWEEN NEURONS, BDNF CONSOLIDATES THE CONNECTION –BDNF PROMOTES THE MYELINATION OF NEURONS –DURING CRITICAL PERIODS BDNF TURNS ON THE NUCLEUS BASALIS, A PART OF THE BRAIN THAT FOCUSES ATTENTION AND KEEPS IT FOCUSED THROUGHOUT THE ENTIRE CRITICAL PERIOD

13. NEUROPLASTICITY BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) –THE NUCLEUS BASALIS IS THE MODULATORY CONTROL CENTER FOR PLASTICITY EXAMPLE-LANGUAGE HAS A CRITICAL PERIOD FROM INFANCY TO 8/PUBERTY. DURING THIS PERIOD LANGUAGE IS EASY TO LEARN. AFTER THE CRITICAL PERIOD IT TAKES SOMETHING NOVEL, IMPORTANT, SURPRISING OR IF ONE MAKES THE EFFORT TO PAY CLOSE ATTENTION –BDNF HELPS CLOSE DOWN THE CRITICAL PERIOD ONCE THE MAIN NEURAL CONNECTIONS ARE IN PLACE (STABILIZES SYSTEM)

14. ADDICTION AND RECOVERY

15. THE SCIENCE OF RECOVERY:GENETICS GENETICSGENETICS –A1 ALLELE OF THE DOPAMINE D2 RECEPTOR GENE –FOUND IN ONE-THIRD OF POPULATION –LOW DOPAMINE TONE

16. THE SCIENCE OF RECOVERY:GENETICS TWIN STUDIES SUGGEST GENES AND ENVIRONMENTAL FACTORS EACH INFLUENCE THE VULNERABILITY TO DEVELOPING ADDICTION STRESS IS ONE, IF NOT THE PRINCIPLE, ENVIRONMENTAL FACTOR THAT INCREASES ADDICTION POTENTIAL IN BOYS WITH THE A1 ALLELE STRESS WAS SIGNIFICANTLY CORRELATED WITH COGNITIVE FUNCTIONAL PROBLEMS NOBLE AND BENTON. THE D2 DOPAMINE RECEPTOR GENE AND FAMILY STRESS. INTERACTIVE EFFECTS ON COGNITIVE FUNCTIONING IN CHILDREN. BEHAV GENET, 1997; 27:33-43.

17. ADDICTION AND RECOVERY Treatment dropout linked to elevated stress response (Drug and Alcohol Depd. 105 (3):202-208, 2009) –Salivary cortisol can predict how long a drug user will remain in treatment –Cortisol measured at base for both men and women in a residential treatment center before giving them stressful tasks –Prior to the stressors cortisol levels were similar for the 21 participants who dropped out as compared to the 81 who completed treatment

18. ADDICTION AND RECOVERY Treatment dropout linked to elevated stress response (Drug and Alcohol Depd. 105 (3):202-208, 2009) (continued) –The patients who dropped out had cortisol levels 3-5 times higher than those patients who remained in treatment –For each unit of increase in cortisol after the stressful tasks, there was a four-fold increase in risk of dropping out

19. THE SCIENCE OF RECOVERY:GENETICS GENETIC VULNERABILITY –SONS OF ALCOHOLICS HAVE DECREASED SENSITIVITY TO ALCOHOL ENORMOUS AMOUNT OF DEVELOPMENTAL STRESS EITHER CAN CAUSE IRREGULARITIES IN BRAIN CHEMISTRY SUCH AS DOPAMINE BLUNTING

20. THE SCIENCE OF RECOVERY:GENETICS WHEN YOU DISCONTINUE TO DRINK CIRCUITS ARE STILL PRESENT –CORTICOTROPIN RELEASING FACTOR (CRF) SYSTEM PRODUCES A CHRONIC STRESS RESPONSE THAT IS A SET-UP FOR RELAPSE –60-70% OF RELAPSE OCCUR UNDER CONDITIONS OF NEGATIVE EMOTIONAL STATE

21. THE SCIENCE OF RECOVERY:GENETICS A shortage of D2 receptors, some researchers surmise, could predispose a person to addiction. Nora Volkow, NIDA Director, led two studies that involved artificially increasing the number of D2 receptors in rats by administering adenoviral vectors directly into their brains. Viral vectors transmit their genetic material and makeup into foreign cells, in this case increasing the number of D2 receptors in the new cells to match their own.

