Hypothesizing that a Pro-Dopaminergic Regulator (KB220z™ Liquid Variant) can Induce "Dopamine Homeostasis" and Provide Adjunctive Detoxification Benefits in Opiate/Opioid Dependence
Kenneth Blum1-10*, Debra Whitney11, Lye Fried9, Marcelo Febo2, Roger L Waite8, Eric R Braverman6, Kristina Dushaj6, Mona Li6, John Giordano8, Zsolt Demetrovics10 and Rajendra D Badgaiyan12
1Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, USA
2Department of Psychiatry & Behavioral Sciences, Keck School of Medicine of USC, USA
3Division of Applied Clinical Research & Education, Dominion Diagnostics, LLC, USA
4Division of Neuroscience- Based Therapy, Summit Estate Recovery Center, USA
5Division of Clinical Neurology, Path Foundation New York, USA
6Division of Personalized Medicine, IGENE, LLC, USA
7Division of Molecular Neurobiology, LaVitaRDS, USA
8National Institute for Holistic Studies in Addiction, USA
9Division of Neuroscience Research and Addiction Therapy, Shores Treatment & Recovery Center, USA
10Department of Clinical Psychology and Addiction, Eotvos Lorand University, Hungary
11Division of Clinical Addiction Medicine, Pure Recovery, USA
12Department of Psychiatry, Laboratory of Molecular and Functional Imaging, University at Minnesota, USA
*Corresponding author: Kenneth Blum, PhD, Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA, Tel: 352-294-4911, Fax: 352-392-9887, E-mail: email@example.com
Clin Med Rev Case Rep, CMRCR-3-125, (Volume 3, Issue 8), Case Series; ISSN: 2378-3656
Received: June 09, 2016 | Accepted: August 13, 2016 | Published: August 16, 2016
Citation: Blum K, Whitney D, Fried L, Febo M, Waite RL, et al. (2016) Hypothesizing that a Pro-Dopaminergic Regulator (KB220z™ Liquid Variant) can Induce "Dopamine Homeostasis" and Provide Adjunctive Detoxification Benefits in Opiate/Opioid Dependence. Clin Med Rev Case Rep 3:125. 10.23937/2378-3656/1410125
Copyright: © 2016 Blum K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
In order to explore the initiation of detoxification of addictive patients to opiates/opioids (along with some other anti-withdrawal agents), we developed a protocol to be utilized in treatment centers particularly with heavily dependent opiate/opioid subjects. Out of 17 subjects, only three received Buprenorphine/Naloxone (Bup/nx) along with KB220Z. In this pilot, we first used a dose of KB220Z of 2 oz twice daily before meals along with clonidine and benzodiazepines and other anti-nausea and sleep aids including Gabapentin. The dose of KB220Z was maintained for 6 days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours, over a 6-day period. The higher dose was employed in another 12 patients.
It is noteworthy that only 3 people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates utilizing data from the Clinical opiate Withdrawal Scale (COWS) pre and post KB220Z. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates. While this does not constitute an acceptable controlled experiment, it does provide some preliminary evidence that agrees with an earlier study. Moreover, because of the utilization of standard detoxifying agents in this detoxification protocol, we cannot make any inference to KB220Z's effects. However, out of 17 subjects, only three required Bup/nx suggesting an interesting finding. If further confirmed in larger studies, the utilization for opiate/opioid detoxification may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification. This paradigm shift may translate to a reduction in utilizing powerful and addictive opioids like buprenorphine and methadone (especially in these patients at high genetic risk for addiction) as not only detoxifying agents, but also maintenance drugs. While extensive research is required, this pilot paves the way for future investigations that could assist in the reduction of addictive opiate/opioid use and mortalities amongst both the young and old in America.
KB220Z liquid variant, Opiate/Opioid addiction, Withdrawal, Bup/nx, Detoxification
It is well-established that dopamine signaling is important in the reward pathway and that aberrations in the reward pathway are related to addiction and that by modulating dopaminergic signaling in the reward pathway, we could develop novel treatment modalities for addiction. We are hereby proposing that one way of potentially reducing the out-of control prescribing and subsequent illicit use of opiate/opioids in America is to consider the utilization of Pro-Dopamine Regulation with a nutraceutical complex called KB220Z.
While short-term use of Buprenorphine/Naloxone (Bup/nx) may have some benefit in the maintenance of opiate/opioid dependence, it is still a powerful addictive pharmaceutical that may reduce societal harm on one hand, but promotes addiction on the other hand. There has been a paucity of research related to opiate/opioid dependence withdrawal that evaluates non-addicting non-opiate safe detoxifying agents by promoting "dopamine homeostasis".
Medication-Assisted Treatment (MAT) is the use of FDA-approved medications, many of which are opioids, for the treatment of opiate/opioid addiction. Two major opioids used to treat opiate/opioid addiction are methadone and buprenorphine, in which the latter has been shown to be nearly 50 times more potent than morphine. Media reports and published drug/addiction policy plans support a greater availability and use of Bup/nx combinations in addiction treatment . Blum et al. have recently commented on raising the limits to 200 patients treated with Bup/nx combinations . Most recently, beginning August 5, 2016, the ceiling will be lifted to 275.
These FDA-approved narcotics in opiate/opioid addiction treatment are definitively habit forming and consequently, addictive just like any other opiate or opioid. They are potentially equally dangerous and capable of the same abuse as any other prescription or illicit narcotic and there is the possibility of street diversion .
Previous work from our laboratory found that long-term Bup/nx use lead to blunted emotional responses in its users. Individuals reported less self-awareness of being happy, sad, and anxious. Over time, Bup/nxin effect caused a "zombie-like" effect on its users .
Moreover, Methadone was cited in nearly 13% of all the overdose deaths reported in the USA, up from about 4% five years earlier . In 2012, Centers for Disease Control and Prevention (CDC) determined that Methadone was the culprit for one-third of U.S. prescription painkiller deaths. The CDC stated that while Methadone accounts for only 2% of painkiller prescriptions in the U.S., the drug accounts for more than 30% of prescription painkiller overdose deaths. Deaths from Methadone were found to be increasing as prescriptions for the drug rose . The CDC also reported that in 2012, there were 41,502 deaths due to drug poisoning, or drug-overdose deaths, in the U.S.; 16,007 of these deaths involved opioids and 5,925 involved heroin .
