Arwen Evenstar Podesta, MD

Integrative Treatments for Addiction

Arwen Evenstar Podesta, MD Speaker: Alkermes, Indivior, Pear Advisory Board: Alkermes, Pear, Sage Surfer Clinical Adjunct Faculty • Tulane University Past President Psychiatry Department • Louisiana chapter of the • Louisiana State American Society of University department Addiction Medicine of Psychiatry (OLOL) (ASAM) Arwen Podesta, MD, DFASAM, 3 DFAPA, ABIHM www.podestawellness.com Attending Physician, Medical Director Distinguished Fellow • Podesta Wellness, LLC • American Psychiatric • Project Cultivate Association (APA) Definition of Addiction

Addiction is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired 4 control over drug use, compulsive use, continued use despite harm, and cravings. (ASAM definition) • 2017-2018, synthetic opioid-related death rates increased by 10%, accounting for 67% of opioid-involved deaths in 2018.1 • 2018 average opioid prescribing rate was 51.4 prescriptions per 100 people, yet some U.S. counties had rates 6x higher. 1 • 2017, cocaine overdoses increased by >34%, with almost 14,000 Americans dying from an overdose. 2 • 2018, 53.2 million people aged 12+ used illicit drugs in the past year. 2 • 1999-2017, U.S. saw 10-fold increase in fatal overdoses What are we involving benzodiazepines. 2 • 2006-2016, Amphetamine prescribing increased 2.5x (7.9 to 20.0 tons). 3 up against? • As of 2019, deaths from meth have more than tripled since 2014.4 • More than 87,000 Americans died of drug overdoses over the 12-month period that ended in September 2020, more than any other year since the current opioid epidemic began in the 1990s.

1. Centers for Disease Control and Prevention. (2020). US opioid prescribing rates map. http://cdc.gov/drugabuse 2. SAMHSA.(2019). 2018 NSDUH national report. SAMHSA.gov 3. Piper et al. (2018). Trends in use of prescription stimulants in the United States and Territories, 2006 to 2016. PLoS ONE 13 (11): e0206100. 4. Centers for Disease Control and Prevention. (2017). Wide-ranging online data for epidemiologic research (WONDER). 5 http://wonder.cdc.gov. Overdose Trends in Four Classes of Opioids

National Fatal Overdose Data for Opiates

(2008-2018)

Wilson N, Kariisa M, Seth P, Smith H, Davis NL. (2020). Drug and Opioid-Involved Overdose Deaths - United States, 2017-2018. MMWR Morb Mortal Wkly Rep. 69(11):290‐297. doi:10.15585/mmwr.mm6911a4 6 Age-adjusted Change in Fatal Opioid Overdoses (2013-2017)

U.S. Opioid Deaths by State

Scholl, L., Seth, P., Kariisa, M., Wilson, N. & Baldwin, G. (2019). Drug and opioid-involved overdose deaths- United States, 2013-2017. Centers for Disease Control: Weekly. 67(5152):1419-1427. Retrieved from: https://www.cdc.gov/mmwr/volumes/67/wr/mm675152e1.htm?s_cid=mm675152e1_w 7 https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm Traditional treatment

• Abstinence based programs • Counseling • 12-step • Medication Assisted Therapy

9 Traditional treatment works … but not well enough

• Typical gold standard evidenced treatment fails 34% of patients • 50% of those who relapsed within the first year [after treatment] relapsed within the first month • Relapse on opioids is risk for overdose/death. NOT ACCEPTABLE

Vista Research Group. (2017). Learning from three years of addiction treatment outcomes research. Retrieved from https://www.vista-research-group.com/outcomes- research Abstinence Medication Assisted Treatment • high relapse after treatment • Average retention in care for those receiving timely buprenorphine was 123 35.6% abstinent 6 months post-treatment • days, naltrexone was 150 days, and • 36.2% abstinent 12 months post-treatment methadone was 324 days, compared to only 67 days for those solely receiving behavioral health services. Detox with psychosocial treatment • Relapse rates > 90% • Maintenance MAT with higher treatment retention than tapering off MAT (66% vs 11%)