22. THE SCIENCE OF RECOVERY:GENETICS In one study involving rats and alcohol, the increased number of D2 receptors led the rodents to consume less alcohol, compared with their baseline intake. In the other study, the D2-receptor increase caused rats to significantly reduce their intake of cocaine.

24. THE SCIENCE OF RECOVERY:GENETICS Association between DA D2 receptor numbers and drug self-administration (PET) –Increased D2 receptors reduced alcohol consumption –Decreased D2 receptors higher risk DA D2 receptor levels influenced by stress and social hierarchyDA D2 receptor levels influenced by stress and social hierarchy

25. THE SCIENCE OF RECOVERY:GENETICS Michael Nader, a researcher at Wake Forest School of Medicine, is investigating ways to raise D2-receptor levels naturally. One experiment he helped conduct focused on five separate groups of four monkeys. Each had been self-administering cocaine to the point of habit and were then deprived of the drug for an eight-month period. To create a picture of D2-receptor availability, the monkeys were given a radioactive tracer that competes with dopamine for receptors.

26. THE SCIENCE OF RECOVERY:GENETICS The monkeys were then randomly put in social groups of four and given the opportunity to self-administer the drug again. Positron emission tomography (PET) imaging of the monkeys over time showed fluctuations in dopamine levels, which allowed the researchers to estimate the changing numbers of available D2 receptors. After only three months, the socially dominant monkeys in each group had naturally increased their numbers of D2 receptors.

27. THE SCIENCE OF RECOVERY:GENETICS There was no increase in the subordinate monkeys. Further, the subordinate monkeys reverted to using cocaine at much higher levels than the dominant monkeys. "There is an interesting relationship between D2-receptor numbers and vulnerability to drug addiction," Nader said. "It appears that individuals with low D2 measures are more vulnerable compared to individuals with high D2- receptor numbers."

28. THE SCIENCE OF RECOVERY:GENETICS Why did the socially dominant monkeys show D2-receptor increases? One hypothesis is environmental enrichment. For the monkeys, it seems, being dominant was the enriching trigger. One physiological consequence of involvement in 12-step meetings, therefore, could be an increase in the natural production of D2 receptors.

30. THE SCIENCE OF RECOVERY:GENETICS Social interventions can change neurobiologySocial interventions can change neurobiology –Increased DA D2 receptors –Reduced self-administration Behavioral interventions could counteract the aversive effects of drug abuse and reinforce the power of group approachesBehavioral interventions could counteract the aversive effects of drug abuse and reinforce the power of group approaches

31. Nucleus Accumbens VentralTegmentalArea Dopamine Opioid Peptides Naltrexone Arcuate Nucleus THE SCIENCE OF RECOVERY: DOPAMINE (DA) TONE

32. TWO TYPES OF LOW DA TONE (CONTINUED)TWO TYPES OF LOW DA TONE (CONTINUED) SYMPTOMS WILL BE THOSE OF REDUCED DA TONE AT NAc REGARDLESS OF THE LOCATION OF FEEDBACK PROBLEMSYMPTOMS WILL BE THOSE OF REDUCED DA TONE AT NAc REGARDLESS OF THE LOCATION OF FEEDBACK PROBLEM FROM TREATMENT PERSPECTIVE WHAT DIFFERENTIATES WHETHER DA OR OPIOID CAUSATION OF LOW DA TONE IS….FROM TREATMENT PERSPECTIVE WHAT DIFFERENTIATES WHETHER DA OR OPIOID CAUSATION OF LOW DA TONE IS…. –HISTORY OF DRUG USAGE AND EFFECTS THAT USER EXPERIENCES

33. THE SCIENCE OF RECOVERY: DOPAMINE (DA) TONE SUFFICIENTSUFFICIENT –DA TONE IN REWARD CIRCUITRY YIELDS ADEQUATE ATTENTIONATTENTION MOTIVATIONMOTIVATION ATTACHMENTATTACHMENT HEDONIC TONEHEDONIC TONE

34. THE SCIENCE OF RECOVERY: DOPAMINE (DA) TONE REDUCED OR LOW DA TONEREDUCED OR LOW DA TONE –ANHEDONIC RELATIVE TO THOSE AROUND THE INDIVIDUAL –SENSE OF NOT FITTING IN –POOR ATTENTION –POOR LEVEL OF MOTIVATION –RESTLESS –IRRITABLE –DISCONTENTED

35. PREFRONTAL CORTICAL DOPAMINE Optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Imaging studies of alcoholics have demonstrated less dopamine in the striatum Volkow ND; Wang GJ; Telang F; Fowler JS; Logan J; Jayne M; Ma Y; Pradhan K; Wong C: Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci 2007; 27:12700–12706