Statistics provided by the CDC further indicate that 5,282 people died from an accidental overdose of methadone, while 5,925 died from heroin: a difference of 643 people within the same year. Despite empirical data that supports a pattern of increasing deaths attributed to Methadone, and also evidence that demonstrates slim difference between the number of Methadone versus heroin deaths (deaths that Methadone were said to prevent), the FDA-approved MAT narcotic is still widely prescribed, available, and deemed safe by the FDA and other advocates for treating opiate/opioid addicts with opiates/opioids.
However, deaths attributed to Bup/nx are harder to track. According to a New York Times report in 2013, the CDC does not track buprenorphine deaths, neither do most emergency rooms, prisons, jails, drug courts, and the majority of medical examiners. A Times analysis of federal data showed that the drug was a "primary suspect" in 420 deaths reported to the FDA since its market availability in 2003. While this may not be medically relevant because of a news report, others have discussed this important issue .
To curtail psychoactive drug abuse and dependence, the FDA has approved a number of pharmaceutical agents that either reduce craving or suppress the pleasurable effect of drugs. While such agents have helped many patients, they have not prevented cravings and relapse completely. This fact is underlined by the recent findings that used data from the sophisticated Comprehensive Analysis of Reported Drugs (CARD™). The study revealed a significant lack of "compliance" to various treatment medications and lack of "abstinence" from psychoactive drug use in both in-patient and outpatient treatment settings .
We agree that short-term use of MAT (possibly from detoxification to less than 12 months), especially Methadone or Bup/nx, may have important benefits regarding preventing unwanted opiate/opioid withdrawal. Moreover, these potent narcotics can induce patient stability ultimately leading to reinstatement of a patient into the workforce and become a so-called "productive member of society," and thereby, reducing societal harm. Understanding the neuropharmacology of MAT and dopaminergic mechanisms, in which blocking of dopamine induces "psychological extinction" (why use if the thrill is gone), is in our opinion, an inadequate and non-cost-effective way to combat America's second opiate/opioid epidemic.
Outlining benefits of buprenorphine and naloxone combinations
Pharmacotherapy in conjunction with controlled withdrawal is currently the most reliable method of opioid detoxification. However, as translational medicine continues to advance and identify genomic markers for opioid sensitivity and dependence, the future holds potential for growth and change .
Bup/nx is an effective treatment therapy for opioid dependence and has similar efficacy to Methadone, although more data are needed. Less frequent dispensing of Bup/nx (e.g., thrice weekly) does not appear to compromise efficacy and can improve patient satisfaction. Bup/nx is more effective than clonidine as a medically supervised withdrawal therapy. Moreover, Bup/nx is a well-tolerated medically supervised withdrawal and maintenance treatment. Thus, sublingual Bup/nx is a valuable pharmacotherapy for the treatment of opioid dependence .
In another study, Ling et al.  compared the effects of a short or long taper schedule after buprenorphine stabilization on patient outcomes, which were measured by opioid-free urine tests at the end of each taper period. They observed that at the end of the taper, 44% of the 7-day taper group (n = 255) provided opioid-free urine specimens, while 30% of the 28-day taper group (n = 261; P = 0.0007) provided opioid-free samples. In addition, there were no reported differences at the 1-month and 3-month follow-ups; the 7-day taper group resulted in 18% and 12% opioid-free specimens, and the 28-day taper group resulted in 18% and 13%, at the 1 month and 3 month follow-ups, respectively). Ultimately, the authors concluded that in individuals terminating buprenorphine pharmacotherapy for opioid dependence, there was no advantage in prolonging the duration of the taper.
While this study provides evidence for the clinical use of Bup/nx in the treatment of opioid withdrawal, as well as favoring short-term use, concerned scientists and clinicians must realize that we are, in essence, only substituting one narcotic for another powerful narcotic. While Bup/nx is a standard in the treatment of opiate/opioid dependence, it is locking people into addiction. Understanding that Bup/nx induces severe withdrawal by itself, and possibly suicide ideation, we attempted to detoxify heavily addicted addicts without Bup/nx.
Characteristics and neuropharmacology of KB220 variants
With this introduction to the existing problem, we now carried out an experiment utilizing a well-researched amino-acid-enkephalinase inhibition therapy known  as Pro-Dopamine Regulator (PDR) for detoxification without the employment of buprenorphine alone or in combination with naloxone in 17 highly addicted opioid addicts. The rationale for the utilization of a KB220 nano-liquid variant is based on a plethora of literature as well as animal and human studies.
Specifically, the patented product is comprised of the following ingredients in validated, evidence-based intake levels: Thiamine, 15 mg (1033% of Daily Value); Vitamin B6, 10 mg (500%); Chromium polynicotinate (as Chrome Mate®), 200 mcg (166%); a fixed dose combination of amino acids and herbs called Synaptose™, which contains DL-Phenylalanine, L-Tyrosine, and Passion Flower Extract; a Metalloglycoside™ Complex containing Arabinogalactans, N-Acetylglucosamine, Astragalus, Aloe Vera, Frankincense Resin, and White Pine Bark Extract; Rhodiola (as RhodiGen™); L-Glutamine; 5-Hydroxytryptophan (5-HTP); Thiamine Hydrochloride; Pyroxidal-5-phosphate; and Pyridoxine HCl. The matching placebo powder is also manufactured by Cephram, Inc. (New Jersey). The resultant product utilized is an aqua, nano-liquid product developed in part by Aqua Power (Utah). The rational of the basic ingredients of KB220Z is provided in table 1.
Table 1: List of KB220Z Ingredients with targets and mechanism of action. View Table 1
D2 receptor activation, especially in the mesolimbic pathway, can be accomplished with "gentle" dopamine (DA) agonist therapy (PDR) involving receptor activation. One possibility is to utilize the nutraceutical complex, KB220Z (PDR), which in pre-clinical and clinical trials, has been shown to mirror the brain reward cascade to potentially induce "dopamine homeostasis."