Gossop M, et al. Addiction. 2003;98(3):291-303. Weiss RD, et al. Arch Gen Psychiatry. 2011;68(12):1238-1246. Mattick RP, et al. Cochrane Database Syst Rev. 2009;(3):CD002209. Nielsen S, et al. Cochrane Database Syst Rev. 2016;(5):CD011117. Fiellin DA, et al. JAMA Intern Med. 2014;174(12):1947-1954. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy. (2018). Medication-assisted treatment for opioid use disorder: Proceedings of a workshop—in brief. Wa Hadland, S.E. et al. (2018). Receipt of timely addiction treatment and association of early medication treatment with retention in care among youths with opioid use disorder. JAMA Pediatr. 172(11): 1029-1037. Get people into treatment

• Destigmatize • Language matters • Addict • Addiction • Addictions • Substance Use Disorders • Dependence • Abuse • Physiological Dependence • Dirty/Clean • Make whole treatment accessible and available • Anyone with a DEA# can apply for X # to prescribe Buprenorphine (2021) • Funding for treatment programs and prevention

12 1. The understanding of opioid-use disorder as 13 a medical illness is still overshadowed by its misconception as a moral weakness or a Four Factors willful choice. Contributing 2. The separation of opioid-use disorder treatment has meant clinicians overlook to Stigma other health issues. 3. Loaded language furthers the stigma on Opioid associated with the condition. Use 4. The criminal justice system’s unwillingness to yield to medical judgment in the treatment Disorders of opioid-use disorders. Language matters

14 Alcohol Stimulant (not FDA approved, all FDA Approved: off-label) -Disulfiram (Antabuse), -Gabapentin, Bupropion, Modafinil, Topiramate, Disulfiram, Baclofen, PO naltrexone , IM naltrexone Propranolol, Naltrexone (Vivitrol), Acamprosate (Campral) Non-FDA-approved: Nicotine -Topiramate (Topamax) FDA Approved; 15 -Baclofen -Bupropion SR (Zyban) -Varenicline (Chantix) Opioids Pharmacotherapy for -Nicotine replacement maintenance FDA Approved: therapies: Patch, gum, lozenge, treatment for various -Methadone inhaler addiction -Buprenorphine (Subutex, Non-FDA Approved; Suboxone, Zubsolv, Bunavail, -Nortriptyline Sublocade) -Naltrexone -Naltrexone (oral naltrexone, Vivitrol) Medications Affecting the Opioid Receptor (MAT for OUD)

(Methadone)

(Buprenorphine)

(Naltrexone)

(Naloxone)

16 X-BOT Comparative Treatment Study

Buprenorphine vs. Extended Release Naltrexone

Overview • 24 week trial, 570 randomized opioid dep, NIDA funded • Partial agonist (Buprenorphine) and antagonists (Extended Release Naltrexone) are not inferior to one another • Access, setting, and patient preference must be considered

Lee, JD et al. (2018). Comparative effectiveness of extended-release naltrexone versus buprenorphine- 17 naloxone for opioid relapse prevention (X:BOT): A multicentre, open-label, randomised controlled trial. The Lancet. 391(10118): 309-318. Integrative and novel approaches to augment traditional addiction treatment

Traditional treatment works … but not well enough

18 • Integrate SUD treatment into primary care to address growing SUD population • The integration of primary care and addiction can help address these often interrelated physical illnesses by ensuring higher quality care • Chronic Disease Approach with Person Centered Care • Self-management and recovery support • Person Centered • Self-directed and based on partnership between individual, providers, and when appropriate, family • Team approach, collaboration • Clinical decisions evidence-based • Information sharing 19 • Community resources (e.g., housing, employment) • Nutrition, relaxation, meditation, creativity, Chinese alternative medicine and herbs, yoga, acupuncture, spirituality and exercise are offered to treat the “whole Integrative individual.” Approaches • Replenish building blocks/ co-factors • Repair of cellular damage • Switch genes back on/off • Epigenetic changes • Support and reversal of cravings • TRANSFORMATION • Detailed clinical interview (personal hx- drug use, effect of drug, MER, RID, Fam hx, recent use) • Blood work up (vitamins, thyroid, infectious dz, anemia, etc.)

