Escolha o Idioma

4/20/2015

DrugFacts: La metanfetamina

La metanfetamina es una droga estimulante que afecta el sistema nervioso central y es similar en estructura a la anfetamina. Debido al alto potencial que tiene para el abuso, la metanfetamina está clasificada como un fármaco de la Lista II de acuerdo a la Ley sobre Sustancias Controladas, y se puede obtener sólo por medio de prescripción médica no renovable. 

Aunque los médicos pueden recetar la metanfetamina, sus usos médicos son limitados y las dosis que se recetan son mucho más bajas que las que normalmente se consumen cuando se abusa. La mayoría de la metanfetamina que se abusa en los Estados Unidos viene de súper laboratorios extranjeros y nacionales, aunque también se puede producir en pequeños laboratorios clandestinos, donde se ponen en peligro a las personas que la elaboran, a los vecinos y al medio ambiente.

¿Cómo se abusa la metanfetamina?

La metanfetamina es un polvo blanco, cristalino, inodoro y amargo que se disuelve fácilmente en agua o alcohol y que se puede fumar, inhalar, inyectar o tomar de forma oral.

¿Cómo afecta la metanfetamina al cerebro?

La metanfetamina aumenta la liberación y bloquea la reabsorción del neurotransmisor dopamina, produciendo concentraciones muy altas de esta sustancia química en el cerebro. Esto constituye un mecanismo de acción común de la mayoría de las drogas de abuso, ya que la dopamina juega un papel importante en la gratificación, la motivación, la sensación de placer y la función motora. 

La habilidad de la metanfetamina de liberar rápidamente la dopamina en las regiones de gratificación del cerebro es lo que produce la euforia intensa o “rush”, que muchos consumidores sienten después de inhalar, fumar o inyectarse la droga.

El abuso crónico de la metanfetamina cambia de forma significativa el funcionamiento del cerebro. Los estudios no invasivos de neuroimágenes del cerebro humano han mostrado alteraciones en la actividad del sistema dopaminérgico que están asociadas con una disminución en el rendimiento motor y un deterioro en el aprendizaje verbal. Asimismo, estudios recientes en personas que han abusado de metanfetamina por periodos prolongados también revelan cambios graves de estructura y función en las áreas del cerebro asociadas con las emociones y con la memoria. Esto podría explicar muchos de los problemas emocionales y cognitivos que se observan en los abusadores crónicos de metanfetamina.

El abuso repetido de la metanfetamina también puede llevar a la adicción, una enfermedad crónica con recaídas caracterizada por la búsqueda y el consumo compulsivo de la droga, que viene acompañada por cambios químicos y moleculares en el cerebro. Algunos de estos cambios perduran mucho tiempo después del cese del consumo de metanfetamina. Sin embargo, se ha observado que algunos cambios se revierten después de periodos sostenidos de abstinencia (por ejemplo, más de 1 año).

¿Qué otros efectos adversos para la salud tiene la metanfetamina?

El consumo de metanfetamina, incluso en pequeñas cantidades, puede resultar en muchos de los mismos efectos físicos de otros estimulantes como la cocaína o la anfetamina, incluyendo una prolongación del estado de vigilia, mayor actividad física, disminución del apetito, aumento de la frecuencia respiratoria, aceleración de la frecuencia cardiaca, irregularidad del latido del corazón, aumento en la presión arterial e hipertermia.

El abuso a largo plazo de la metanfetamina tiene muchas consecuencias negativas, entre ellas, una pérdida extrema de peso, problemas dentales graves (boca de metanfetamina o “meth mouth”), ansiedad, confusión, insomnio, perturbaciones en el estado de ánimo y comportamiento violento. Las personas con historial de abuso prolongado de metanfetamina también demuestran varias características psicóticas, como paranoia, alucinaciones visuales y auditivas y delirio (por ejemplo, la sensación de tener insectos que caminan debajo de la piel).

Otras consecuencias que pueden resultar del abuso de la metanfetamina incluyen la transmisión del VIH y de la hepatitis B y C. Los efectos intoxicantes de la metanfetamina por cualquier vía de administración pueden alterar el juicio y la inhibición y hacer que los usuarios practiquen actividades peligrosas, por ejemplo, comportamientos sexuales de riesgo. Los toxicómanos que se inyectan la droga pueden transmitir el VIH y otras enfermedades infecciosas a través de agujas o jeringuillas contaminadas u otros equipos utilizados para inyectar la droga, cuando éstos se comparten entre varias personas. 
El abuso de la metanfetamina también puede empeorar la evolución del VIH y sus consecuencias. Los estudios indican que el VIH causa mayor daño neuronal y cognitivo en las personas VIH+ que tienen historial de abuso prolongado de metanfetamina en comparación con las personas VIH+ que no usan la droga.

¿Qué opciones de tratamiento existen?

Actualmente, la mayoría de los tratamientos eficaces para la adicción a la metanfetamina son intervenciones integrales cognitivo-conductuales. Por ejemplo, un tratamiento que ha logrado reducir el abuso de metanfetamina es el Modelo Matriz, un enfoque integral de tratamiento conductual que combina terapia conductual, educación familiar, consejería individual, grupo de apoyo de 12 pasos, pruebas de detección para el consumo de drogas y fomento de actividades no relacionadas a las drogas.

