Pathways to Substance Use and Abuse

Neuroscience medicine clinicians encounter patients every day who have both a mental and substance use disorder.

This co-occurrence, or comorbidity, complicates diagnosis, treatment and outcome.

The exact mechanism for this comorbidity issue is unclear.

A recent study out of Washington University in St. Louis and King's College London provides some insight into this comorbidity issue.

They examined participants in the Study of Addiction: Genetics and Environment (SAGE). These subjects provided genetic samples and psychiatric interviews to the research team.

Five psychiatric disorders were studied including attention deficit hyperactivity, autism spectrum disorder, major depression, bipolar disorder and schizophrenia. A initial finding ruled out any link between genetic risk for autism spectrum disorder and any substance use/abuse risk.

The remaining four psychiatric disorders did increase risk for substance use and abuse in a general manner. This means genetic risk for ADHD, bipolar disorder, major depression and schizophrenia all contribute to a general risk for substance use/abuse across all drug categories.

Additionally, the team reported some specific drug use/abuse with individual genetic risk for ADHD, bipolar disorder, major depression and schizophrenia. These specific pathways included:

• Major depression polygenetic risk score and non-problem cannabis use
• Major depression polygenetic risk score and severe cocaine dependence
• Schizophrenia polygenetic risk score and  non-problem cannabis use and severe cannabis dependence
• Schizophrenia polygenetic risk score and severe cocaine dependence

The take-home message from this study is that genetic risk for many psychiatric disorders also contributes to a increased risk for general substance use/abuse. Additionally, some psychiatric disorders appear to increase risk for specific substance use/abuse issues.

Prevention, assessment and treatment services need to address this relationship and the needs for each component of illness in those with comorbidity.

Individuals with more interest in this topic can access the free full-text manuscript by clicking on the link in the citation below.

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Image is an original graphic produced by me based on content in the manuscript.

Carey CE, Agrawal A, Bucholz KK, Hartz SM, Lynskey MT, Nelson EC, Bierut LJ, & Bogdan R (2016). Associations between Polygenic Risk for Psychiatric Disorders and Substance Involvement. Frontiers in genetics, 7 PMID: 27574527

Cannabis Use Declines with Aerobic Exercise

Improvement in addiction treatment interventions in needed.  Many substance dependence individuals end up with with a chronic illness with frequent relapse following periods of abstinence.

Aerobic exercise appears to be a candidate for a treatment component in a variety of addictive disorders.  Aerobic exercise may produce a variety of changes in the brain that may influence craving and drug use.

Mechanisms induced by aerobic exercise that might influence drug craving and drug use include:

• Alteration in the brain reward circuit
• Increased release of brain dopamine and changes in dopamine receptor sensitivity
• Decrease in anxiety and depressive symptoms 

Maciej Bukowski and colleagues at Vanderbilt University recently published a trial of cannabis craving and use in a series of subjects.  Regular cannabis user were enrolled in a ten session intervention that included ten 30 minute supervised treadmill periods.  Subjects exercised at 60% of their calculated maximum heart rate. 

All subjects met DSM-IV criteria for cannabis dependence.  Subjects were not involved in any formal substance abuse treatment program and did not express a desire to reduce or discontinue their cannabis use.  Subjects were using an average of 33.5 standard joint equivalents of cannabis at the beginning of the study.  The average daily cannabis use of the subjects is displayed in the plot below taken from the manuscript:

The plot demonstrates a significant reduction in daily cannabis use during the active aerobic exercise period. Daily joint use dropped from approximately six joints per day to an average of about two to three joints per day during the exercise period.  Following completion of the exercise phase, daily joint use climbed up again approaching the run-period levels.

This study was not done in a treatment-seeking sample.  It is unclear whether a similar effect would be seen in treatment seeking samples.  The study did not include a control sample.  Nevertheless, this study should stimulate research in treatment samples.  It suggests that regular aerobic exercise may be a valuable component of treatment for cannabis dependence.  Extended aerobic exercise may be valuable in the longer term reduction of cannabis use in those with cannabis dependence.

Chemical model of tetrahydrocannabinol (the psychoactive substance in cannabis) from the Creative Commons file at Wikipedia authored by Ben Mills.

Cannabis use Creative Commons Attribution License plot from Plos One manuscript authored by Maciej Bukowski and colleagues referenced below.

Buchowski MS, Meade NN, Charboneau E, Park S, Dietrich MS, Cowan RL, & Martin PR (2011). Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults. PloS one, 6 (3) PMID: 21408154

Age-Specific Psychotic Effects with Cannabis Use

There is increasing evidence that some users of cannabis may be vulnerable to adverse cognitive effects including psychotic symptoms. Many adult casual users of cannabis appear to have minimal cognitive effects. However, younger users and those with underlying mood or psychotic disorders may experience significant adverse consequences of regular and heavy cannabis abuse. A previous post linking cannabis-related psychosis to family history of psychosis is posted here.