20 • Urine testing (specific drugs in system, pregnancy) Precision • Genetic testing Approaches • Other testing- toxins, gut microbiota, etc. Opioid Detox

21 Opioid Detoxification

• Often superior if multiple modalities are implemented • Buprenorphine (short or long term) • Comfort medications • Percutaneous nerve field stimulator • Bridge • S.T. Genesis • IV NAD (opi and alcohol) • IV Ketamine

22 Percutaneous nerve field stimulator

• FDA authorized in 2017 • Small electrical nerve stimulator placed behind the ear emitting electrical pulses to stimulate branches of certain cranial nerves, providing relief from opioid withdrawal symptoms including sweating, gastrointestinal upset, agitation, insomnia and joint pain. Can be used up to 5 days. • Bridge device (masimo.com/bridge) • S.T. device (speranzatherapeutics.com)

23 Percutaneous nerve field stimulator

24 Opioid, Alcohol or other drug detox

25 Nicotinamide Adenine Dinucleotide (NAD+)

• Craving reduction with IV NAD+ • Adenosine hypothesis (combines w DA, creates a dimer, that dimer modulates the dopamine receptor • Modulates MAO-A transcription (role in modulating anxiety and depression within the stress response pathway) • Mitochondrial fission hypothesis (regulates energy homeostasis – having an effect on drug-seeking behavior, specifically in cocaine use) • NAD is implicated in oxytocin signaling – important in food selection, promoting health and stress resistance Delivery systems- SPG (under study, pilot data being gathered) – used because couldn't get a vein, so used subQ, patches , spg, - good response. • -8-isoprostane (markers of oxidative stress)-increased in addicts compared to non. after NAD opioid patients had continue decrease after NAD, vs alcohol pts

Braidy, N., Villalva, M. D., & van Eeden, S. (2020). Sobriety and Satiety: Is NAD+ the Answer?. Antioxidants (Basel, Switzerland), 9(5), 425. https://doi.org/10.3390/antiox9050425

26 Figure 2. NAD Significantly Reduces Craving Ratings Associated With Opiate and Alcohol Withdrawal At Five And Ten Days of Treatment 10 OPIATE 9 ALCOHOL 8 7 6 5 4

Craving Rating Craving 3 2 * 1 0 DAY 1 DAY 5 DAY 10 Pairwise T-tests Conducted on Day 1 vs Day Axis5 and Title Day 1 vs Day 10 in Opiate (n=29) and Alcohol (n=24) Groups. * indicates p < 0.01. Society for Neuroscience, 2015 Poster Presentation. Intravenous Administration of Nicotinamide Adenine Dinucleotide Significantly Reduces Self Report Craving Ratings Associated with Opiate and Alcohol Withdrawal *S. L. BROOM1, R. MESTAYER2, E. STULLER3, D. COOK4, J. CARSON2, K. SIMONE2, P. NORRIS2, P. HOTARD2 1Dept Psychol, William Carey Univ., Hattiesburg, MS; 2Springfield Wellness Center, Springfield, LA; 3Stullerresettings, LLC; 4 Genomics

28 Using Genomics for Addiction and Mental Health

Companies that use pharmacogenomics:

•Genesight – Analyzes how your genes affect outcomes with medications used to treat depression, anxiety, ADHD and other mental health conditions •Genomind – Analyzes genetic implications for 130 mental health medications and is both pharmacodynamic and pharmacokinetic. •IntellxxDNA™ – Uses some pharmacogenomic interventions such as ADHD med response and some addiction medication response.