36. PREFRONTAL CORTICAL DOPAMINE Less dopamine in the prefrontal cortex, which governs executive functions, is important because it could impair the addicted person’s ability to learn and utilize informational/behavioral strategies critical to relapse prevention. This is supported by literature that links prefrontal cortical dopamine with executive functions, such as attention, working memory, behavioral flexibility, and risk/reward decision making, all of which are impaired in addictive disorders such as alcoholism. Floresco SB; Magyar O: Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology (Berl) 2006; 188:567–585

37. PREFRONTAL CORTICAL DOPAMINE It is tempting to speculate that the failure to incorporate past negative consequences in a decision to drink alcohol during abstinence is related to decreased prefrontal cortical dopamine in alcoholism. Unclear whether decreased dopamine transmission in alcoholism represents a premorbid trait or alcohol-induced state Narendran, et al. Decreased Prefrontal Cortical Dopamine Transmission in Alcoholism. Am J Pscyhiatry. 2014;171:881-888. doi:10.1176/appi.ajp.2014.13121581

38. THE SCIENCE OF RECOVERY: DOPAMINE (DA) TONE INCREASING DA TONE AT NAcINCREASING DA TONE AT NAc –THREE POSSIBLE APPROACHES INCREASE AMOUNT OF DA RELEASED- CURRENTLY HAVE MEDS LIKE SUBOXONE THAT WILL DO THISINCREASE AMOUNT OF DA RELEASED- CURRENTLY HAVE MEDS LIKE SUBOXONE THAT WILL DO THIS INCREASE NUMBER OF RECEPTORS-MEDS NOT AVAILABLE FOR THISINCREASE NUMBER OF RECEPTORS-MEDS NOT AVAILABLE FOR THIS REDUCING REUPTAKE OF DA-HAVE MEDS THAT WILL DO THIS (PROVIGIL)REDUCING REUPTAKE OF DA-HAVE MEDS THAT WILL DO THIS (PROVIGIL)

39. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: THE OPIATE EXPERIENCE HIGH ABNORMALLY NORMAL SUBJECTIVE W/DRAWAL ACUTE ABSTINENCE SYN.

40. THE SCIENCE OF RECOVERY: DOPAMINE (DA) TONE SUBUTEXSUBUTEX-Buprenorphine. sublingual (SL) –2mg and 8mg tablets SUBOXONESUBOXONE-Buprenorphine/Naloxone SL tablets AND FILM Zubsolv SL PARTIAL AGONISTPARTIAL AGONIST –Increasing dose does not increase effect like a full agonist

42. THE SCIENCE OF RECOVERY: DOPAMINE (DA) TONE BUPRENORPHINE-Very high affinity for mu opioid receptor Mu receptor will choose buprenorphine over other opioids Buprenorphine will displace other opioids Slow dissolution from mu receptor –Half-life on receptor is 34-36 hrs –Heroin on and off receptor in millisecond –At Buprenorphine dose of 16mg almost no binding to other opioids

43. PHARMACOLOGICAL NALTREXONE (Revia, Vivitrol) Pure antagonist Poor compliance –Less than 10% for street addicts Better compliance –Healthcare professionals –Parole/Probation New suspension with q30d administration should dramatically increase compliance and reliability of drug

44. VIVITROL Carton Components 44

45. VIVITROL

46. VIVITROL

47. VIVITROL

48. VIVITROL

49. VIVITROL

50. Important Safety Information VIVITROL is contraindicated in patients receiving opioid analgesics or with current physiologic opioid dependence,patients in acute opiate withdrawal, any individual who has failed the naloxone challenge test or has a positive urine screen for opioids, or in patients who have previously exhibited hypersensitivity to naltrexone, PLG, carboxymethylcellulose or any other components of the diluent. VIVITROL patients must be opioid free for a minimum of 7-10 days before treatment. Attempts to overcome opioid blockade due to VIVITROL may result in a fatal overdose. In prior opioid users, use of opioids after discontinuing VIVITROL may result in a fatal overdose because patients may be more sensitive to lower doses of opioids. VIVITROL[full prescribing information]. Cambridge, MA: Alkermes, Inc; May 2009. 50