Asimismo, las intervenciones de manejo de contingencias han demostrado ser eficaces ya que proporcionan incentivos tangibles a cambio de tomar parte en el tratamiento y mantenerse abstemio. Actualmente, no hay medicamentos aprobados para el tratamiento de la adicción a la metanfetamina; sin embargo, ésta es un área de investigación activa para el NIDA.

¿Cuál es la magnitud del abuso de la metanfetamina?

Estudio de Observación del Futuro (MTF, por sus siglas en inglés)

El Estudio de Observación del Futuro del 2008, una encuesta nacional sobre el consumo de drogas entre los estudiantes de 8º, 10º y 12º grado, ha demostrado una disminución general en el abuso de metanfetamina en los últimos años, sin embargo, continúa siendo preocupante. Los resultados de la encuesta muestran que el 2.3 por ciento de estudiantes de 8º grado, el 2.4 por ciento de estudiantes de 10º grado y el 2.8 por ciento de estudiantes de 12º grado han probado metanfetamina alguna vez en la vida. 

Además, en el 2008 el 0.7 por ciento de estudiantes de 8º grado, el 0.7 por ciento de estudiantes de 10º grado y el 0.6 por ciento de estudiantes de 12º grado eran usuarios actuales, es decir, habían abusado de la metanfetamina en el mes anterior a la encuesta. Del 2007 al 2008, el abuso de metanfetamina en la categoría de “en el año anterior a la encuesta” se mantuvo estable en los tres grados encuestados.

Uso de metanfetamina por estudiantes Estudio de Observación del Futuro del 2008Uso**8º grado10º grado12º gradoEn la vida 2.3% 2.4% 2.8%
En el año anterior 1.2% 1.5% 1.2%
En el mes anterior 0.7% 0.7% 0.6%

Encuesta Nacional sobre el Uso de Drogas y la Salud (NSDUH, por sus siglas en inglés)

El número de personas de 12 años de edad o mayores que reportaron haber usado metanfetamina en el año anterior a la encuesta disminuyó de 1.9 millones en el 2006 a 1.3 millones en el 2007. Se calcula que unos 529,000 americanos (el 0.2 por ciento de la población) eran usuarios actuales de metanfetamina (habían usado la droga por lo menos una vez en el mes anterior). De las 157,000 personas que usaron metanfetamina por primera vez en el 2007, la edad media del primer uso fue de 19.1 años, menor que la edad media de 22.2 años registrada en el 2006.

Molly

La MDMA (3,4-metilendioximetanfetamina), comúnmente conocida como éxtasis y más recientemente como “Molly”, es una droga sintética psicoactiva y similar al estimulante metanfetamina y al alucinógeno mezcalina. Causa un efecto vigorizante, euforia, calidez emocional, empatía hacia los demás, y distorsiones en la percepción sensorial y del tiempo.
Inicialmente, la MDMA fue popular entre los adultos jóvenes y adolescentes blancos en los clubes nocturnos o en “raves” (fiestas de baile de larga duración), pero ahora la droga afecta a una gama más amplia de usuarios y grupos étnicos.

¿Cómo se abusa la MDMA?

La MDMA se toma por vía oral, generalmente en forma de cápsula o pastilla. El término popular “Molly” (argot para “molecular”) se refiere a la forma de polvo cristalino puro de la MDMA, que por lo general se vende en cápsulas. Sus efectos duran aproximadamente de 3 a 6 horas, aunque no es raro que los usuarios repitan la dosis cuando los efectos de la primera dosis comienzan a disiparse. Comúnmente se toma en combinación con otras drogas. Por ejemplo, algunos hombres homosexuales y bisexuales que viven en áreas urbanas informan que consumen la MDMA como parte de sus experiencias con diversas drogas, entre ellas, la cocaína, GHB, metanfetamina, ketamina y el medicamento para la disfunción eréctil llamado sildenafil (Viagra).

¿Cómo afecta la MDMA al cerebro?

La MDMA actúa aumentando la actividad de tres neurotransmisores: la serotonina, la dopamina y la norepinefrina. Los efectos emocionales y sociales de la MDMA probablemente son causados directa o indirectamente por la liberación de grandes cantidades de serotonina, la cual influye en el estado de ánimo (así como en otras funciones tales como el apetito y el sueño). La serotonina también desencadena la liberación de las hormonas oxitocina y vasopresina, que juegan un papel importante en el amor, la confianza, la excitación sexual y otras experiencias sociales. Esto puede explicar los sentimientos característicos de empatía y cercanía emocional producidos por la droga. Los estudios realizados tanto en ratas como en humanos han demostrado que la MDMA eleva los niveles de estas hormonas.
Sin embargo, el aumento de la serotonina causada al tomar MDMA agota el suministro en el cerebro de esta sustancia química importante, provocando secuelas negativas, incluyendo confusión, depresión, problemas para dormir, deseo vehemente de consumir la droga y ansiedad. Estos problemas se pueden presentar poco tiempo después de consumir la droga o hasta días o semanas después.
Algunos consumidores establecidos de la MDMA pueden experimentar confusión duradera, depresión, trastornos del sueño, y problemas de atención y memoria, aunque es posible que algunos de estos efectos se deban al consumo de otras drogas en combinación con la MDMA (especialmente la marihuana).