In an earlier unpublished, but submitted study, we observed the functional connectivity patterns between several brain structures and areas of the reward system under resting conditions in rats. Experiments were designed to test whether the observed resting state functional connectivity (rsFC) is influenced by administration of a putative dopaminergic agonist, KB220Z™ .
To understand our rationale for evaluating KB220Z in the present study, we offer the following evidence for clinical benefit of neuro-mechanisms involved in producing dopamine homeostasis. KB220 variants (nutraceutical complex) have been extensively studied and tested . As reported in detailed review articles [14,15], on both animals and humans to date, many references show that KB220 variants enhance brain enkephalin levels in rodents. Variants of KB220, also have the potential to reduce alcohol-seeking behavior in C57/BL mice and these variants can pharmacokinetically convert ethanol acceptance in preferring mice to non-preferring mice. In humans, KB220Z has demonstrated reduction of drug and alcohol withdrawal symptomatology (i.e., decreased need for benzodiazepines), fewer days with withdrawal tremors, evidence of a lower building up to drink (BUD) score, and elimination of severe depression on the Minnesota Multiphasic Personality Inventory (MMPI). In a double-blind placebo controlled study, patients in recovery treatment had reduced stress response (measured by the skin conductance level [SCL]), and significantly improved Physical Scores and behavioral, emotional, social and spiritual (BESS) scores. There was a six-fold decrease in American Medical Association (AMA) rates when comparing KB220 variants to placebo groups after detoxification. One-year relapse rates, for both cocaine and alcohol abusers, faired significantly better than known average relapse rates for these two psychoactive substances. Healthy volunteers demonstrated an enhanced focus (Table 2).
Table 2: Clinical benefits of KB220Z. View Table 2
There is also evidence of reduced craving for alcohol, heroin, cocaine, and nicotine. Also, reductions in inappropriate sexual behavior and reduced post-traumatic stress disorder (PTSD) symptoms, such as lucid nightmares, have been reported [16,17]. Quantitative electroencephalic (qEEG) studies in humans  have found that KB220Z modulates theta power in anterior cingulate cortex in abstinent psychostimulant abusers . In abstinent heroin addicts, a single dose of KB220Z compared to placebo in a pilot study  resulted in activation of the Nucleus Accumbens (NAc) as well as activation and improvement of the prefrontal-cerebellar-occipital neural network. In addition, it was found that carriers with the DRD2 A1 allele showed a significant Pearson correlation in terms of enhanced compliance to KB220Z treatment relative to carriers of the normal compliment of DRD2 receptors in known obese patients . This further suggests the importance of low dopamine function equating to better treatment outcome. These studies, including double-blinded control studies and others [22-25], have demonstrated positive effects on both craving attenuation and relapse prevention. Most recently, Steinberg et al.  showed increased activation of the anterior cingulate brain region using low-resolution brain electromagnetic tomography (LORETA) in attention-deficit/hyperactivity disorder (ADHD) patients.
In fact, it has been shown that DNA-directed compensatory overexpression of the DA D2 receptors (a form of gene therapy) results in a significant reduction in alcohol and cocaine craving behavior in drug-preferring rodents [27-30]. In addition, dopamine D4 receptor knockout mice also predict future alcohol intake . Moreover, in vitro bromocyrptine induced D2 receptor proliferation in rats  causes a reduced D2 receptor density in vivo chronically.
Achieving better treatment outcomes requires an understanding that the maintenance of steady "dopaminergic homeostasis" [33-35] is essential for achieving pleasurable experiences from ordinary daily activities and for relieving stress. Untreated impairments in the homeostatic balance of the DA signaling can facilitate aberrant substance-related disorders and process addictions  elucidated in former publications as Reward Deficiency Syndrome (RDS) [37,38]. The scientific research in this field is charged with the challenge of developing non-hazardous, non-addicting agents with dopaminergic up-regulating agonistic properties.
As has been proposed previously, activation, rather than blocking, mesolimbic dopaminergic reward circuitry in the long-term treatment of RDS is the preferred modality even in treating hypersexuality [39,40]. Although, the acute treatment should consist of preferential blocking of postsynaptic NAc DA receptors (D1-D5), the long-term mesolimbic activation of the dopaminergic system should involve the release and/or activation of DA at the NAc site. There must be focus on balancing the interaction of D1 and D2 receptor signaling.
This theory suggests that excessive craving behavior can be attributed to reduced number of DA D2 receptors, an effect of carrying, for example, the DRD2 A1 allelic genotype; whereas a normal or sufficient density of D2 receptors, including other normal genetic expressions such as Orexin and Pro-opiomelacortin (POMC),results in reduced craving and relapse and normal sleep patterns [41,42]. A goal, in terms of preventing substance abuse, could be to induce a proliferation of D2 receptors in individuals who are genetically vulnerable. While in vivo experiments that use a typical D2 receptor agonist induce down-regulation , in vitro experiments have shown that in spite of genetic antecedents, constant stimulation with a known D2 agonist, bromocriptine, results in significant proliferation of D2 receptors within the DA system, but chronic treatment of another D2 receptor agonist, quinpirole, results in down-regulation, instead of up-regulation or balance proposed for KB220Z and that is a reason for failure in treatment .
Based on the current literature, new strategies are needed to treat RDS since the traditionally used therapeutic agents have had limited success in treatment of psychoactive substance abuse and relapse prevention and may require genetic testing leading to personalized medicine .
As denoted above, we were compelled to design the current case series and we were optimistic because previous work in our laboratory suggested potential positive clinical outcomes. For example, in 1988, we found improvement in a double-blind evaluation of the nutritional supplement KB220 variant, in a 30-day inpatient alcohol and drug rehabilitation center . The KB220 variant is uniquely designed to elevate levels of enkephalin (s), serotonin, and catecholamines, while balancing GABA, to offset functionally deficient neurotransmitters in alcoholics. Twenty-two patients were studied. The KB220 variant patients, as compared to the control group, (a) had a lower BUD score (1 vs. 2); (b) required no PRN benzodiazepines (0% vs. 94%); (c) ceased tremoring at 72 h, as compared to 96 h; and (d) had no severe depression on the MMPI, in contrast to 24% of the control group. These preliminary data suggest that KB220 variant is a valuable adjunct to therapy by aiding the patient's physical adjustment to a detoxified state, while facilitating a more positive response to behavioral therapy.