51. THE SCIENCE OF RECOVERY:GLUTAMATE NOTION THAT ADDICTION EQUALS TOO MUCH DOPAMINE IS A GROSS OVERSIMPLIFICATIONNOTION THAT ADDICTION EQUALS TOO MUCH DOPAMINE IS A GROSS OVERSIMPLIFICATION IN ANIMAL STUDIESIN ANIMAL STUDIES –EVEN WHEN DA RECEPTORS ARE BLOCKED SOME DRUG-SEEKING BEHAVIOR PERSISTS EXTERNAL CUE DRIVENEXTERNAL CUE DRIVEN –DRUGS AFFECTING DA DIRECTLY HAVE BEEN INEFFECTIVE –INDIRECT APPROACHS SUCH AS INCREASING GABA EFFECT AND REDUCING GLUTAMATE EFFECT SEEM MORE PROMISING (EXAMPLE- TOPIRIMATE) BRAIN WORKS. VOL 18, NO 5, SEPT/OCT 2008, PGS 1 AND 2.

52. THE SCIENCE OF RECOVERY: GLUTAMATE TWO STAGE MODEL OF ADDICTION –STAGE 1-OCCASIONAL DRUG USE BECOMES INCREASINGLY CHRONIC AND UNCONTROLLED. THE NEUROBIOLOGICAL SOURCE OF THESE SYMPTOMS IS DRUG-INDUCED DEREGULATION OF THE BRAIN’S REWARD CENTER DOPAMINE –STAGE2-ADDITIONAL FEATURES INCLUDE WITHDRAWAL SYMPTOMS, PERSISTENT VULNERABILITY TO RELAPSE WITH ALTERATIONS IN DECISION MAKING AND OTHER COGNITIVE PROCESSES DRUG-INDUCED SIGNALS BY NEUROTRANSMITTER GLUTAMATE FROM BRAIN AREAS PRIMARILY ASSOCIATED WITH JUDGMENT

53. THE SCIENCE OF RECOVERY: GLUTAMATE CHANGES IN BRAIN GLUTAMATE SIGNALING INDUCED BY CHRONIC DRUG EXPOSURE HAS A WIDE VARIETY OF NEUROBIOLOGICAL EFFECTS INSTRUMENTAL IN THE TRANSITION FROM DRUG ABUSE TO ADDICTION (KAVALIS,2009) THESE NEURAL ALTERATIONS LIMIT THE ABILITY TO ADAPT TO NEW INFORMATION (TO STOP TAKING DRUGS IN SPITE OF ADVERSE CONSEQUENCES)AND STRENGHTEN THE POWER OF DRUG LEARNED ASSOCIATIONS

54. ADDICTION AND RECOVERY:GLUTAMATE DRUGS AND ALCOHOL REDUCE FLEXIBILITY IN BRAIN INCLUDING REGIONS NEEDED TO CHANGE HABITS –NEEDED TO TRANSLATE WILL INTO ACTION GLUTAMATE CAN HELP REPLENISH THIS FLEXIBILITY ADDICTS STRUGGLE TO BREAK OLD HABITS EVEN THOSE NOT RELATED TO DRUG USE

55. ADDICTION AND RECOVERY:GLUTAMATE ADDICTS CAN LEARN A NEW RULE BUT RUN INTO PROBLEMS WHEN THE RULES CHANGE –COCAINE AND ALCOHOL ABUSERS WERE ASKED TO PRESS KEY EACH TIME THEY SAW A GREEN RECTANGLE ON THE SCREEN –AFTER 500 REPETITIONS TOLD NOT TO PRESS KEY WHEN SAW GREEN RECTANGLE –CONTROLS EASILY ADAPTED WHILE ADDICTS KEPT PUSHING THE KEY EVEN AFTER GIVEN FEEDBACK IMPAIRED REVERSAL LEARNING DUE TO DRUG USE AND NOT GENETICS

56. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: GLUTAMATE Addiction as impairment in reversal learning IN ADDICTION… “WHEN I USE DRUGS I FEEL GOOD” CHANGES TO “WHEN I USE DRUGS BAD THINGS HAPPEN” NEW RULE BUT CANNOT ADAPT

57. ADDICTION AND RECOVERY:GLUTAMATE IMPAIRMENT IN PREFRONTAL CORTEX (PFC) TO REGIONS THAT DRIVE HABITUAL BEHAVIOR SUCH AS THE NUCLEUS ACCUMBENS (NAc) –NEURONS IN PFC RELEASE GLUTAMATE WHICH BINDS TO RECEPTORS AT NAc –THIS TRIGGERS A DISCHARGE OF ELECRICITY THAT CAUSES MESSAGE TO BE PASSED ALONG –THESE SYNAPSES BECOME RIGID IN ADDICTION –NO MATTER HOW MUCH GLUTAMATE IS RELEASED THE SAME AMOUNT OF ELECRICAL ACTIVITY OCCURS –CANNOT FULLY USE THE INFORMATION COMING FROM THE PFC KALIVAS AND VOLKOW. NEW MEDICATIONS FOR DRUG ADDICTION HIDING IN GLUTAMATERGIC NEUROPLASTICITY. MOLECULAR PSYCHIATRY, Vol. 16, no. 10, pages 974-986; October 2011.