¿Es adictiva la MDMA?

Hasta ahora, las investigaciones sobre las propiedades adictivas de la MDMA han tenido resultados variables, pero sí sabemos que algunos usuarios informan tener síntomas de dependencia, incluyendo el consumo continuado a pesar de conocer el daño físico o psicológico, tolerancia (o la disminución de la respuesta a la droga) y los efectos del síndrome de abstinencia.
La MDMA afecta a los mismos sistemas de neurotransmisores que las otras drogas adictivas. Si bien los experimentos han demostrado que los animales se auto-administran MDMA, lo que es un indicador importante del potencial de abuso de una droga, el grado de auto-administración es menor que con otras drogas ilícitas como la cocaína.

¿Qué otros efectos adversos para la salud tiene la MDMA?

Muchos de los efectos físicos de la MDMA son iguales a los de otros estimulantes como la cocaína y las anfetaminas. Éstos incluyen aumento en la frecuencia cardiaca y la presión arterial, lo cual tiene un mayor riesgo en personas que tienen problemas circulatorios o enfermedades del corazón. Otros usuarios pueden tener síntomas como tensión muscular, contractura involuntaria de la mandíbula, náuseas, visión borrosa, mareos y escalofríos o sudoración.
En dosis altas, la MDMA puede alterar la capacidad del organismo de regular la temperatura. En ocasiones raras pero impredecibles, esto puede producir un aumento agudo de la temperatura corporal (hipertermia), que puede causar insuficiencia del hígado, de los riñones o del sistema cardiovascular, o incluso la muerte. La MDMA puede interferir con su propio metabolismo (es decir, su degradación dentro del organismo), haciendo que se acumulen concentraciones potencialmente peligrosas de la droga en el cuerpo si se toma repetidamente durante un periodo corto de tiempo.
Agravando los riesgos de la droga, está el hecho de que las pastillas de éxtasis e incluso las cápsulas supuestamente de “Molly” pura, a veces en realidad contienen otras drogas en lugar de o además de la MDMA. Éstas pueden incluir la efedrina (un estimulante), el dextrometorfano (un supresor de la tos), la ketamina, la cafeína, la cocaína, la metanfetamina, o incluso, más recientemente, las catinonas sintéticas (los ingredientes psicoactivos en las drogas conocidas como “sales de baño”). Estas sustancias son perjudiciales si se toman solas, pero pueden ser particularmente peligrosas cuando se mezclan con la MDMA. Los usuarios que combinan intencionalmente o no este tipo de mezcla con sustancias adicionales como la marihuana o el alcohol, pueden estar exponiéndose a un riesgo aún mayor de sufrir efectos adversos para la salud.
Por otra parte, los efectos de la MDMA que promueven el contacto cercano con otras personas y su consumo en contextos cargados de sexualidad (especialmente en combinación con el sildenafil) pueden alentar prácticas sexuales arriesgadas, las mismas que son un factor de riesgo para contraer o transmitir el VIH y la hepatitis.

¿La MDMA tiene algún valor terapéutico?

La MDMA se utilizó por primera vez en la década de los setenta, no como una droga recreativa, sino como una ayuda en la psicoterapia, aunque sin contar con el soporte de los ensayos clínicos ni la aprobación por parte de la Administración de Drogas y Alimentos de los Estados Unidos (FDA, por sus siglas en inglés). En 1985, la Administración para el Control de los Estupefacientes (DEA, por sus siglas en inglés) incluyó a la MDMA en la Categoría I de la Ley sobre Sustancias Controladas, es decir, como una droga con alto potencial de abuso y sin ningún uso medicinal reconocido. Algunos investigadores siguen interesados en su potencial terapéutico cuando se administra en condiciones cuidadosamente controladas. Actualmente se están realizando algunos ensayos clínicos en los que se la está probando como una posible ayuda farmacoterapéutica para el tratamiento del trastorno del estrés postraumático (TEPT o PSTD, por sus siglas en inglés) y de la ansiedad en pacientes con cáncer terminal.

New drugs and drug use trends

New drugs and drug use trends often burst on the scene rapidly. NIDA’S Community Epidemiology Work Group (CEWG), which functioned through 2014, was a network of researchers in major metropolitan areas and some states across the United States that reported data on emerging trends and patters of drug use. 

NIDA’s National Drug Early Warning System (NDEWS) replaces the CEWG and reports on emerging trends and patterns of drug use in many of the same metropolitan areas and states as the CEWG, but also reports data from other areas of the nation, as problems arise. On this page we will provide periodic updates based on NDEWS reports and other reliable information, as well as links for where to go for more information.

"Flakka" (alpha-PVP)
Use of a dangerous synthetic cathinone drug called alpha-pyrrolidinopentiophenone (alpha-PDP), popularly known as "Flakka," is surging in Florida and is also being reported in other parts of the country, according to news reports.