The second article that provided rationale for this experiment involved withdrawal from Bup/nx and maintenance with the putative dopamine agonist KB220 variant. Specifically, it was found that at 432 days post Bup/nx withdrawal, the patient was being maintained on KB220 and had been urine tested and was opioid free . Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait . This preliminary case data suggest that the daily use of KB220 could provide a cost-effective alternative substitution adjunctive modality for Bup/nx. The authors encouraged double-blind randomized placebo-controlled studies to test the proposition that KB220 may act as a putative natural opioid substitution maintenance adjunct. More importantly, it is unknown if the KB220 variant could actually be used as a front-line detoxification agent.
Preliminary evidence of KB220Z liquid as an opiate/opioid detoxification agent
Certainly, there is a great need to find a way to detoxify patients addicted to opiates/opioids, without utilizing either methadone or any other opiate/opioid, including Bup/nx or buprenorphine alone. The main premise here is to detoxify these highly opiate/opioid addicted patients, who are possibly genetically prone to addictive behaviors, by providing endorphinergic-glutaminergic-dopaminergic balance  by employing KB220Z liquid variant.
In order to explore the possibility of initiation of detoxification of addictive patients to opiates/opioids (along with some other drugs), we developed a protocol to be utilized in treatment centers with heavily dependent opiate/opioid subjects. The experiment was approved by the PATH Foundation NY IRB committee, and consent forms were filled out by each patient enrolled in the study.
It is to be noted that a treatment center in Los Angeles, CA was selected for this pilot experiment. The center has detoxified many addicted patients and the staff utilizes a number of pharmaceuticals to assist in the detoxification process including: Buprenorphine alone, and in the combined form with naloxone in a 4:1 ratio; Escitalopram: Ondansetron, Gabapentin: Trazodone, Hydroxyzine: Duloxetine, Risperidone: Methocarbamol, Lamotrigine: Quetiapine, Lorazepam: Bupropion, Ketorolac: Clonidine. The doses of these drugs differed across the 17 patients. To determine if KB220Z could replace Bup/nx in their regimen, the center carried out detoxification on a number of patients without the administration of Bup/nx by substituting KB220Z.
Out of 17 subjects, because of patient demand, only two received Bup/nx along with KB220Z. In this pilot, we first used a 2 oz dose of KB220Z twice daily before meals along with clonidine and benzodiazepines. The dose of KB220Z was maintained for 6 days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours over a 6-day period. It was noted that the intensity of withdrawal symptoms as measured by the Clinical Opiate Withdrawal Scale COWS was reduced with the use of the higher dose. The higher dose was employed in additional12 patients.
It is noteworthy that only 3 subjects have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The subjects have been maintained without any additional Bup/nx for a minimum of 120 days. However, one patient, a 21-year-old female addicted to methadone and amphetamines, has now been maintained on just KB220Z for about 7 months (Table 3). After 120-day period, the other subjects were no longer followed up, so we are unable to determine how long they have remained on KB220Z. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates.
Table 3: Demographics of five poly-drug abusing patients detoxified with KB220Z without bup/nx. View Table 3
The following demographics are provided for the initial five patients taking the lower 2 oz dose of KB220Z twice daily, and then maintained on ½ oz of KB220Z twice daily for at least 120 days. The importance here is that during the detoxification period of 6 days, none of these patients required Bup/nx. The center reported that the withdrawal symptomatology was not intense for any of these five patients (Table 3). Unfortunately, these patients have not been followed for the past 120 days, except for the patient cited above. The intensity of withdrawal was assessed by the attending staff and self-reported as well. In a follow-up study we will be able to quantitative the severity of withdrawal symptoms on a larger cohort compared to patients undergoing opiate/opioid withdrawal without KB220Z variant. Until this additional required study is performed we must cautiously interpret this pilot experiment.
As we mentioned the dose for anti-withdrawal pharmaceuticals varied with each patient and to address this issue the following dosage is provided for the five initial participants. Similar dosage was obtained for the additional 12 participants:
21-Year-old female: Detoxing from Amphetamines and Meth-Bp 115/60 P 55, Bp 106/75 P 82, Bp 115/78 P 72. Client was taking Synaptamine 2 oz once a day, Lamictal 200 mgs once a day, Quetiapine 50 mgs once a day at night for insomnia, Lamotrigine 200 mgs once a day at night for anxiety, Gabapentin 600 mgs four times a day for anxiety, Seroquel 50 mgs at night. Detox was not intense required no Suboxone.
32-Year-old male: Detoxing from THC, Benzos, and Oxycontin- Bp 128/88 P 90, BP 137/91 P 90, Bp 145/78 P 86, Bp 149/111 P 84, Bp 129/97 P102, BP 139/84 P85, BP 117/99 P 90, Bp 138/80 P 108, Bp 127/98 83 Bp 153/89 P 83- Client was taking Synaptamine 2o z two times a day, Lexapro 40 mgs once a day, Zofran as needed for nausea, Gabapentin 600 mgs 1-2 tabs at night as needed for sleep, Trazodone 50 mgs-100 mgs 1-2 tabs at night as needed for sleep, Vistaril 25 mgs - 50 mgs every 4 hours as needed for nausea/vomiting/anxiety. Detox was not intense required no Suboxone.
37-Year-old female: Detoxing from Opiod and Meth -BP 139/82 P 83, 78/59 P93, Bp 128/72 P 80, Bp 136/92 88, Bp 113/89 P 79, Bp 120/88 P80, Bp 110/78 P 86-Client was taking Synaptamine 2 oz every morning, Cymbalta 30 mg every morning, Trazadone 25 mgs-50 mgs every night, Clonidine 0.1 mgs once a night, Gabapentin 300 mgs two times a day, Toradol 10 mgs two times a day as needed for pain. Detox was not intense required no Suboxone.