58. ADDICTION AND RECOVERY:GLUTAMATE RESEARCH SUGGESTS THAT SEVERAL PARTS OF THE SYNAPSE ARE DAMAGED –COCAINE DECREASES AMOUNT OF GLUTAMATE FLOATING OUTSIDE OF THE NEURON IN NAc PROBABLY CAUSED BY REDUCED NUMBER OF GLUTAMATE-SUPPLYING PROTEIN PUMPS LOCATED IN GLIAL CELLS THESE PUMPS WORK BY IMPORTING CYSTEINE FROM THE EXTRACELLULAR SPACE AND EXPORTING GLUTAMATE INTO THAT SPACE SUPPLYING MORE CYSTEINE SHOULD CAUSE INCREASE IN GLUTAMATE SUPPLY

60. ADDICTION AND RECOVERY:GLUTAMATE N-ACETYLCYSTEINE (NAC) –USED IN ACETAMINOPHEN OVERDOSE AND AS MUCUS BUSTER IN COUGH SYRUPS –IN 2009 KALIVAS SHOWED IN RATS NAC SPURRED THE BRAIN’S GLUTAMATE PUMPS INTO OVERDRIVE RESTORING GLUTAMATE BALANCE AND PLASTICITY TO THE SYNAPSE –IN 2011 KALIVAS LINKED NAC-INDUCED NEUROPLASTICTY TO LESS RELAPSELIKE BEHAVIOR IN RATS –PRELIMINARY STUDIES IN HUMANS SHOW REDUCTION IN DRUG USE WITH NAC SOLIS. A LIFELINE FOR ADDICTS. SCIENTIFIC AMERICAN MIND. MARCH/APRIL 2013, PG. 40-44.

61. ADDICTION AND RECOVERY:GLUTAMATE Clinical trials of N-acetylcysteine to prevent relapse to drug abuse have demonstrated moderate efficacy N-acetylcysteine raises extracellular glutamate in the critically important nucleus accumbens region of the reward system. At lower doses of the medication, the released glutamate stimulates presynaptic receptors (mGluR2/3) on neurons; at higher doses, more glutamate is released and an additional, postsynaptic receptor (mGluR5) is also stimulated.

62. ADDICTION AND RECOVERY:GLUTAMATE The presynaptic stimulation dampens neuronal activity in the nucleus accumbens and, in rats, reduces the tendency to respond to cocaine- associated cues. The postsynaptic stimulation has opposite effects: it intensifies neuronal activity and partly offsets the positive effect on animals’ responses to drug cues. Kupchik, YM, Moussawi K, Tang XC, Wang X, Kalivas BC, Kolokithas R, Ogburn KB, Kalivas PW. The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biological Psychiatry 71(11):978–986, 2012.

63. CORTICOSTRIATAL CIRCUITRY

64. DOPAMINE CIRCUITS –NIGROSTRIATAL CIRCUIT –MESOLIMBIC CIRCUIT –MESOCORTICAL CIRCUIT

65. NIGROSTRIATAL CIRCUIT The nigrostriatal pathway, or the nigrostriatal bundle (NSB), is a dopaminergic pathway that connects the substantia nigra with the striatum and is particularly involved in the production of movement. Loss of dopamine neurons in the substantia nigra is one of the main pathological features of Parkinson’s disease. This pathway is also implicated in producing tardive dyskinesia one of the side-effects of antipsychotic drugs.

66. NIGROSTRIATAL CIRCUIT

67. MESOLIMBIC CIRCUIT The mesolimbic pathway begins in the ventral tegmental area and connects to the limbic system via the nucleus accumbens, the amygdala, and the hippocampus as well as to the medial prefrontal cortex. The mesolimbic pathway is shown to be associated with feelings of reward and desire, this pathway is heavily implicated in neurobiological theories of addiction, schizophrenia and depression.