Alpha-PVP is chemically similar to other synthetic cathinone drugs popularly called "bath salts," and takes the form of a white or pink, foul-smelling crystal that can be eaten, snorted, injected, or vaporized in an e-cigarette or similar device. Vaporizing, which sends the drug very quickly into the bloodstream, may make it particularly easy to overdose. Like other drugs of this type, alpha-PVP can cause a condition called "excited delirium" that involves hyperstimulation, paranoia, and hallucinations that can lead to violent aggression and self-injury. The drug has been linked to deaths by suicide as well as heart attack. It can also dangerously raise body temperature and lead to kidney damage or kidney failure.

U.S. and British Columbia Issue Alerts on Fentanyl

The U.S. Drug Enforcement Agency (DEA) has issued a nationwide alert about the dangers of fentanyl and related compounds (fentanyl analogues). Fentanyl, an opioid that is 50-100 times more powerful than morphine, is both abused on its own and commonly added to heroin to increase its potency. Fentanyl and fentanyl-laced heroin have been a concern for over a decade and have caused numerous overdose deaths among injection drug users in several U.S. cities.

Heroin is not the only drug that can be laced with fentanyl, however. Officials in Vancouver, British Columbia, Canada, recently issued public warnings about a wide range of fentanyl-laced drugs causing overdose deaths among users. They warn that fentanyl is now being concealed in non-injection drugs, including oxycodone and various "party drugs" in powder or pill form, as well as in marijuana (although no deaths have been confirmed from fentanyl-laced marijuana). Because of this new threat, British Columbia officials are urging all recreational drug users to "know their source."

HIV Outbreak in Indiana Linked to Abuse of Opana

Health officials in Indiana have announced a fast-spreading outbreak of new HIV cases in the southeastern portion of the state that are linked to injection drug abuse of the powerful prescription opioid painkiller Opana. Injecting drugs and sharing injection equipment is one of the main routes of transmitting HIV. Also, a few new HIV cases in southeastern Indiana were transmitted sexually.

Officials advise that people in southeastern Indiana who have engaged in needle sharing or unprotected sex should get tested for HIV and then re-tested after 2-3 months, as HIV may not appear on tests immediately when the virus is contracted. To reduce risk of contracting HIV, avoid injection drug use, sharing or re-using needles, and having unprotected sex or sex with commercial sex workers.

Warning from Europe: "Superman" pills

An alert was recently issued in The Netherlands warning about pills with a distinctive Superman logo, sold as MDMA (also called ecstasy or Molly) but actually containing a lethal dose of another substance, PMMA (paramethoxymethylamphetamine). These pills have not been reported in the U.S., but four people in the UK are thought to have died after taking these pills.

New Synthetic Cannabinoids—“Cloud 9,” “Mojo,” etc.

Makers of designer drugs that are chemically similar to marijuana’s active ingredient THC—called synthetic cannabinoids or colloquially “synthetic marijuana” or “synthetic pot”—are constantly creating new products to evade legal bans on older compounds. Despite the similarity on the molecular level, these drugs are much more dangerous than marijuana, and have resulted in very serious health consequences including overdoses and aggressive or suicidal behavior in users.

Some new compounds have recently emerged that are sending many users to the hospital in cities around the country. They include: 

AB-PINACA, AB-FUBINACA (sold as “Cloud 9,” “Relax,” or “Crown”) is sold as a liquid in eyedropper bottles and often used with vaporizing devices—e-cigarettes or “hookah pens.” Numerous hospitalizations in Michigan prompted the Macomb County Health Department to issue an emergency warning and ban on the sale of these drugs, which are reported to cause hallucinations, aggressive behavior, racing heartbeat, drowsiness, and vomiting. 

MAB-CHMINACA, ADB-CHMINACA (sold as “Mojo,” “Spice,” “K2,” and “Scooby Snax”) resulted in over 150 hospital visits in Baton Rouge and Lafayette, LA in October, prompting the governor to ban the drug in that state. It is reported to cause severe agitation, anxiety, and paranoia; raised heartbeat and blood pressure; nausea and vomiting; muscle spasms, seizures, and tremors; intense hallucinations and psychotic episodes, including suicidal fixations and other harmful thoughts. 

Caffeine Powder



The death of an Ohio high school senior caused by an overdose of powdered caffeine has prompted the FDA to issue a safety advisory about caffeine powders. Bulk bags of pure caffeine powder are readily available online, and these products may be attractive to young people looking for added caffeine stimulation or for help losing weight, but they are extremely dangerous. Just a teaspoon of pure caffeine powder is equivalent to about 25 cups of coffee—a lethal amount. Besides death, severe caffeine overdose can cause fast and erratic heartbeat, seizures, vomiting, diarrhea, and disorientation—symptoms much more extreme than those of drinking too much coffee or tea or consuming too many sodas or energy drinks.

Although caffeine is generally safe at the dosages contained in popular beverages, caffeine powder is so potent that safe amounts cannot be measured with ordinary kitchen measuring tools, making it very easy to overdose on them even when users are aware of their potency. The FDA thus recommends that consumers avoid caffeine powder altogether, and wishes to alert parents to the existence of these products and their hazards.