Companies that look at root cause genomics

•IntellxxDNA™ – Studies over 500 clinically relevant SNPs to improve outcomes, preventing chronic illnesses and optimizing brain health. Focuses on extensive genomic contributing factors to addiction, OCD, anxiety, depression, inflammation, detox, nutrigenomics, methylation, PANDAS, PANS, and Autism. •Genomind – 15 SNPs relating to depression, anxiety primarily focused on the body’s sensitivity or response to certain medications. How do you use genomics to your benefit?

• Studying genomics can help you understand the pathophysiology of disease. • Genomics allows you to make better, patient specific clinical decisions. • Personalized medicine approach helps patients get well faster. • IntellxxDNA™ is a clinical decision support tool designed specifically for functional and integrative clinicians. • Covers functional medicine core topics like gut health, inflammation, detox, nutrigenomics as well as mental wellness panels

Slides adapted with permission. © IntellxxDNA™2021. All rights reserved Plus Many More topics…. The IntellxxDNA™ report is a great online educational tool, that will help you learn genomics as you use it.

- Different reports available: - Typical psychiatric concerns - Reversal of cognitive decline

32 • Ketamine can possibly offer another way to tackle the reconsolidation-interference approach not IV Ketamine addressed by top down CBT approaches • A framework that addiction is reward behavior, can possibly reward center learned process alter • 90 heavy beer drinking subjects • Memory retrieval +Ketamine Maladaptive • Memory retrieval + Placebo Reward • Ketamine only Memories • 10 days post Ketamine: Memory retrieval + Ketamine • craved alcohol significantly less • drank significantly less than • Decreased weekly number of drinking days.

Das, R.K. (2019). Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nature Communications. 10: 5187 Ketamine Assisted Psychotherapy (KAP)

• A single dose of Ketamine combined with mindfulness improved treatment outcomes for those with cocaine dependence • 55 individuals randomized to ketamine IV for 5 hours vs midazolam IV (control) plus 5 weeks mindfulness based relapse prevention • 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, vs with 10.7% in the midazolam group • The bioavailability of oral ketamine is low (8% for esketamine and 24% for ketamine), yet studies are very promising that oral plus therapy consolidates therapeutic goals. Useful so far in depression, anxiety, bipolar. Likely will have utility with addiction, in some circumstances.

Dakwar E, et al. Am J Psychiatry. 2019;176(11):923-930. 34 Rosenblat J. D., Carvalho A. F., Li M., Lee Y., Subramanieapillai M., McIntyre R. S. (2019). Oral ketamine for depression: a systematic review [published correction appears in

Psilocybin (+CBT) and smoking cessation

• Small study- 15 psychedelic naïve daily smokers, each having tried to quit multiple times. • Psilocybin (+CBT) 6 month outcome: 80% success

• Traditional treatment outcomes • Varenicline 6 month outcome: 35% • Nicotine replacement 6 month outcome: 30%

35 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286320/ (2015 study, johns Hopkins) Meta-analysis of 6 RCTs showing significance of LSD for alcohol dependence

Krebs TS, Johansen PØ. Lysergic acid diethylamide (LSD) for alcoholism: meta- analysis of randomized controlled trials. J Psychopharmacol. 2012 Jul;26(7):994- 1002. doi: 10.1177/0269881112439253. Epub 2012 Mar 8. PMID: 22406913.

36 37 38 There was evidence for a beneficial effect of LSD on alcohol misuse (OR, 1.96; 95% CI, 1.36-2.84; p = 0.0003). Between-trial heterogeneity for the treatment effects was negligible (I² = 0%). Secondary outcomes, risk of bias and limitations are discussed. A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.