68. MESOLIMBIC CIRCUIT

69. MESOCORTICAL CIRCUIT The mesocortical pathway is a dopaminergic pathway that connects the ventral tegmental area to the cerebral cortex, in particular the prefrontal cortex It is essential to the normal cognitive function of the dorsolateral prefrontal cortex and is thought to be involved in cognitive control, motivation and emotional response Schizophrenia, ADHD

70. CORTICOSTRIATAL CIRCUITRY This impairment could arise from two general pathologies in corticostriatal circuitry: addicts could have pathologically strengthened drug- seeking behaviors, or they could have pathological impairments in the capacity to control drug-seeking behaviors. These two possibilities are not mutually exclusive. Corticostriatal circuitry has two subcircuits: the limbic subcircuit, which comprises brain regions such as the prefrontal cortex, the amygdala, the nucleus accumbens (NAc) and the ventral tegmental area (VTA); and the motor subcircuit, which contains the motor cortex, the dorsal striatum and the substantia nigra.

71. CORTICOSTRIATAL CIRCUITRY Corticostriatal projections are responsible not only for generating learnt, well-established behaviors such as in drug taking, but also for changing behaviors in response to a variable environment, and thereby generating new adaptive behaviors Addicts have difficulty modulating drug-seeking behaviors with information that should suppress the behavior

72. CORTICOSTRIATAL CIRCUITRY The NAc serves as a gateway through which information that has been processed in the limbic subcircuit gains access to the motor subcircuit. Relapse to compulsive drug seeking arises from an impaired ability of the limbic subcircuit to effectively process and/or use the negative environmental contingencies associated with relapse. The result is that behavior is dominated by the previously learnt, well-established drug-seeking strategies.

73. THE SCIENCE OF RECOVERY: COGNITIVE FUNCTION Addiction is a disorder of altered cognition Addiction impacts… –LEARNING –MEMORY –ATTENTION –REASON –IMPULSE CONTROL Effects are particularly disruptive when exposed during brain development and in the co-occurring population

74. THE SCIENCE OF RECOVERY: COGNITIVE FUNCTION Cognitive deficits in chronic drug abuse –Withdrawal produces cognitive symptoms Cocaine-deficits in cognitive flexibility Amphetamine-deficits in attention and impulse control Opioids-deficits in cognitive flexibility Ethanol-deficits in working memory and attention Cannabis-deficits in cognitive flexibility and attention Nicotine-deficits in working memory and declarative learning

75. THE SCIENCE OF RECOVERY: COGNITIVE FUNCTION Why give an alcoholic or addict a 60 minute didactic or video? A new format –15-20 minute simple didactic How to participate in treatment –10 minute questionnaire –30 minute discussion group

76. THE SCIENCE OF RECOVERY: COGNITIVE FUNCTION I THINK……….. I FEEL………….. I LEARNED…… MY FUTURE BEHAVIOR WILL CHANGE…

77. THE SCIENCE OF RECOVERY RELAPSE FALLS ALONG A SPECTRUMRELAPSE FALLS ALONG A SPECTRUM

78. THE SCIENCE OF RECOVERY CRAVING MANAGEMENT Though some relapse triggers can be consciously avoided, such as people, places and things related to drug use, other subconscious triggers related to the brain's reward system may be impossible to avoid - - they can gain entry to the unconscious brain, setting the stage for relapse. Baclofen, commonly used to prevent spasms in patients with spinal cord injuries and neurological disorders, can help block the impact of the brain's response to "unconscious" drug triggers well before conscious craving occurs.

79. THE SCIENCE OF RECOVERY CRAVING MANAGEMENT Subliminal drug "reminder cues" (the sights, sounds, smells, and memories of the drug) could activate the brain's reward circuit. 23 cocaine-dependent men, ages 18 to 55. Each reported using cocaine on at least eight of 30 days before screening. Inclusion in the study required that they stay for up to 10 days in a supervised inpatient drug treatment facility, be drug-free for the duration, not be on any medication affecting dopamine or neurotransmitter response, and have no history of psychosis, seizures, or brain syndromes unrelated to cocaine use.

80. THE SCIENCE OF RECOVERY CRAVING MANAGEMENT Upon admission, patients were randomized to receive baclofen or placebo. Over the first six days, patients in the baclofen group received the medication in increasing dosage to 60 mg. While on the full 60 mg dose of baclofen, patients were placed in an fMRI and shown a series of images, to measure their neural responses to "ultra-brief" pictures of cocaine or other comparison pictures. Each of the ultra-brief 33 msec "target" pictures was immediately followed by longer picture of non-drug objects or scenes. Under these conditions, the participants are aware of the longer pictures, but the ultra-brief target pictures remain completely outside conscious awareness -- they are "backward-masked."