Sex Under the Influence of Drugs or Alcohol


Donald A. Calsyn, PhD, Sarah J. Cousins,  Mary A. Hatch-Maillette, Alyssa Forcehimes, Raul Mandler, Suzanne R. Doyle, George Woody 

Introduction

Heterosexual men

Sexual behavior in the context of substance use is a growing area of scientific focus due to its role as a potential risk factor for the transmission of HIV and other sexually transmitted infections (STI). Substance users may engage in a wide range of risky behaviors such as trading sex for drugs or money, vaginal and anal intercourse without condoms, or sex with multiple partners.

Despite the increasing prevalence of HIV and STIs among heterosexual substance users, research typically focuses on men who have sex with men (MSM), and MSM who are injection drug users (IDUs). However, 23% of new HIV cases between 1994 and 2000 were heterosexual IDUs. Knowledge of the relationship between sex and drugs, particularly for heterosexual men in treatment, is lacking, and the current study seeks to address this information gap.

Methodological approaches

Normative data concerning sex under the influence is limited and its relationship to HIV transmission risk is not well understood. To better understand the link between drug use and sexual behavior, researchers have used approaches such as situational association or event analysis. Situational association studies inquire how often high risk sex occurred while under the influence. A correlational temporal link between sex under the influence and high-risk sex is made in these studies, but it does not permit causal inferences. 

Event analyses offer contextual information by assessing a target “critical” incident in detail, providing for a stronger causal inference. For example, recent studies have found that the link between sex and drugs may depend on the context of the incident and partner type. However event analyses are limited in that the target event may or may not be characteristic of the individual's typical or most risky sexual behavior. Therefore, methods that combine both situational association and event analyses would provide the most complete picture of sexual behavior in the context of drug use.

Specific substances and their effects

Specific substances may be linked to different sexual effects, user expectations, and levels of sexual risk. Although it is widely accepted that stimulant use can enhance sexual pleasure, and that high levels of alcohol and opioid use suppress male sexual performance, little research has examined the differences in perceived feelings, performance, and function between the range of drugs that are commonly used by treatment seeking individuals. Rawson et al. examined differences between drug category and sexual effects while under the influence. 

They found that cocaine and methamphetamine users were more likely to associate drug use with sexual behavior, and reported more positive sexual effects while under the influence, than alcohol and opiate users. For example, stimulant users were more likely to report that drug use was so strongly associated with sex that it would be difficult for them to separate it from sexual behavior, and that drug use made them preoccupied with sex and/or significantly elevated their sex drive.

Aims and Hypotheses

Further characterization of patients' experiences with sex under the influence could inform HIV/STI risk reduction interventions for specific drug classes. To this end, this study aimed to use both situational and event analyses to better understand HIV/STI risk, and the degree to which it is influenced by drugs and alcohol. We examined not only sexual risk behaviors, but also patient perceptions of enhancements and impairments associated with sex under the influence. 

Our initial aim is to identify the prevalence of sex under the influence for a diverse group of men in substance abuse treatment. We hypothesize that sex under the influence will be: 1) associated with sexual risk behaviors (sex with a casual partner, sex without condoms and anal intercourse); 2) associated with sexual enhancements and impairments depending on the type of substance class (more enhancements associated with stimulants, and more impairments associated with opiates and alcohol); 3) associated with temptations to use drugs or alcohol to meet sexual needs and desires.

Methods

Participants

Participants were 505 men enrolled in an HIV risk reduction study that was conducted in seven methadone maintenance (n = 242) and seven outpatient, non-medication assisted psychosocial outpatient (n = 263) treatment programs in the United States. These treatment programs were diverse in terms of region, population density, and HIV prevalence. 

Sites were urban (e.g. Philadelphia, PA), suburban (e.g., Norwalk, CT) and rural (e.g., Huntington, WV), and were located in the Northeast, South, Midwest, Southwest, and West. HIV prevalence data at each site was not collected as part of this study, but some sites (e.g. Staten Island, NY, San Francisco, CA) were in cities known to have higher rates of HIV than others (e.g., Santa Fe, NM, High Point, NC). Specific sites are listed elsewhere. The parent study compared a 5-session HIV risk reduction intervention developed specifically for men, Real Men Are Safe (REMAS), to a standard 1-session HIV/AIDS education group intervention (HIV-Ed).

Participants were men aged 18 and above who were in substance abuse treatment, reported engaging in unprotected vaginal or anal intercourse during the prior 6 months, were willing to be randomly assigned to one of two interventions and complete study assessments, and were able to speak and understand English. 

Participants were recruited between May, 2004 and October, 2005, and were self-referred in response to recruitment posters displayed in clinics, announcements at group therapy meetings, and clinic “open houses” designed to introduce the study to clinic patients. Participants were also referred to the study by clinic counselors and/or staff. Exclusion criteria included: showing observable, gross mental status impairment – including severe distractibility, incoherence or retardation-- as measured by the Mini Mental Status Exam or by primary clinician report, having a primary sexual partner who was intending to become pregnant while the participant was enrolled in the trial, or being in methadone maintenance treatment for less than 30 days. The HIV status of participants was unknown.