Schubart and colleagues in the Netherlands and UCLA recently analyzed the rates of reporting psychotic experiences in European (primarily Dutch-speaking)adolescents and young adults. They looked specifically for the rates of endorsement of psychotic and mood symptoms in adolescents grouped by frequency and quantity of cannabis use.
Psychotic symptom experience is commonly grouped into what are known as positive symptoms or negative symptoms. Positive symptoms of psychosis typically include delusions, auditory hallucinations and visual hallucinations. Negative symptoms of psychosis typically include loss of motivation, withdrawal, and lack of goal directed productivity.

Over 17,000 young adults participated in the survey with over two thirds of the respondents being classified as users. Looking at the entire group of regular cannabis users, their scores on measures of psychosis and depressive symptoms did not differ from those who reported not using cannabis.

However, two factors among the users identified subgroups with signficant endorsement of symptoms of psychopathology:

• Cannabis users who initiated use before the age of 12 were three times more likely than non-users to be in the top 10% of scores on psychotic positive symptoms
• Regular heavy cannabis users (greater than 25 euros spent per week on cannabis) were 2.8 to 3.4 times more likely to be in the top 10% of scorers on scales of positive and negative psychotic symptoms as well as depressive symptoms.

The authors noted in the discussion that this cross-sectional design can not prove a causal pathway. It is possible that young people with psychotic symptoms may be more likely to begin using cannabis. Additionally, they note that young age of onset of cannabis use may also indicate a larger cumulative exposure that could be related to psychotic and mood symptoms.

However, they do note their findings are consistent with the possibility that tetrahydrocannabinol (or other cannabis drugs)may have increased toxicity "during critical phases of brain maturation". There may be a window of vulnerability to the effcts of cannabis. Use after passing through this window, limited cannabis use may have limited cognitive effect. Early cannabis use and heavy chronic use may be a much different story. 

Photo of a black and yellow argiope spider from North Palm Beach Florida courtesy of Yates Photography.

Schubart CD, van Gastel WA, Breetvelt EJ, Beetz SL, Ophoff RA, Sommer IE, Kahn RS, & Boks MP (2010). Cannabis use at a young age is associated with psychotic experiences. Psychological medicine, 1-10 PMID: 20925969

Ecstasy Designer Drug 2C-E and a Death in Oklahoma

Chemical Structure 2C-E

If you are a parent of a teenager I hope you took chemistry in high school or college because you are going to need it.  The reason you are going to need it is the emergence of designer drugs of abuse.  Designer drugs typically have a parent compound that is chemically modified.  There are two key reasons to modify existing illegal compounds: 1.) the new compound may not be illegal until state and federals laws can be modified and 2.) the new compound may have potent psychoactive effects.

Unfortunately, some effects of the designer drugs may not be so beneficial.  A young adult Oklahoma woman died recently after ingesting a designer drug known as 2C-E.  Additionally, seven young adults at the same party were hospitalized for adverse effects. 

The number and type of designer drugs is pretty extensive.  The parent compounds for some of these designer drugs include marijuana (tetrahydrocannabinol), ecstasy (MDMA), PCP and the opiate drug fentanyl.  2C-E is a designer drug derived from phenethylamine.

Deaths due to ecstasy use are uncommon.  Many deaths in ecstasy users occur in the context of alcohol and other drug use making the specific contribution from ecstasy unclear.  MDMA may contribute to risk of death through seizure, cardiac arrhythmia, hyperthermia or water intoxication.  MDMA may cause inappropriate release of the endogenous hormone ADH (antidiuretic hormone) that can cause low serum sodium, brain edema and death via water intoxication.

Given the acute toxic effects on multiple users of 2C-E in Oklahoma, the potential for toxic contaminants will need to be explored. 2C-E is thought to block the 5-HT2A (serotonin) receptor.  There is some evidence this effect is potentiated in those taking a selective serotonin reuptake inhibitory antidepressant drugs like Prozac.  Some of these designer drugs can be ordered online.  There is essentially no safety data so users are the defacto guinea pigs.  Autopsy results in the Oklahoma death will not be known for weeks.

Here is a listing of the compounds listed by parent compound type from a recent research review that explored the metabolism of these compounds.

2C phenethylamine compounds

(2C-B), 4-bromo-2,5-dimethoxy-beta-phenethylamine

(2C-I), 4-iodo-2,5-dimethoxy-beta-phenethylamine

(2C-D), 2,5-dimethoxy-4-methyl-beta-phenethylamine

(2C-E), 4-ethyl-2,5-dimethoxy-beta-phenethylamine

(2C-T-2), 4-ethylthio-2,5-dimethoxy-beta-phenethylamine and

(2C-T-7) 2,5-dimethoxy-4-propylthio-beta-phenethylamine

Beta-keto designer drugs

 (butylone, bk-MBDB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butan

(ethylone, bk-MDEA), 1-one2-ethylamino-1-(3,4-methylenedioxyphenyl)propan

(methylone, bk-MDMA) 2-methylamino-1-(3,4-methylene notdioxy notphenyl)propan

pyrrolidino notphenones

(MPBP) 4-methyl-pyrrolidinobutyrophenone

(PVP) alpha-pyrrolidinovalerophenone

(PCPr) N (1 phenylcyclohexyl) propanamine

phencyclidine (PCP)-derived drugs

(PCEEA),N-(1-phenylcyclohexyl)-2-ethoxyethanamine

PCMPA), N-(1-phenylcyclohexyl)-3-methoxypropanamine

(PCMEA), (N-(1-phenylcyclohexyl)-2-methoxyethanamine

Tryptamines

(5-MeO-DIPT), 5-methoxy-N,N-diisopropyl nottryptamine

Alpha methylfentanyl

(alpha-MF) alpha-methylfentanyl

(3-MF) 3-methylfentanyl

Cannabis Compounts-K2, Spice

Cannabicyclohexanol

HU-210

JWH-018

JWH-073

Chemical model of the drug 2C-E from Wikipedia Creative Commons authored by sbrools.