39 Ibogaine

• Ibogaine is one of a dozen alkaloids present in the root bark of the Tabernanthe iboga plant, traditionally used in Gabon, Cameroon and other parts of West central Africa in Shamanic rituals of the Bwiti religion (Alper, 2001). Around 1960, ibogaine gained more attention in the West when Howard Lotsof, an opioid-dependent patient, discovered that ibogaine might be a useful therapeutic tool in the treatment of drug addiction, particularly in the alleviation of opioid craving (Alper, 2001; Brown, 2013)

Schenberg EE, de Castro Comis MA, Chaves BR, da Silveira DX. Treating drug dependence with the aid of ibogaine: a retrospective study. J Psychopharmacol. 2014 Nov;28(11):993-1000. doi: 10.1177/0269881114552713. Epub 2014 Sep 29. PMID: 25271214. 40 41 Ibogaine treatment in polysubstance use disorders

• Retrospective study • N=75; alcohol, cannabis, cocaine and crack users (72% poly- susbstance) • Treatment occurred between Jan 2005 – March 2013 • Twenty ibogaine HCl sessions (20%) occurred between 2008 and 2009, 53 (40%) between 2010 and 2011 and 52 (40%) between 2012 and March 2013 • All 75 patients underwent at least one ibogaine session. • 33 (44%) took it twice • 14 (19%) took it three times • 5 (7%) participated in four sessions • 2(3%) were administered ibogaine five times • 1(1%) took ibogaine nine times. • Mean time interval between the first and second ibogaine sessions among all participants was 245.34 ± 226.297 days (range 31–979)

42 Ibogaine treatment in polysubstance use disorders- Results • No serious adverse reactions or fatalities • 61% of participants abstinent • Participants treated with ibogaine only once reported abstinence for a median of 5.5 months and those treated multiple times for a median of 8.4 months (p < 0.001) • Both single or multiple treatments led to longer abstinence periods than before the first ibogaine session (p < 0.001) • Results suggest that physician supervised ibogaine along with psychotherapy can facilitate prolonged periods of abstinence, without side effects or complications.

43 Cannabinoids may aid in the reduction of the opioid use epidemic

 CB1 and mu opioid receptors share many similarities  Distributed in similar regions of the brain  periaqueductal gray, locus coeruleus, ventral tegmental area, nucleus accumbens, prefrontal cortex, central amygdala, bed nucleus of stria terminalis, caudate, putamen, substantia nigra, dorsal hippocampus, raphe nuclei, and medial basal hypothalamus  Bidirectional relationship in the reward pathway of drug misuse  Both are G-protein coupled receptors  In pre-clinical models, coadministration of opioids and cannabinoids attenuated the development of opioid tolerance  Numerous pre-clinical studies have shown that cannabis and cannabinoids decrease opioid withdrawal symptoms BUT CB1 agonism also increases the rewarding properties of opioids

• Mechanisms underlying cannabis alteration of opioid consumption are still to be determined • There is significant pre-clinical in rodent models suggesting that CBD • does not have reinforcing effects in rodents, supporting low potential for misuse. • reduces the rewarding aspects of multiple drugs of abuse, such as cocaine, amphetamine and nicotine • attenuates morphine drug-induced conditioned place preference and cue- induced reinstatement of heroin self-administration in rats, without creating any aversive or rewarding effects on its own

Wiese B, Wilson-Poe AR. Emerging Evidence for Cannabis' Role in Opioid Use Disorder. Cannabis Cannabinoid Res. 2018 Sep 1;3(1):179-189. doi: 10.1089/can.2018.0022. PMID: 30221197; PMCID: PMC6135562. 45 Escitalopram vs Psilocybin for depression • Phase 2, double-blind, randomized, controlled trial, N=59 • Patients with long-standing, moderate-to-severe major depressive disorder, • compared psilocybin with escitalopram over a 6-week period. Patients assigned in a 1:1 ratio to receive: • Two separate doses of 25 mg of psilocybin 3 weeks apart + 6 weeks of daily placebo (psilocybin group) • Two separate doses of 1 mg of psilocybin 3 weeks apart + 6 weeks of daily oral escitalopram (escitalopram group) • All patients received psychological support. • Primary outcome: change from baseline in score on Quick Inventory of Depressive Symptomatology–Self-Report

Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021 Apr 15;384(15):1402-1411. doi: 10.1056/NEJMoa2032994. PMID: 33852780. 46 47 Primary outcomes: At 6 weeks, no significant difference in outcomes. Hyperbaric Oxygen

 The proposed mechanism of action of hyperbaric oxygen in traumatic brain injury is that increasing oxygenation of blood and tissues to supraphysiological levels results in the improvement of neuronal functioning by the reactivation of metabolic or electrical pathways.

