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Biomedical subjects

Mark S Gold

Publications and source records attributed to Mark S Gold.

At least 19 recordsLinked to original sources
PubMed2025

Precision Genomics: A Reality Having Universal Impact in a New Era of Psychiatry - Lessons Learned, Past and Present.

Addiction neuroscience explores the complex interplay between genetic, neurobiological, environmental, and socio-spiritual factors underlying substance and behavioral addictions. Over the past three decades, research in this domain has identified critical molecular and epigenetic mechanisms-particularly those affecting dopaminergic signaling and reward pathways-that contribute to both vulnerability and resilience to addictive behaviors. Central to this understanding is the concept of reward deficiency syndrome (RDS), first introduced by Kenneth Blum, which posits that hypodopaminergic functioning predisposes individuals to seek maladaptive rewards. Advances in neurogenetics, including the identification of key polymorphisms such as the DRD2 A1 allele, have paved the way for precision tools like the genetic addiction risk severity (GARS®) test. This test, alongside pro-dopaminergic nutraceutical interventions like KB220, demonstrates the potential for early detection and individualized treatment of "pre-addiction" risk states. Despite ongoing reliance on opioids for opioid use disorder (OUD), emerging paradigms advocate for dopamine homeostasis through non-addictive, integrative approaches. Furthermore, the integration of whole genome sequencing data can be used for Genome-Wide Association Studies (GWAS), multi-omics, and machine learning into clinical practice holds promise for advancing personalized medicine in addiction treatment. As the field progresses, addressing health equity and improving genomic representation across populations remain critical goals. This evolving framework underscores the importance of leveraging genomic insights to prevent, predict, and personalize interventions for addiction and mental illness at scale.

Disorder↗
PubMed2025

Multi-Locus Pro-Dopaminergic Restoration of Reward Brain Circuitry in Reward Deficiency Rescinds Mono-Pharmaceutical Targeting.

Dopaminergic dysfunction in reward circuitry is well-documented as a contributor to addictive behaviors. Evidence indicates that changes in synchronous neural activity between brain regions mediating reward and cognitive functions may significantly contribute to substance-related disorders. In this commentary we highlight findings showing that the pro-dopaminergic nutraceutical (KB220) enhances functional connectivity between reward and cognitive brain areas in both animal and human studies. Animal studies demonstrate that KB220 activates important brain reward-related regions, including the nucleus accumbens, anterior cingulate gyrus, anterior thalamic nuclei, hippocampus, and prelimbic and infralimbic loci. Kb220 induced significant functional connectivity, enhanced neuroplasticity, and improved dopaminergic functionality within the brain reward circuitry with effects localized to these regions rather than broader distributed across the brain. In abstinent heroin-dependent individuals, acute KB220 administration significantly induced BOLD activation in caudate-accumbens dopaminergic pathways relative to placebo. Furthermore, data from 36 clinical trials and preclinical studies encompassing over 1,000 subjects, demonstrate that KB220 supports "dopamine homeostasis" across various reward deficiency behaviors. Clinical outcomes and quantitative electroencephalogy (qEEG) results underscore KB220's potential anti-craving/anti-relapse effects in addiction and other psychiatric disorders through direct or indirect dopaminergic modulation. Based on a review of the existing knowledge and further intensive investigation, we propose that instead of relying on mono-pharmaceutical approaches, the scientific community should endorse multi-loci dopaminergic restoration of reward brain circuitry as a fundamental paradigm for addressing mental illness.

Alcohol Use Disorder (AUD)↗
PubMed2007

The effects of buprenorphine on fentanyl withdrawal in rats.

RATIONALE: Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of severe chronic pain. Discontinuation of fentanyl administration has been shown to induce a negative emotional state. OBJECTIVES: The aim of the present studies was to investigate the effects of the partial mu-opioid receptor agonist buprenorphine on the negative emotional state associated with precipitated and spontaneous fentanyl withdrawal in rats. MATERIALS AND METHODS: Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function. Somatic signs were recorded from a checklist of opioid abstinence signs. RESULTS: Naloxone induced a deficit in brain reward function in rats chronically treated with fentanyl. Buprenorphine dose-dependently prevented the naloxone-induced deficit in brain reward function. Discontinuation of fentanyl administration was also associated with a deficit in brain reward function. After explantation of the minipumps, the administration of buprenorphine induced a potentiation of brain reward function in the fentanyl-withdrawing rats, but did not affect brain reward function of saline-treated control rats. Buprenorphine prevented the somatic withdrawal signs associated with spontaneous fentanyl withdrawal and attenuated the somatic signs associated with precipitated fentanyl withdrawal. CONCLUSIONS: Buprenorphine prevents affective and somatic fentanyl withdrawal signs. Moreover, buprenorphine is rewarding in rats previously exposed to fentanyl, but not in opioid-naïve rats. This pattern of results suggests that buprenorphine may be an effective treatment for the anhedonic-state associated with fentanyl withdrawal, but further study of buprenorphine's abuse potential is warranted.