81. THE SCIENCE OF RECOVERY CRAVING MANAGEMENTNT What the team found was that the patients who were treated with baclofen showed a significantly lower response in the reward and motivational circuits to subliminal cocaine cues versus neutral cues, as compared to the placebo-treated control group. K. A. Young, T. R. Franklin, D. C. S. Roberts, K. Jagannathan, J. J. Suh, R. R. Wetherill, Z. Wang, K. M. Kampman, C. P. O'Brien, A. R. Childress. Nipping Cue Reactivity in the Bud: Baclofen Prevents Limbic Activation Elicited by Subliminal Drug Cues. Journal of Neuroscience, 2014; 34 (14)

82. ROBIN WILLIAMS “I realized... you keep going with this, you’ll wake-up in a field with a small animal,” laughed Williams. “If you’re violating your standards faster than you can lower them, time to go away.”

83. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT YOU CANNOT EXTINGUISH A BAD HABIT; YOU CAN ONLY CHANGE IT

84. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT THE CUE TRIGGERS THE ROUTINE AND ALSO TRIGGERS THE CRAVING FOR THE REWARD TO COME

85. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT When a habit begins the whole brain is activated as it actively processes all of the stimuli After this phase the higher brain begins to reduce level of activation Then even the memory centers reduce activity BASAL GANGLIA has now taken control of recalling the patterns and acting on them

86. BASAL GANGLIA

87. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT LOOP

88. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT CUE AND REWARD BECOME INTERTWINED CREATING A CRAVING (CONDITIONING) In a habit the brain reduces emphasis on decision making Pattern unfolds automatically unless you find a new routine After craving develops, cannot extinguish a bad habit, you can only change it

89. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT LOOP

90. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT ALMOST ANY HABIT CAN CHANGE IF YOU KEEP THE SAME CUE(S) AND SAME REWARD ALCOHOLICS ANONYMOUS changes the habit loop ALCOHOLICS ANONYMOUS succeeds because it helps use the same cues and get the same rewards but shifts the routine

91. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT To change a habit must address the same cues and rewards as before and feed the craving by inserting a new routine WHAT DO ALCOHOLICS AND ADDICTS CRAVE? –It isn’t a craving to be drunk –Physical effects of alcohol are the least rewarding (the same can be said for cocaine, methamphetamine, etc.) –Is it connection, reduce anxiety, forget worries? –Meetings and companionship-another bar to escape to, catharsis, distraction

92. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT What is the pleasure we seek in the first place? –Is it… COMPLETION RELAXATION TO FORGET TO CONNECT TO REWARD MYSELF TO GIVE ME COURAGE TO FEEL LIKE YOU BELONG AS ONE OF THE GROUP

93. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT ALMOST ANY HABIT CAN CHANGE IF YOU KEEP THE SAME CUE(S) AND SAME REWARD ALCOHOLICS ANONYMOUS changes the habit loop –AA offers… Escape Catharsis Distraction Relief via talking

94. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT ALCOHOLICS ANONYMOUS succeeds because it helps use the same cues and get the same rewards but shifts the routine AA forces new routines for what to do each night as opposed to drinking To change a habit must address the same cues and rewards as before and feed the craving by inserting a new routine WHAT DO WE CRAVE? –Is it connection, reduce anxiety, forget worries? –Meetings and companionship-another bar to escape to, catharsis, distraction

95. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT What is the thirst behind the thirst? –“I was thirsty because I was feeling incomplete and alcohol helped me feel more connected, more alive.” –Bill Wilson, “Before A.A. we were trying to drink God out of a bottle.” –Gerald May- a deep yearning for fulfillment or completion; a longing to love and be loved and a desire for the source of this love-God

96. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT What is the thirst behind the thirst? His craving for alcohol was the equivalent, on a low level, of the spiritual thirst of our being for wholeness, expressed in medieval language: the union with God.” –The great analyst Carl J. Jung put it thus, “His craving for alcohol was the equivalent, on a low level, of the spiritual thirst of our being for wholeness, expressed in medieval language: the union with God.” –An intense, urgent, or abnormal desire or longing. At the time it seems more painful than any other longing. It subsumes us and we are a slave to it…and it seems it will never end. Although not understood in that moment, it is really a powerful thirst to go “home.”