30-Year-old male: Detoxing from Heroin and Meth BP 130/90 P 103, Bp 130/83 P 85, Bp 130/83 P 86, Bp 115/80 P 80, Bp 108/66 P 75, Bp 174/95 P 84, Bp 115/90 P 100, Bp 137/83 P 80, Bp 140/102 P 105, Bp 130/85 P 88. Client was taking Synaptamine 2 oz twice a day, Risperdone 1 mg once a day, Robaxin 500 mgs - 1000 mgs four times a day, Gabapentin 300 mgs four times a day, Ativan 0.25 mgs-0.5 mgs every 4 hours, Suboxone 2 mgs/0.5 mgs twice a day for 3 days, Wellbutrin 300 mgs once a day. Detox was not intense required no Suboxone.
Patient # 5
34-Year-old male detoxing from meth: Bp 125/88 P 104, Bp 100/70 P 75, Bp 120/70 P 100, Bp 120/80 P 110, Bp 130/60 P 105, Bp 140/104 P 84, Bp 121/77 P 98, Bp 135/102 P 111, Bp 140/98 P 95 Client was taking 2 oz of Synaptamine every morning along with Wellbutrin 150 mgs every morning, Clonidine 0.1 mgs four times a day and Trazodone 50 mgs at night. Detox was not intense required no Suboxone.
Demographics on the additional 12 patients are available from the treatment center and could be retrieved on request by contacting the corresponding author of this article.
While this does not constitute an acceptable controlled experiment, it does provide some preliminary evidence that agrees with our earlier case study as previously discussed above, whereby utilizing KB220Z in the nano pill form in a female patient who was maintained opiate/opioid free as measured by a drug-urine screen for at least 432 days . In this earlier study, we could not provide the patient with KB220Z because unlike the liquid form, the patient could not tolerate the pill during intensive withdrawal.
While these results are somewhat encouraging, they do not provide adequate information concerning the real benefit of KB220Z in its liquid form, other than it was safe and easy to take during drug withdrawal when compared to previous tablet forms. Moreover, because of the utilization of a number of standard detoxifying agents utilized in this detoxification protocol, we cannot make any inference to KB220Z's effects. However, out of 17 patients, only two required Bup/nx suggesting an interesting finding, whereby if further confirmed in larger studies may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification followed by maintenance with KB220Z. This must be considered as a pilot and we caution against any interpretation of these preliminary results.
This is the first case report concerning liquid KB220Z and detoxification of known opiate/opioid dependent individuals. In the current study, we decided to evaluate the effect of KB220Z in a nano-liquid with regard to opioid withdrawal symptomatology in 17 patients with a primary diagnosis of drug addiction to opioids or amphetamines/methamphetamine or a combination thereof. The intent of this pilot study was an attempt to withdraw these patients without the use of buprenorphine alone or in combination of naloxone (Bup/nx).
We are cognizant of the important utility of Bup/nx in the short-term treatment of opiate/opioid addiction. It is well known that Bup/nx is a partial μ-opioid agonist combined with the opioid antagonist naloxone in a 4:1 ratio. According to some , this combination is safe and beneficial to treat illicit and prescription-opioid dependence. Bup/nx has a lower abuse potential, carries less stigma, and allows for more flexibility than methadone. Bup/nx is indicated for in-patient, ambulatory medically assisted withdrawal (acute detoxification), and long-term substitution treatment (maintenance) of patients who have a mild-to-moderate physical dependence. A stepwise long-term substitution treatment with regular monitoring and follow-up assessment is usually preferred, as it has better outcomes in reducing illicit opioid use, minimizing concomitant risks such as human immunodeficiency virus and hepatitis C transmission, retaining patients in treatment, and improving global functioning. While this seems like a very plausible treatment option approved by the FDA, it is rift with long-term problems as outlined by a number of reports [1,3,15,48-51].
Medically supervised opioid withdrawal is a complex and constantly evolving exercise in multimodal therapy that draws from the expertise of a variety of clinical specialties. In a number of studies to date, it has been reported that acute substitution and weaning off of opioids has been performed utilizing opioid agonists, partial agonists (e.g., buprenorphine), mixed agonist/antagonists (e.g., Bup/nx), and α2 adrenergic agonists with some success.
While thousands of patients are being treated with these 'classic' opioid-withdrawal techniques, traditional treatment approaches are being challenged by the emergence of innovative techniques based on an understanding of the neurochemistry of addiction [49,50,52]. Most importantly, Blum's earlier experiment showing a significant reduction of alcohol withdrawal in a residential United Sates recovery and treatment center has been further validated in this pilot study .
In this pilot observational study, it is noteworthy that only 3 people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates utilizing data from the Clinical opiate Withdrawal Scale (COWS) pre and post KB220Z.
In summary, it is our hypothesis that future steps to overcome the current opiate/opioid epidemic in the United States claiming at least 127 people dying every day from narcotic overdoses must consider newer and better ways to not only detoxify individuals from prescription opioids like methadone and buprenorphine, but induce "dopamine homeostasis" as a maintenance goal free of any opiates/opioids. This is easily said, but may be difficult in practice. In this regard, we encourage additional research in this most perplexing area.
The authors are grateful to Margaret A. Madigan for her expert edits. We are also appreciative of the staff of the treatment center in Los Angeles, CA as mentioned in this paper.
Marcelo Febo is the recipient of NIDA NIH DA038009 and Rajendra D. Badgaiyan is the recipient of NIH grants: 1R01NS073884 and 1R21MH073624.
Conflict of Interest
Kenneth Blum, PhD, is the inventor of KB220Z and his company Synaptamine holds a number of U.S. and foreign patents that have been licensed to LaVita RDS. Drs. Blum (Chairman), Febo and Badgaiyan is on the Scientific Advisory Board of LaVita RDS. There are no other conflicts of interest to report.