Analgesics, Opioid↗
PubMed2006

Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats.

Nicotine dependence is a chronic mental illness that is characterized by a negative affective state upon tobacco smoking cessation and relapse after periods of abstinence. It has been hypothesized that cessation of nicotine administration results in the activation of brain corticotropin-releasing factor (CRF) systems that leads to the negative affective state of withdrawal. The aim of our experiments was to investigate the role of brain CRF systems in the deficit in brain reward function associated with the cessation of nicotine administration in rats. The intracranial self-stimulation procedure was used to assess to negative affective aspects of nicotine withdrawal as this procedure can provide a quantitative measure of emotional distress in rats. In the first experiment, mecamylamine induced a dose-dependent elevation in brain reward thresholds in nicotine-treated rats. In the follow-up experiment, it was shown that pretreatment with the corticotropin-receptor antagonist D-Phe CRF((12-41)) prevents the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. In the third experiment, the effect of D-Phe CRF((12-41)) on the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal was investigated. Administration of D-Phe CRF((12-41)) 6 h after the explantation of the nicotine pumps, did not result in a lowering of the brain reward thresholds. These findings indicate that antagonism of CRF receptors prevents, but not reverses, the deficit in brain associated with nicotine withdrawal. These data provide support for the hypothesis that a hyperactivity of brain CRF systems may at least partly mediate the initiation of the negative affective aspects of nicotine withdrawal.

Animals↗
PubMed2006

Calpain- and caspase-mediated alphaII-spectrin and tau proteolysis in rat cerebrocortical neuronal cultures after ecstasy or methamphetamine exposure.

Abuse of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) and methamphetamine (Meth or Speed) is a growing international problem with an estimated 250 million users of psychoactive drugs worldwide. It is important to demonstrate and understand the mechanism of neurotoxicity so potential prevention and treatment therapies can be designed. In this study rat primary cerebrocortical neuron cultures were challenged with MDMA and Meth (1 or 2 mM) for 24 and 48 h and compared to the excitotoxin N-methyl-D-aspartate (NMDA). The neurotoxicity of these drugs, as assessed by microscopy, lactate dehydrogenase release and immunoblot, was shown to be both dose- and time-dependent. Immunoblot analysis using biomarkers of cell death showed significant proteolysis of both alphaII-spectrin and tau proteins. Breakdown products of alphaII-spectrin (SBDPs) of 150, 145, and 120 kDa and tau breakdown products (TBDPs) of 45, 32, 26, and 14 kDa were observed. The use of the protease inhibitors calpain inhibitor SJA6017 and caspase inhibitors z-VAD-fmk and Z-D-DCB, attenuated drug-induced alphaII-spectrin and tau proteolysis. The calpain inhibitor reduced the calpain-induced breakdown products SBDP145 and TBDP14, but there was an offset increase in the caspase-mediated breakdown products SBDP120 and TBDP45. The caspase inhibitors, on the other hand, decreased SBDP120 and TBDP45. These data suggest that both MDMA and Meth trigger concerted proteolytic attacks of the structural proteins by both calpain and caspase family of proteases. The ability of the protease inhibitors to reduce the damage caused by these drugs suggests that the treatment arsenal could include similar drugs as possible tools to combat the drug-induced neurotoxicity in vivo.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Is speeding a form of gambling in adolescents?

Speeding is a major contributor to motor vehicle accidents, which are the leading cause of death in adolescents. This study compares the extent to which adolescents with gambling behavior and substance use reported driving over the posted speed limits ("speeding"). Florida adolescents ages 13-17 (n = 1051) were surveyed, and asked about gambling activities, problems related to gambling, substance use, demographic questions, and speeding. Of the 562 respondents who were drivers, the gender distribution was 52.1% male and 47.9% female. Of those respondents, 76.9% were Caucasian, 6.8% were African American, 10.1% were Hispanic, and 6.1% were Native American/Asian/Other. Simple correlation analysis revealed that self-reported speeding is significantly related to gambling behavior and substance use. When a linear regression model was used, four factors showed the most significant influence on self-reported speeding: past year gambling tendency, age, trouble with the police due to drinking, and tranquilizer usage. Gambling behavior and high-risk speeding (driving ≥ 10 mph over speed limit) also were noted to be positively correlated. Our data indicate a relationship between risky driving, gambling, and other risk-taking behaviors in adolescents, and support the hypothesis that speeding may be a form of gambling behavior in this age group.