48 https://www.ncbi.nlm.nih.gov/books/NBK253746/  Sample of N = 340 pts w addiction (223 alcohol, 68 other, 49 49 HBOT: opioid)  Group of 155 receiving HBOT + MAT (experimental) with Comparing group of 185 receiving MAT alone (control)  Group receiving HBOT + MAT showed an approximate two- MAT with fold decrease in the duration of their treatment stay, with quicker reduction in psycho-neurological and physiological HBOT to symptoms associated with substance use.

MAT Only in  Also showed positive increase in markers for healthier Detox and cardiovascular functioning.  Experimental group showed far better and quicker recovery, Recovery where positive effects lasted even after conclusion of their treatment.

Epifanova, NM. (1995). Hyperbaric oxygenation in the treatment of patients with drug addiction, narcotic addiction and alcoholism in the post-intoxication and abstinence periods. Anestaziol Reanimatol. (3):34-9. Acupuncture technique Theralase (laser acupuncture)

NADA

50 Acupuncture for Substance Use Disorder: Review of the NADA technique • Study by Russel and colleagues (2010), N=261, of SUD individuals receiving NADA for 3 months showed stat sig reduction in overall use of substance (p= 0.01) and decrease in withdrawal symptoms (p < 0.05).

• Study by Ashton and colleagues (2009), N = 162 of alcohol users receiving NADA each week showed stat sig decrease in alcohol consumption at 2 months (p < 0.001) and 6 months (p < 0.001) • Also showed significant improvements on psychological measures: BDI; Beck Depr Inv (p < 0.002), CGI: Clin Glob Impr (p < 0.001), ASI: Add Sev Index (p < 0.05), Anxiety (p < 0.05)

• Study by Jassen and colleagues (2005), N = 86, tested program retention of methamphetamine users receiving NADA regularly each week. • Stat sig predictor of program retention at 30 days (p < 0.0001), 60 days (p < 0.05), 90 days (p < 0.001), 120 days (p < 0.01) and 150 days (p < 0.05).

• Many studies which report using NADA technique for only several days did not yield much significance. • Studies using NADA regularly each week for several weeks had more promising results

Motlagh et al. (2016). Acupuncture therapy for drug addiction. Chin Med. 11:16. DOI 10.1186/s13020-016-0088-7 51 NADA technique

Carter, K., Olshan-Perlmutter, M., Marx, J., Martini, J. F., & Cairns, S. B. (2017). NADA ear acupuncture: An adjunctive therapy to improve and maintain positive outcomes in substance abuse treatment. Behavioral Sciences. 7(2), 37. https://doi.org/10.3390/bs7020037 Theralase (laser acupuncture) for smoking cessation • 549 adult subjects • Each received up to 5 laser treatments on specific auricular and peripheral acupuncture points with the Theralase therapeutic medical laser system • At the 30 day follow-up, 405 subjects had met the outcome criteria and had reduced their consumption of tobacco products by 25% or more (73.8%) • 373 of those subjects (67.9%) completely eliminated use of tobacco products • 32 of those subjects (5.8%) did not quit but reduced tobacco by at least 25% • 144 subjects showed less than 25% improvement in the quantity of tobacco products consumed at baseline (26.2%) • There were no adverse effects reported by any subject