KB and DW designed the study. The first draft of the paper was written by KB, DW, ML, and KD. The detoxification information was gathered by DW. The clinical aspects of detoxification were checked by LF and JG. The discussion section was vetted by ZD, MF, and RDB. RDB helped write the discussion section. ERB added clinical comments to the manuscript and assisted in development of the IRB.
Blum K, Oscar-Berman M, Femino J, Waite RL, Benya L, et al. (2013) Withdrawal from Bup/nx and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note. J Addict Res Ther 4.
Blum K, Gold MS, Clark HW, Dushaj, Kand Badgaiyan RD. Should the United States Government Repeal Restrictions on Bup/nx Treatment? Sub Use Misuse (in Press)
Furst RT (2014) Diffusion and diversion of suboxone: an exploration of illicit street opioid selling. J Addict Dis 33: 177-186.
Hill E, Han D, Dumouchel P, Dehak N, Quatieri T, et al. (2013) Long term Suboxone™ emotional reactivity as measured by automatic detection in speech. PLoS One 8: e69043.
Jones CM, Baldwin GT, Manocchio T, White JO, Mack KA (2016) Trends in Methadone Distribution for Pain Treatment, Methadone Diversion, and OverdoseDeaths - United States, 2002-2014. MMWR 65: 667-671.
Paulozzi LJ, Mack KA, Jones CM (2012) Vital Signs: Risk for Overdose from Methadone Used for Pain Relief – United States, 1999-2010. MMWR 61: 493-497.
Warner M, Hedegaard H, Chen LH (2014) Trends in Drug-Poisoning Deaths Involving Opioid Analgesics and Heroin: United States, 1999-2012. CDC Health E-Stats.
Loreck D, Brandt NJ, DiPaula B (2016) Managing Opioid Abuse in Older Adults: Clinical Considerations and Challenges. J Gerontol Nurs 42: 10-15.
Blum K, Han D, Femino J, Smith DE, Saunders S, et al. (2014) Systematic evaluation of "compliance" to prescribed treatment medications and "abstinence" from psychoactive drug abuse in chemical dependence programs: data from the comprehensive analysis of reported drugs. PLoS One 9: e104275.
Plunkett A, Kuehn D, Lenart M, Wilkinson I (2013) Opioid maintenance, weaning and detoxification techniques: where we have been, where we are now and what the future holds. Pain Manag 3: 277-284.
Orman JS, Keating GM (2009) Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence. Drugs 69: 577-607.
Ling W, Hillhouse M, Domier C, Doraimani G, Hunter J, et al. (2009) Buprenorphine tapering schedule and illicit opioid use. Addiction 104: 256-265.
Blum K, Febo M, Badgaiyan RD, Perez PD, Colon-Perez LM, et al. (2015) Putative dopamine agonist KB220z enhances resting state brain reward circuit functional connectivity. Society of Neuroscience Conference, Neuroscience Meeting Planner, Chicago, Il.
Miller M, Chen AL, Stokes SD, Silverman S, Bowirrat A, et al. (2012) Early intervention of intravenous KB220IV--neuroadaptagen amino-acid therapy (NAAT) improves behavioral outcomes in a residential addiction treatment program: a pilot study. J Psychoactive Drugs 44: 398-409.
Chen TJ, Blum K, Chen AL, Bowirrat A, Downs WB, et al. (2011) Neurogenetics and clinical evidence for the putative activation of the brain reward circuitry by a neuroadaptagen: proposing an addiction candidate gene panel map. J Psychoactive Drugs 43: 108-127.
McLaughlin T, Blum K, Oscar-Berman M, Febo M, Agan G, et al. (2015) Putative dopamine agonist (KB220Z) attenuates lucid nightmares in PTSD patients: role of enhanced brain reward functional connectivity and homeostasis redeeming joy. J Behav Addict 4: 106-115.
McLaughlin T, Blum K, Oscar-Berman M, Febo M, Demetrovics Z, et al. (2015) Using the Neuroadaptagen KB200z™ to Ameliorate Terrifying, Lucid Nightmares in RDS Patients: the Role of Enhanced, Brain-Reward, Functional Connectivity and Dopaminergic Homeostasis. J Reward Defic Syndr 1: 24-35.
Braverman ER, Blum K (1996) Substance use disorder exacerbates brain electrophysiological abnormalities in a psychiatrically-ill population. Clin Electroencephalogr 27: 5-27.
Blum K, Chen TJ, Morse S, Giordano J, Chen AL, et al. (2010) Overcoming qEEG abnormalities and reward gene deficits during protracted abstinence in male psychostimulant and polydrug abusers utilizing putative dopamine D₂ agonist therapy: part 2. Postgrad Med 122: 214-226.
Blum K, Liu Y, Wang W, Wang Y, Zhang Y, et al. (2015) rsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts. Postgrad Med 127: 232-241.
Blum K, Chen TJH, Chen ALC, Rhoades P, Prihoda TJ, et al. (2008) Dopamine D2 receptor Taq A1 allele predicts treatment compliance of LG839 in a subset analysis of pilot study in the Netherlands. Gene Therapy and Molecular Biology 12: 129-140.
Blum K, Trachtenberg MC, Ramsay JC (1988) Improvement of inpatient treatment of the alcoholic as a function of neurotransmitter restoration: a pilot study. Int J Addict 23: 991-998.
Mclaughlin T, Oscar-Berman M, Simpatico T, Giordano J, Jones S, et al. (2013) Hypothesizing repetitive paraphilia behavior of a medication refractive Tourette's syndrome patient having rapid clinical attenuation with KB220Z-nutrigenomic amino-acid therapy (NAAT). J Behav Addict 2: 117-124.
Miller DK, Bowirrat A, Manka M, Miller M, Stokes S, et al. (2010) Acute intravenous synaptamine complex variant KB220™ "normalizes" neurological dysregulation in patients during protracted abstinence from alcohol and opiates as observed using quantitative electroencephalographic and genetic analysis for reward polymorphisms: part 1, pilot study with 2 case reports. Postgrad Med 122: 188-213.