Adolescent↗
PubMed2006

Second-hand exposure to aerosolized intravenous anesthetics propofol and fentanyl may cause sensitization and subsequent opiate addiction among anesthesiologists and surgeons.

We hypothesize that aerosolization of anesthetics administered intravenously to patients in the operating room may be an unintended source of exposure to physicians. This may lead to inadvertent sensitization, which is associated with an increased risk for developing addiction. This may contribute to the over-representation of certain specialties among physicians with addiction. We retrospectively reviewed the de-identified demographic information of all licensed physicians treated for substance abuse in the State of Florida since 1980, to determine if medical specialty was associated with addiction in this group of individuals. Then, to identify the potential for exposure, two mass spectrometry assays were developed to detect two intravenously administered drugs, fentanyl and propofol, in air. Since 1980, 7.6% of licensed Florida physicians underwent treatment for addiction. Addiction in anesthesiologists was higher than expected. Opiate abuse was greater in anesthesiologists and surgeons compared to other specialties. Aerosolized fentanyl was detected in the air of the cardiothoracic operating room, in patients' expiratory circuits, and in the headspace above sharps boxes, but not in adjoining hallways. Aerosolized propofol was detected in the expirations of a patient undergoing transurethral prostatectomy. While access and stress may place anesthesiologists and surgeons at greater risk for substance abuse, an additional risk factor may be unintended occupational exposure to addictive drugs. This report provides preliminary evidence of detection of aerosolized intravenous anesthetics using two newly developed analytical methods. We conclude that the potential exists for chronic exposure to low levels of airborne intravenously administered drugs. Further studies are under way to determine the significance of this exposure.

Aerosols↗
PubMed2006

Caffeine content of decaffeinated coffee.

Caffeine is the most widely consumed drug in the world with coffee representing a major source of intake. Despite widespread availability, various medical conditions necessitate caffeine-restricted diets. Patients on certain prescription medications are advised to discontinue caffeine intake. Such admonition has implications for certain psychiatric patients because of pharmacokinetic interactions between caffeine and certain anti-anxiety drugs. In an effort to abstain from caffeine, patients may substitute decaffeinated for caffeinated coffee. However, decaffeinated beverages are known to contain caffeine in varying amounts. The present study determined the caffeine content in a variety of decaffeinated coffee drinks. In phase 1 of the study, 10 decaffeinated samples were collected from different coffee establishments. In phase 2 of the study, Starbucks espresso decaffeinated (N=6) and Starbucks brewed decaffeinated coffee (N=6) samples were collected from the same outlet to evaluate variability of caffeine content of the same drink. The 10 decaffeinated coffee samples from different outlets contained caffeine in the range of 0-13.9 mg/16-oz serving. The caffeine content for the Starbucks espresso and the Starbucks brewed samples collected from the same outlet were 3.0-15.8 mg/shot and 12.0-13.4 mg/16-oz serving, respectively. Patients vulnerable to caffeine effects should be advised that caffeine may be present in coffees purported to be decaffeinated. Further research is warranted on the potential deleterious effects of consumption of "decaffeinated" coffee that contains caffeine on caffeine-restricted patients. Additionally, further exploration is merited for the possible physical dependence potential of low doses of caffeine such as those concentrations found in decaffeinated coffee.

Caffeine↗
PubMed2006

Fentanyl abuse and dependence: further evidence for second hand exposure hypothesis.

We have proposed a novel hypothesis regarding the potential role of occupational or second-hand exposure in physician substance use, abuse, and addiction. While only 5.6% of licensed physicians in Florida are anesthesiologists, nearly 25% of physicians followed for substance abuse/dependence are anesthesiologists. When we sort by drug of choice, anesthesiologists have more opioid abuse and dependence than other physicians and appropriate controls. Abuse of one opioid, fentanyl, appears to be increasing and has been noted among the State of Florida's causes of opioid deaths. Fentanyl and sufentanyl are commonly administered highly potent opioid analgesics, as much as 80-800 times as potent as morphine. We have recent data from the State of Florida impaired physicians database, which has allowed us to categorize all fentanyl abusing and/ or dependent physicians. Just knowing that a physician abuses fentanyl gives you a good clue as to their specialty; 75% are anesthesiologists! While drug abuse researchers, oncologists and others who handle drugs of abuse everyday, have no greater incidence of opioid abuse or dependence, anesthesiologists are at the top of every list. Can this be due to just access and stress? We have proposed an alternative hypothesis of second hand exposure. To test this hypothesis, we developed a sensitive LC/MS/MS assay to measure the intravenous anesthetic and analgesic agents, propofol and fentanyl in air. Not only did we detect propofol and fentanyl in cardiovascular surgery operating room air, we also found the highest concentrations were close to the patient's mouth where anesthesiologists work for hours. Like tobacco, second hand opioid exposure can sensitize and change the brain making abuse, dependence and behavioral disorders more likely. Thus environmental exposure and sensitization may be an important risk factor in physician addiction. Second hand exposure may affect treatment outcome and explain anesthesiologist's inability to return to work in the operating room. We are developing an animal model for second hand exposure and additional studies of the operating room and cardiac anesthesiologists are underway.