The analyses reported here focused on a subsample of men from the main trial who reported engaging in sex only with women in the prior 90 days. Of the 590 men eligible for randomization in the main trial, 43 reported sex with men, 41 reported no sexual activity in the prior 90 days, and one did not answer questions regarding sex under the influence of drugs or alcohol. Participants were not queried about lifetime sexual patterns, thus men who had had sex with men in the past, but not in the prior 90 days, may have been included in the sample.

Assessment and Case Identification Procedures

The Sexual Behavior Interview (SBI) was administered as part of the baseline assessment battery, prior to randomization to intervention condition. The baseline assessments were administered preferably within 7—but not longer than 30--days after screening for the parent trial. There were no expectations placed on participants to change their drug related behavior while they were waiting to begin the study intervention. The SBI items were selected or adapted from the SADAR (Sex and Drug Abuse Relationship Interview, and the SERBAS (Sexual Risk Behavior Assessment Schedule. Behaviors assessed included:
1) frequency of unprotected vaginal, anal, and oral sex by partner type (main vs. casual); 
2) number, gender, and perceived HIV status of partners; 
3) percentage of times sex occurred under the influence of drugs or alcohol over the prior 90 days, and 
4) a detailed query of the most recent sexual event that had occurred prior to the assessment day that included: 
how many days ago was the event, was the participant and/or partner under the influence, if so which drug(s), what sex acts took place, were condoms used, was there sexual enhancement or sexual dysfunction, degree of sexual satisfaction/pleasure (0= not at all pleasurable, 5= a pleasurable, enjoyable experience, but nothing special, 10= extremely pleasurable), and how typical the experience was (0=much less enjoyable than usual, 5=similar to your usual sexual experience, 10=much more enjoyable than usual). In addition, participants were asked if they had been tempted to use drugs in the past 90 days to “enhance your sexual experience” or “increase the likelihood of a sexual encounter occurring” and if so, which drugs they were tempted to use. SBI items were administered using the audio computer assisted structured interview (ACASI) method as it elicits more information about high-risk behaviors than face-to-face interviews.

For each drug/drug class (heroin, cocaine, methamphetamine, cannabis, benzodiazepines, alcohol) participants were asked to “Please estimate the percent of times in the past 3 months that you were under the influence of [drug of abuse] when engaging in sex acts.” Responses of greater than 0 for any drug were coded as “sex under the influence, prior 90 days.” 

For analyses of the most recent event analyses, participants were classified as under the influence (yes or no), and as having a partner under the influence (yes or no). Participants were not provided a definition for “under the influence.” Participants were free to assess for themselves whether they were “under the influence.” Since all of the participants were in substance abuse treatment the investigators felt it likely that any use by these individuals would most likely lead to an intoxicated state. However, some participants may have consumed substances of abuse at less than intoxication levels and still considered themselves under the influence. 

To be included in the most recent event analyses, the event had to have occurred in the past 90 days. For some analyses, cases were classified as under the influence if the participant or his partner were under the influence. Participants were also grouped according to the drug of abuse to which they reported being under the influence. Cocaine and methamphetamine were grouped into a stimulant category due to a low prevalence of methamphetamine use.

Data analyses

Analyses compared the various drug use groups while under the influence or not under the influence in the last 90 days, and during the most recent event, on the following domains: demographics, specific sexual acts, condom use, and temptation to combine sex and drugs in the future. For continuous measures t-tests were used. For dichotomous variables contingency table analysis utilizing the χ2 statistic was employed. For analyses that compared being “under the influence of any drug” or “partner being under the influence of any drug” with “not being under the influence,” the p value was set at 0.05. 

Analyses of “under the influence of specific drugs/drug classes” involved examining five drug categories separately, and were conducted using Bonferroni adjusted alpha levels of .01 per test (.05/5). To determine which drugs the men were more tempted to use to meet sexual needs, pairwise comparisons of differences between dependent proportions were calculated.

Results

Prevalence of sex under the influence

Most men (73.3%) reported engaging in sex under the influence of drugs or alcohol during the prior 90 days, however the percent reporting sex under the influence at the most recent event dropped to 39.1% (See Table 1). Most men (72.6%) reporting sex under the influence at the most recent event reported their partners were also under the influence. An additional 5.2% of men reported that their partners were under the influence when the men themselves were not. Alcohol, cocaine, heroin and cannabis were the most frequently used drugs. Men who were not married, in methadone treatment, and who had been employed for fewer days were more likely to report sex under the influence in the past 90 days (See Table 2). Similarly, men reporting that they or their partner were under the influence during the most recent event were more likely to be older, not married, in methadone treatment, employed for fewer days, and report there had been more days since their most recent sexual event.
Table 1

Percent of men reporting, for themselves or their women partners, sex under the influence of drugs or alcohol in the last 90 days and during their last sexual encounter.

Table 2
Sample demographics

Hypothesis 1: sexual risk behaviors

Regarding specific risky sexual behaviors, men endorsing sex under the influence at the most recent event were more likely to engage in anal intercourse, have a casual (versus main) partner for that event, and if having vaginal or anal sex with a casual partner, be less likely to use a condom than men denying sex under the influence (Table 3). 