53 Digital therapeutics and devices

54 reSET- for individuals with substance use disorder (not just alcohol use, and not only opioids) reSET-O- for individuals with opioid use disorder, taking partial Digital agonist (buprenorphine) Therapeutics: • FDA authorized prescription digital applications for smartphones • 12 weeks per prescription • CBT, Fluency Training, Contingency Management reSET & reSET-O • 24-7 are the 1st • Clinician dashboard to monitor progress and use PDT to FDA • Augments therapy • reSEt outcomes: A 12-week clinical study showed that patients authorization, using reSET were more than 2x more likely to abstain from Dec 2018 substance use than those who didn't use reSET • reSEt-O outcomes: 82% of patients that added reSET-O to buprenorphine regimen stayed in treatment during the 12 weeks vs 68% who did not add reset-O to buprenorphine Digital Therapeutics: reSET & reSET-O Cranial electrotherapy stimulation (CES)

• Neurostimulation • Transcranial pulsed-current stimulation via electrodes to the head • Daily use for 20-30 minutes • Anxiety, Pain, Insomnia, Depression • FDA cleared devices • Alpha-Stim • Fisher Wallace Stimulator • CES Ultra (Neuro-Fitness, LLC) • Caputron MindGear • Neurocare NeuroMICRO

57 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882621/ Alpha-Stim

58 Alpha-stim

59 Coordination of care platforms for individuals and caregivers

• Digital apps for individuals that integrate into platforms of providers (and EHRs) to help members and caregivers navigate a convoluted healthcare system

• Goal • improve health outcomes of a high-risk individual by synchronizing information • increase revenue opportunities • lower costs • A care coordination platform allows providers to quickly and securely share patient records and provide wrap around services, increasing level of care if needed

60 61 …

62 We drive mental healthcare at your own terms

SageSurfer provides technology to deliver evidence based integrated care

Focused on both Mental Focused on SUD only, no Focused mostly on Health & SUD; personalized patient tools, no AI primary care, does not patient tools; integrate with integrate into personal full-circle of care team support. Wearable therapeutics

Many wearables are in development to monitor and even give biofeedback and Pavlovian cues For multiple types of substances.

Most that are available target nicotine and alcohol.

64 Deep Brain Stimulation (n of 1)

June 18,2021 65 Novel therapeutics, in the pipeline • Zpharm • Cravv, a cytisine-based tobacco addiction management • Virtual Rehab • Combining Virtual Reality/Augmented Reality evidence-based solutions to improve mental health and well being • Amygdala Neuroscience • developing ANS-6637, a new chemical entity selective and reversible mitochondrial aldehyde dehydrogenase 2 (ALDH2) inhibitor. Acting in the brain, ANS-6637 prevents pathophysiologic dopamine surge, without changes to basal dopamine • Opioid Vaccine • Through the NIH HEAL Initiative, teams are developing multiple opioid vaccines including a new fentanyl vaccine • Kinoxis Therapeutics • Utilizing small molecules to target the brain oxytocin system to treat addiction to all major addictive substance classes and also to intervene across all stages of the addiction cycle 66 Cytisine for smoking Cessation 68 • Early identification • Coping skill enhancement IN • Chronic, Patient Centered • Connection care approach • Dopamine tone CONCLUSION • Multiple courses of • Improve brain and body treatment may be required function for success • Damage repair • Adequate time frame is 69 Addiction is a needed—3+ months to • TRANSFORMATION produce stable behavior complex change- the longer the better disorder • Relapse is likely, expect it! • Pharmacotherapy • Accountability • Behavior change Anything to improve patient outcomes: Traditional + Precision + Integrative = 😃😃❣

The whole is greater than the sum of its parts

- Aristotle

70 1.Addiction is a complex, relapsing medical disease, associated with the reward cycle in the midbrain 2.Optimal treatment includes a chronic disease model, patient centered care approach 3.An adequate time frame for treatment is needed, 3+ months 4.Individualized multi-modal treatment improves outcomes 5.Pharmacotherapy (cover the opioid receptor) plus behavior changes, plus repair and restore Thank you!

Arwen Podesta, MD www.podestawellness.com