Brown RJ, Blum K, Trachtenberg MC (1990) Neurodynamics of relapse prevention: a neuronutrient approach to outpatient DUI offenders. J Psychoactive Drugs 22: 173-187.
Steinberg B, Blum K, McLaughlin, Lubar J, Febo M, et al. (2016) The effect of a Pro-Dopamine Regulator (KB220Z) as observed using low-resolution electromagnetic tomography (LORETA) in an adult ADHD case study. Open J of Clin Med Case Rep 1121.
Thanos PK, Volkow ND, Freimuth P, Umegaki H, Ikari H, et al. (2001) Overexpression of dopamine D2 receptors reduces alcohol self-administration. J Neurochem 78: 1094-1103.
Thanos PK, Rivera SN, Weaver K, Grandy DK, Rubinstein M, et al. (2005) Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking. Life Sci 77: 130-139.
Thanos PK, Taintor NB, Rivera SN, Umegaki H, Ikari H, et al. (2004) DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and non-preferring rats attenuates alcohol drinking. Alcohol Clin Exp Res 28: 720-728.
Thanos PK, Michaelides M, Umegaki H, Volkow ND (2008) D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats. Synapse 62: 481-486.
Thanos PK, Roushdy K, Sarwar Z, Rice O, Ashby CR Jr, et al. (2015) The effect of dopamine D4 receptor density on novelty seeking, activity, social interaction, and alcohol binge drinking in adult mice. Synapse 69: 356-364.
Boundy VA, Pacheco MA, Guan W, Molinoff PB (1995) Agonists and antagonists differentially regulate the high affinity state of the D2L receptor in human embryonic kidney 293 cells. Mol Pharmacol 48: 956-964.
Sparta DR, Jennings JH, Ung RL, Stuber GD (2013) Optogenetic strategies to investigate neural circuitry engaged by stress. Behav Brain Res 255: 19-25.
Blum K, Thompson B, Demotrovics Z, Femino J, Giordano J, et al. (2015) The Molecular Neurobiology of Twelve Steps Program & Fellowship: Connecting the Dots for Recovery. J Reward Defic Syndr 1: 46-64.
Gold MS, Badgaiyan RD, Blum K (2015) A Shared Molecular and Genetic Basis for Food and Drug Addiction: Overcoming Hypodopaminergic Trait/State by Incorporating Dopamine Agonistic Therapy in Psychiatry. Psychiatr Clin North Am 38: 419-462.
Smith DE (2012) The process addictions and the new ASAM definition of addiction. J Psychoactive Drugs 44: 1-4.
Blum K, Oscar-Berman M, Badgaiyan R, Braverman ER, Gold MS (2014) Hypothesizing Darkness Induced Alcohol Intake Linked to Dopaminergic Regulation of Brain Function. Psychology (Irvine) 5: 282-288.
Blum K, Gold MS (2011) Neuro-chemical activation of brain reward meso-limbic circuitry is associated with relapse prevention and drug hunger: a hypothesis. Med Hypotheses 76: 576-584.
Blum K, Badgaiyan RD, Gold MS (2015) Hypersexuality Addiction and Withdrawal: Phenomenology, Neurogenetics and Epigenetics. Cureus 7: e290.
Miller D, Miller M, Blum K, Badgaiyan RD, Febo M (2015)Addiction Treatment in America: After Money or Aftercare? J Reward Defic Syndr 1: 87-94.
Modestino EJ, Blum K, Oscar-Berman M, Gold MS, Duane DD, et al. (2015) Reward Deficiency Syndrome: Attentional/Arousal Subtypes, Limitations of Current Diagnostic Nosology, and Future Research. J Reward Defic Syndr 1: 6-9.
Zhou Y, Leri F (2016) Neuroscience of opiates for addiction medicine: From stress-responsive systems to behavior. Prog Brain Res 223: 237-251.
Bogomolova EV, Rauschenbach IY, Adonyeva NV, Alekseev AA, Faddeeva NV, et al. (2010) Dopamine down-regulates activity of alkaline phosphatase in Drosophila: the role of D2-like receptors. J Insect Physiol 56: 1155-1159.
Subramaniam S, Lucki I, McGonigle P (1992) Effects of chronic treatment with selective agonists on the subtypes of dopamine receptors. Brain Res 571: 313-322.
Blum K, Badgaiyan RD, Agan G, Fratantonio J, Simpatico T, et al. (2015) Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction. J Reward Defic Syndr 1: 65-68.
Blum K, Febo M, Fahike C, Archer T, Bergren U, et al. (2015) Hypothesizing balancing endorphinergic and glutaminergic systems to treat and prevent release to Reward Deficiency Behaviors : Coupling D-Phenyalalnine and N-Acetyl L-Cysteine [NAC]as a novel therapeutic modality. Clin Med Rev Case Rep 2: 076.
Magura S, Fraser R, Gill K (2014) Utilizing buprenorphine-naloxone to treat illicit and prescription-opioid dependence. Neuropsychiatr Dis Treat 10: 587-598.
Badgaiyan RD, Sinha S, Blum K (2015) Do We Really Need to Continue Pharmacotherapy for Opioid Use Disorder (OUD) Indefinitely? J Reward Defic Syndr 1: 16-19.
Blum K, Oscar-Berman M, Jacobs W, McLaughlin T, Gold MS (2014) Buprenorphine Response as a Function of Neurogenetic Polymorphic Antecedents: Can Dopamine Genes Affect Clinical Outcomes in Reward Deficiency Syndrome (RDS)? J Addict Res Ther pii: 1000185.
Blum K, Chen TJ, Bailey J, Bowirrat A, Femino J, et al. (2011) Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential? Mol Neurobiol 44: 250-268.
Blum K, Febo M, McLaughlin T, Cronjé FJ, Han D, et al. (2014) Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)™ as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric. J Behav Addict 3: 149-156.
Ling W (2016) A Perspective on Opioid Pharmacotherapy: Where We Are and How We Got Here. J Neuroimmune Pharmacol.