Similarly, men who reported their partner was under the influence during the most recent event were more likely to engage in anal intercourse, receive fellatio, have a casual partner, and if having vaginal or anal sex with a casual partner, be less likely to use a condom than men reporting their partners were not under the influence. Since being under the influence at the most recent sexual event was associated with being with a casual partner, the sexual behavior data was re-analyzed for regular partners only. 

This was done to determine if casual partner status may have explained the differences in specific sexual behavior. The results were unchanged regardless of partner status. Those under the influence were more likely to engage in anal sex when either the participant or his partner was under the influence, and fellatio was performed more often when the partner was under the influence (results not shown).

Table 3
Sexual acts, condom use and partner type during the most recent sexual encounter as a function of being under the influence

When these analyses were repeated for being under the influence of specific drugs, each drug was associated with a greater likelihood of having a casual sexual partner during the most recent event (analyses not shown, all p values ≤.01). However different drugs were not associated with different sex acts.

Hypothesis 2: sexual enhancements and impairments

Men who reported not being under the influence during the most recent sexual event rated that encounter as more pleasurable (M=8.04, SD=2.35) than men who were under the influence (M=6.91, SD=2.61, t=4.95, p< .001). Similarly, men not under the influence reported that the most recent event was more enjoyable than usual (M=6.86, SD=2.55) compared to men who combined sex and drugs (M=5.73, SD=2.79, t=4.51, p<. 001).

Listed in Table 4 are the sexual responses of participants who reported being under the influence during their most recent event. In this analysis, more enhancements than impairments were reported, with over 65% of these respondents reporting increased sexual desire, delayed orgasm and decreased sexual inhibition. However, sexual impairments were also very common with over 40% reporting erectile dysfunction and/or difficulty reaching orgasm. 

Similarly, of participants who had partners under the influence, the following participant perceptions of partner enhancements were attributed to 65% or more of their partners: increased desire, increased lubrication, increased sexual sensation, and decreased inhibition (see Table 5). Interestingly, participants reported less sexual impairment for their women partners, in that difficulty reaching orgasm was the only impairment reported by more than 25% of the sample.

Table 4
Sexual enhancements and impairments endorsed by participants during their most recent sexual encounter

Table 5
Sexual enhancements and impairments participants endorse about their female partners during their most recent sexual encounter

Also reported in Tables 4 and ​and 5 are the sexual enhancements and impairments associated with specific drugs. For sexual enhancements, only alcohol (increased sexual desire, both self and partner) and benzodiazepines (decreased social inhibition, both self and partner) were associated with more enhancements. Only decreased desire-self (heroin) and premature ejaculation (drugs other than benzodiazepines) were differentially associated with being under the influence.

Hypothesis 4: using drugs to meet sexual needs

That the prospect of enhancing sex or enhancing sexual opportunities might serve as a relapse trigger is evident in Table 6. Not surprisingly, men who reported engaging in sex under the influence during the past 90 days or during the most recent sexual encounter were more likely to report having been tempted to use drugs either to enhance their experience and/or increase the likelihood that a sexual event would occur. Even for men denying sex under the influence during the past 90 days, nearly 25% reported they had been tempted to use drugs to meet sexual needs. Men were significantly more likely to report being tempted to use cocaine compared to all other substances (except alcohol) to meet these needs. Similarly, men were significantly more likely to report being tempted to use alcohol compared to all other substances except cocaine and heroin to meet these needs.
Table 6
Men in treatment reporting temptation to use drugs to meet sexual needs in prior 90 days.

Discussion

Heterosexual men in substance abuse treatment commonly reported having sex under the influence of drugs. Situational association analyses showed that the majority (73%) reported engaging in sex under the influence in the past 90 days, while event analyses showed that 39% (and nearly three-quarters of their partners) reported combining sex and drugs at their most recent sexual event. Being under the influence at the most recent event was characterized by increased prevalence of anal sex, casual partner sex, and less condom use as compared to not being under the influence.

These findings are consistent with the literature linking sex under the influence and high risk sexual behaviors among men who have sex with men and injection substance users. Prior work often focused on specific populations such as men who have sex with men, injection drug users, urban residents, or meth users. The present study expanded the scope of earlier work as it provided results from a sample of in-treatment heterosexual men in urban and rural, and methadone maintenance and outpatient psychosocial programs.

Establishing a connection between high-risk behavior and the use of substances is a central issue for both prevention and treatment. A major difficulty is that self-reports are often not entirely accurate, particularly in high risk populations who engage in higher rates of casual sex. In the present study, two self-report methods were used to investigate the frequency of sex under the influence. In the first, participants were asked to report the percentage of times sex occurred under the influence of drugs or alcohol over the prior 90 days. 

In the second, participants were asked to provide a detailed assessment of their most recent sexual event, including the substances used, sexual acts performed, enhancement or impairment secondary to drug use, and use of condoms. Since some individuals may have had sex under the influence in the recent past, but not at their most recent event, it is likely that the discrepancy between the two methods points to an underestimate when most recent event analysis is utilized.