97. THE SCIENCE OF RECOVERY: THE SCIENCE OF RECOVERY: HABIT REPLACEMENT ROUTINES ONLY BECOME DURABLE NEW BEHAVIORS WHEN SPIRITUALITY IS ADDED (this is what gets you through the major crises in your life) PATTERN: –Could only stay sober by habit replacement until a major crisis hit –Add spiritual element and now can get through these tough times

98. DOPAMINE (DA) TONE-GENDER DIFFERENCES WOMEN ESCALATE FASTER TO HEAVY USE WOMEN MORE READILY SUCCUMB TO SOCIAL AND PHYSICAL DAMAGE REPRODUCTIVE HORMONES MAY UNDERLIE THIS SUSCEPTIBILITY –REMOVE OVARIES OF FEMALE RAT (NO LONGER PRODUCE ESTROGEN) AND REDUCE DRUG SEEKING BEHAVIOR FOR COCAINE AND AMPHETAMINE

99. DOPAMINE (DA) TONE-GENDER DIFFERENCES ESTROGEN MAY SPUR ADDICTION BY STIMULATING BRAINS REWARD PATHWAYS ENHANCING “HIGH” BY INCREASING DA (ANTHES, EMILY. “SHE’S HOOKED”. SCIENTIFIC AMERICAN MIND. MAY/JUNE 2010, PGS.14-15.) PROGESTERONE APPEARS TO OPPOSE ESTROGEN’S ABILITY TO PROMOTE ADDICTION GIVE BOTH ESTROGEN AND PROGESTERONE TO RATS WITHOUT OVARIES AND NO ACCELERATION OF ADDICTION

100. DOPAMINE (DA) TONE-GENDER DIFFERENCES FEMALE RESPONSE VARIES ACROSS MENSTRUAL CYCLE AS LEVELS OF ESTROGEN AND PROGESTERONE WAX AND WANE (2007, SUZETTE EVANS, COLUMBIA UNIVERSITY) –STIMULANTS MORE PLEASURABLE TO WOMEN DURING ESTROGEN-DOMINATED FOLLICULAR PHASE WHICH OCCUPIES APPROXIMATELY 2 WEEKS FROM ONSET OF PERIOD UNTIL OVULATION THAN DURING THE LUTEAL PHASE AFTER OVULATION WHEN BOTH ESTROGEN AND PROGESTERONE ARE HIGH

102. DOPAMINE (DA) TONE-GENDER DIFFERENCES ASKED ONE-HALF OF 202 FEMALE CIGARETTE SMOKERS TO TRY TO ABSTAIN DURING LUTEAL PHASE AND THE OTHER HALF TO TRY TO ABSTAIN DURING THE ESTROGEN RICH FOLLICULAR PHASE –THIRTY-FOUR (34) PERCENT OF WOMAN IN FIRST GROUP HAD NOT SMOKED AT 30 DAYS –FOURTEEN (14) PERCENT OF WOMEN IN THE SECOND GROUP HAD NOT SMOKED AT 30 DAYS (2008, SHARON ALLEN, UNIVERSITY OF MINNESOTA MED SCHOOL)

103. DOPAMINE (DA) TONE- GENDER DIFFERENCES Smoking today's concentrated pot might be risky business for women, according to new research. Thanks to their estrogen levels, female rats are at least 30 percent more sensitive than males to the pain-relieving qualities of THC -- the key active ingredient in cannabis, research shows. Females also develop tolerance to THC more quickly. These sensitivities could increase vulnerability to negative side effects like anxiety, paranoia and addiction.

104. DOPAMINE (DA) TONE- GENDER DIFFERENCES Margaret Haney at the Columbia University Medical Center, has shown that women are more susceptible to cannabis abuse and dependence than men. Haney has documented a cannabis withdrawal syndrome of irritability, sleep disruption and decreased food intake that tends to be more severe in women. Women also have a greater tendency to relapse when trying to stop using the drug

105. DOPAMINE (DA) TONE- GENDER DIFFERENCES We're finding with THC is that you get a very clear spike in drug sensitivity right when the females are ovulating -- right when their estrogen levels have peaked and are coming down Alexa A. Wakley, Jenny L. Wiley, Rebecca M. Craft. Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat. Drug and Alcohol Dependence, 2014; DOI: 10.1016/j.drugalcdep.2014.07.02910.1016/j.drugalcdep.2014.07.029 Washington State University. "Estrogen increases cannabis sensitivity, study shows." ScienceDaily. ScienceDaily, 3 September 2014..