Farah R, & Farah R (2008). Ecstasy (3,4-methylenedioxymethamphetamine)-induced inappropriate antidiuretic hormone secretion. Pediatric emergency care, 24 (9), 615-7 PMID: 18797371

Meyer MR, & Maurer HH (2010). Metabolism of designer drugs of abuse: an updated review. Current drug metabolism, 11 (5), 468-82 PMID: 20540700

Cannabis Use and Psychosis (Part 2)

I reviewed a research study last fall examining a Dutch study of cannabis use and psychotic symptoms.  That post is linked here.  In summary, the study suggested cannabis probably does not produce psychotic symptoms in the majority of users.  However, if you have a family member with a psychotic disorder (suggesting you may have a genetic risk for psychosis) you may be more likely to experience psychotic symptoms (i.e. hallucinations/delusions) with cannabis use.  This risk may be increased with higher potency cannabis formulations.

Now two additional research publications weigh in on this issue.  Both were published in the February 2011 issue of Archives of General Psychiatry.  Both studies come from the Genetic Risk and Outcome of Psychosis (GROUP) study sample.

The first manuscript summarized the results of study using a sibling-control and cross-sibling comparison.  Eleven hundred twenty subjects with a psychotic disorder were compared to 1057 siblings and 590 controls. In summary the results of this study were:

• You were much more likely to report psychotic symptoms (both positive and negative psychotic symptoms) with cannabis use if you had a sibling with psychosis
• Siblings using cannabis resembled psychotic siblings in their ratings much more than siblings not using cannabis
• The statistical analysis of the relationship pointed to a familial risk increasing cannabis sensitivity, rather than familial risk increasing use of cannabis

So this finding in in line with the original study.  Families may resemble each other in the way they respond to cannabis.  Some families may be particularly more likely to have psychotic symptoms in the context of cannabis use.

The second study takes another step to try to explain this relationship.  Can candidate genes be identified that are linked to this cannabis-linked psychosis effect?  If so, do these genes make biological sense or do they seem to just likely be random associations.

The answers proposed by the GROUP investigators are intriguing.  

• Sixteen single nucleotide proteins (SNPs) showed significant interactions
• The AKT1 gene status (C/C genotype) increased risk of psychosis after cannabis use
• AKT1 gene status explained 19% of the variance of psychotic symptoms in siblings with recent cannabis use
• The AKT1 gene is regulated by endogenous cannabanoid signaling
• This signal is downstream from the dopamine D2 receptor--a receptor known to be involving in psychosis and the target of antipsychotic drugs

The authors note that their proposed mechanism explains two commonly clinical findings:

• antipsychotic drugs do not block the psychotic effect of THC in those that experience psychosis with the drug
• substance abusing patients with schizophrenia respond more poorly to antipsychotic treatment

The explanation would be the endocannabanoid AKT1 effect is downstream from the D2 receptor.  Blocking the D2 receptor would have limited effects downstream from the receptor.

These two studies add to support for a role for cannabis to be a potential risk factor for some forms of psychosis and schizophrenia.  The genetic and molecular correlations in this study a mutually supportive.  So the take home message seems to be the same--there just seems to be more support the message is research based.  Some individuals may have a genetic risk for psychotic symptoms related to cannabis use.  This is not a trivial risk.  If you have a sibling or other relative with psychosis, or if you experience psychotic symptoms with cannabis use, don't use cannabis.

Photo of Back Yard Blue Jay in Tulsa after Snowfall Courtesy of Yates Photography

., Kahn, R., Linszen, D., van Os, J., Wiersma, D., Bruggeman, R., Cahn, W., de Haan, L., Krabbendam, L., & Myin-Germeys, I. (2010). Evidence That Familial Liability for Psychosis Is Expressed as Differential Sensitivity to Cannabis: An Analysis of Patient-Sibling and Sibling-Control Pairs Archives of General Psychiatry DOI: 10.1001/archgenpsychiatry.2010.132

van Winkel, R., , ., Kahn, R., Linszen, D., van Os, J., Wiersma, D., Bruggeman, R., Cahn, W., de Haan, L., Krabbendam, L., & Myin-Germeys, I. (2010). Family-Based Analysis of Genetic Variation Underlying Psychosis-Inducing Effects of Cannabis: Sibling Analysis and Proband Follow-up Archives of General Psychiatry, 68 (2), 148-157 DOI: 10.1001/archgenpsychiatry.2010.152