Blum K, Calhoun W, Merritt J, Wallace JE (1973) L-DOPA: effect on ethanol narcosis and brain biogenic amines in mice. Nature 242: 407-409.
Blum K, Wallace JE, Calhoun W, Tabor RG, Eubanks JD (1974) Ethanol narcosis in mice: serotonergic involvement. Experientia 30: 1053-1054.
Blum K, Briggs AH, Trachtenberg MC, Delallo L, Wallace JE (1987) Enkephalinase inhibition: Regulation of ethanol intake in mice. Alcohol 4: 449-456.
Blum K, Trachtenberg MC, Elliott CE, Dingler ML, Sexton RL, et al. (1988) Enkephalinase inhibition and precursor amino acid loading improves inpatient treatment of alcohol and polydrug abusers: double-blind placebo-controlled study of the nutritional adjunct SAAVE. Alcohol 5: 481-493.
Blum K, Allison D, Trachtenberg MC, Michael C, Williams RW, et al. (1988) Reduction of both drug hunger and withdrawal against advice rate of cocaine abusers in a 30 day inpatient treatment program by the neuronutrient Tropamine. Current Therapeutic Research 43: 1204-1214.
Blum K, Trachtenberg MC, Cook DW (1990) Neuronutrient effects on weight loss in carbohydrate bingers: an open clinical trial. Curr Ther Res 48: 217-233.
Cold JA (1996) NeuRecover-SATM in the Treatment of Cocaine Withdrawal and Craving: A Pilot Study. Clinical Drug Investigation 12: 1-7.
DeFrance JF, Hymel C, Trachtenberg MC, Ginsberg LD, Schweitzer FC, et al. (1997) Enhancement of attention processing by Kantroll in healthy humans: a pilot study. Clinical Electroencephalography 28: 68-75.
Blum K, Cull JG, Chen TJH, Swan SG, Holder JM, et al. (1997) Clinical evidence for effectiveness of Phencal™ in maintaining weight loss in an open-label, controlled, 2-year study. Current Therapeutic Research 55: 745-763.
Ross J (2001) Amino-acid precursor and enkephalinase inhibition therapy: evidence for effectiveness in treatment of "Reward Deficiency Syndrome (RDS) with particular emphasis on eating disorders. Mol Psychiatry 6: S1-8.
Chen TJ, Blum K, Payte JT, Schoolfield J, Hopper D, et al. (2004) Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy. Med Hypotheses 63: 538-548.
Blum K, Chen TJ, Meshkin B, Downs BW, Gordon CA, et al. (2006) Reward deficiency syndrome in obesity: a preliminary cross-sectional trial with a Genotrim variant. Adv Ther 23: 1040-1051.
Chen TJ, Blum K, Waite RL, Meshkin B, Schoolfield J, et al. (2007) Gene\Narcotic Attenuation Program attenuates substance use disorder, a clinical subtype of reward deficiency syndrome. Adv Ther 24: 402-414.
Blum K, Chen TJH, Downs BW, Meshkin B, Blum SH, et al. (2007) Synaptamine (SG8839), TM An Amino-Acid Enkephalinase Inhibition Nutraceutical Improves Recovery of Alcoholics, A Subtype of Reward Deficiency Syndrome (RDS). Trends in Applied Sciences Research 2: 132-138
Chen TJH, Blum K, Kaats G, Braverman ER, Eisenberg A, et al. (2007) Chromium Picolinate (Crp) A putative Anti-Obesity Nutrient Induces Changes In Body Composition As Function Of The Taq1 Dopamine D2 Receptor Gene. Gene Ther Molbiol 11: 161-170.
Blum K, Chen TJH, Williams L, Chen ALC, Downs William B, et al. (2007) A short-term pilot open label study to evaluate efficacy and safety of LG839, a customized DNA directed nutraceutical in obesity: Exploring Nutrigenomics. Gene Therapy and Molecular Biology 12: 371-382.
Blum K, Chen AL, Chen TJ, Rhoades P, Prihoda TJ, et al. (2008) LG839: anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome. Adv Ther 25: 894-913.
Blum K, Chen AL, Chen TH, Bowirrat A, Waite RL, et al (2009) Putative targeting of dopamine D2 receptor function in Reward deficiency Syndrome (RDS) by Synaptamine Complex Variant (KB220): clinical trial showing anti-anxiety effects. Gene Therapy Molecular Biology 13: 214-230.
Braverman ER, Braverman D, Acrui V, Kerner M, Downs BW, et al. (2010) Sustainable Weight Loss and Muscle Gain Utilizing the Rainbow Diet™: Targeting Noradrenergic and dopaminergic Mechanistic Sites, Hormonal Deficiency Repletion Therapy and Exercise: A case report. The American Journal of Bariatric Medicine 25: 18–28.
Blum K, Stice E, Liu Y, Giordano J, Morse S, et al. (2011) "Dopamine Resistance" in brain reward circuitry as a function of DRD2 gene receptor polymorphisms in RDS: Synaptamine complex variant (KB220) induced "Dopamine Sensitivity" and enhancement of happiness. XIX World Congress of Psychiatric Genetics, Washington D.C.
Chen D, Liu Y, He W, Wang H, Wang Z (2012) Neurotransmitter-precursor-supplement intervention for detoxified heroin addicts. J Huazhong Univ Sci Technolog Med Sci 32: 422-427.
Blum K, Oscar-Berman M, Stuller E, Miller D, Giordano J, et al. (2012) Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms. J Addict Res Ther 3: 139.
McLaughlin T, Febo M, Badgaiyan R, Barh D, Dushaj K, et al. (2016) KB220Z™ a Pro-Dopamine Regulator Associated with the Protracted, Alleviation of Terrifying Lucid Dreams. Can We Infer Neuroplasticity-induced Changes in the Reward Circuit? Journal of Reward Deficiency Syndrome & Addiction Science 2: 3-13.
Beitscher-Campbell H, Blum K, Febo M, Madigan MA, Giordano J, et al (2016) Pilot Clinical Observations Between Food and Drug Seeking Derived from Fifty Cases Attending an Eating Disorder Clinic. Journal of Behavioral Addictions.