Analgesics, Opioid↗
PubMed2006

Ecstasy toxicity: a comparison to methamphetamine and traumatic brain injury.

Ecstasy use is a growing problem in the United States. Techniques to demonstrate and characterize the toxicity associated with its use have been limited and employed infrequently. In this study, we compare the deleterious effects of ecstasy use in rats with that of methamphetamine and traumatic brain injury. Specifically, we investigate the degradation of structural proteins alphaII-spectrin and tau by the pro-necrotic calpain and pro-apoptotic caspase systems. Ecstasy-induced neurotoxicity is shown after 24 hours, although to a much lesser extent than that of methamphetamine or traumatic brain injury. Neurotoxicity is still evident after 72 hours. Furthermore, apoptosis of the liver is seen 72 hours after ecstasy use. Use of protease inhibitors may be useful in preventing ecstasy-induced toxicity.

Animals↗
PubMed2005

Concurrent calpain and caspase-3 mediated proteolysis of alpha II-spectrin and tau in rat brain after methamphetamine exposure: a similar profile to traumatic brain injury.

Neurotoxicity in rat cortex and hippocampus following acute methamphetamine administration was characterized and compared to changes following traumatic brain injury. Doses of 10, 20, and 40 mg/kg of methamphetamine produced significant increases in calpain- and caspase-cleaved alpha II-spectrin and tau protein fragments, suggesting cell injury or death. Changes in proteolytic products were significantly increased over vehicle controls. Use of fragment specific biomarkers detected prominent calpain-mediated protein fragments in the cortex and hippocampus while caspase-mediated protein fragments were also detected in the hippocampus. Remarkably, proteolytic product increases at the 40 mg/kg dose after 24 h were as high as those observed in experimental traumatic brain injury. Use of calpain and caspase proteolytic inhibitors may be useful in preventing methamphetamine-induced neurotoxicity.

Animals↗
PubMed2005

The role of corticotropin-releasing factor-like peptides in cannabis, nicotine, and alcohol dependence.

The corticotropin-releasing factor (CRF)-like peptides, which include the mammalian peptides CRF, urocortin 1, urocortin 2, and urocortin 3, play an important role in orchestrating behavioral and physiological responses that may increase an organism's chance of survival when confronted with internal or external stressors. There is, however, evidence that a chronic overactivity of brain CRF systems under basal conditions may play a role in the etiology and maintenance of psychiatric disorders such as depression and anxiety disorders. In addition, there is evidence of a role for CRF-like peptides in acute and protracted drug abstinence syndromes and relapse to drug-taking behavior. This review focuses on the role of CRF-like peptides in the negative affective state associated with acute and protracted withdrawal from three widely abused drugs, cannabis, nicotine, and alcohol. In addition, we discuss the high comorbidity between stress-associated psychiatric disorders and drug dependence. A better understanding of the brain stress systems that may underlie psychiatric disorders, acute and protracted drug withdrawal, and relapse to drug-taking behavior may help in the development of new and improved pharmacotherapies for these widespread psychiatric disorders.

Alcoholism↗
PubMed2005

Can drug design inhibit abuse?

A recent federal report indicates that prescription drug abuse is now the second leading category of illicit drug use, following marijuana use. Control strategies typically focus on reducing the diversion of prescription drugs from legitimate sources. The proliferation of unregulated Internet sources, however, has rendered control strategies less effective. This study examines a new approach that focuses on reducing abusability through the use of abuse-resistant drug designs. Drugs with and without such designs are compared and abuse levels assessed using multiple sources. In every instance, drugs employing abuse-resistant designs were found to have significantly lower levels of abuse than comparator drugs without such designs.

Clinical Pharmacy Information Systems↗