Regardless of whether rates are accurate or an underestimate, the frequency of sex under the influence over the past 90 days highlights the association between sex and drug use, and the varying effects of specific substances on sexual experience and performance. For treatment purposes, highlighting a connection between the two behaviors is worth clinical focus as it might be a step toward change. 

Although event analysis may underestimate the rate of sex under the influence, it encourages the recall of contextual features related to sexual activities. Including similar questions about the relationship between sexual behavior and drug use in clinical practice may strengthen the ability to draw causal inferences that could lead to reductions in risky behavior, for example by pointing out discrepancies between wishes and actual behaviors in motivational interviewing approaches.

Our results showed that men in treatment reported many sexual enhancements associated with combining sex and drugs. Studies often cite stimulants as having the strongest association with sexual enhancements. Consistent with those studies, men in this study identified cocaine as the substance they were most tempted to use to enhance a sexual experience. Beyond simply stimulants, however, analyses of the most recent event show a sex-drug connection occurring across multiple substance categories. In this sample, at least 50% of treatment-seeking men reported sexual benefits for themselves and their partners at their most recent encounter, regardless of the substance used at the time. 

Although 71% of men reported that stimulants increased their sexual desire, alcohol was endorsed significantly more often (77%) than any other drug. The current study only viewed substance use related sexual enhancements in reference to the most recent sexual event and not to the participants' primary drug of abuse as was done in the Rawson et al. study. It is likely that men who had a history of negative experiences of sex under the influence of their primary drug of abuse would be less likely to have been under the influence of that substance at the most recent sexual event. 

Nor did the assessment ask men to compare sexual enhancements across drugs. Thus a participant could have reported sexual enhancement associated with one substance at the most recent sexual event, but if asked to compare which was most enhancing, might have ranked another substance higher.

While the majority reported enhancements, less than 50% of the sample reported any sexual impairment for themselves or their partners across drug categories. Only one impairment, dysorgasmia, was endorsed by nearly half the sample. Although many of the substances of abuse are associated with sexual impairment, the less frequent report of impairment during the most recent sexual event may be because participants who used a particular substance at the most recent event are the least likely to have experienced these impairments in the past. 

They may therefore be a biased group who is less prone to impairments with that particular drug while under the influence, or they may be less aware of any negative connection between their substance and sexual performance and thus less likely to have endorsed it on the SBI.

Although substance abuse counselors may be reluctant to discuss sexual issues with their clients, these data show that relapse prevention discussions might benefit from acknowledging how sex and drugs are inter-related, as well as encourage individuals to take responsibility for safe sex rather than blame the substance. The findings on sexual enhancements and impairments may function as a tool for treatment providers to address this issue. 

Consistent with the decisional balance model often utilized in motivational interviewing, patients could be asked to weigh the pros (enhancements) and cons (impairments) associated with sex under the influence. A focus on the cons of being under the influence as well as alternative ways to obtain some of the enhancements without substances could be explored. In addition, counselors can point to the sexual satisfaction data from the current study showing that men who did not engage in sex under the influence at the most recent event reported the experience to be more pleasurable than men who did.

Summary

The majority of men in substance abuse treatment had combined sex and drugs over the past 90 days, and nearly 40% had been under the influence at their most recent event, believing the substances improved the sexual experience. Combining sex and drugs was associated with increased risk for sexual behaviors likely to spread HIV/STI. Nearly three-quarters of men were tempted in the prior 90 days to use drugs to enhance the sexual experience or increase the likelihood of sex. It appears, therefore, that sex is a strong relapse trigger for a variety of substances, not simply for stimulants. Patients might therefore benefit from interventions that focus on the interplay between sexual behavior and substance use. Future research endeavors might focus on the development and evaluation of such interventions.

BACKGROUND ON ADOLESCENT SUBSTANCE USE

Substance use during adolescence has been associated with alterations in brain structure, function, and neurocognition. This review will present the current research regarding typical adolescent brain development and the subtle but significant abnormalities in indices of brain functioning associated with alcohol and drug use during this critical developmental period. 

Studies using neuropsychological assessment and structural and functional imaging will be discussed to help elucidate the relationship between neurocognition with alcohol and marijuana use. Additionally, methodological issues in neuroimaging and neuropsychological assessment research will be reviewed.

While several decades of research with adults have shown that chronic heavy drinking is associated with adverse consequences on the adult brain, this relationship has only recently been explored in the adolescent brain. Understanding the effects of alcohol and drug use on adolescent neurocognition is crucial, being that rates of use increase dramatically between ages 12 and 18. 

Epidemiological studies have shown that past month alcohol use increases from 17% to 45% between 8th and 12th grade, and illicit drug use prevalence expands from 8% to 22%. Lifetime rates indicate that 73% of youth have used alcohol and 48% have used illicit drugs by their senior year of high school. In the past year, 23% of youth meet diagnostic criteria for a substance use disorder (alcohol or drug abuse or dependence) by age 20.

While the developing brain may be more resilient to neurotoxic effects, exposure to alcohol and drugs during a period of critical neurological development may interrupt the natural course of brain maturation and key processes of brain development. In fact, adolescence may be a period of heightened vulnerability for alcohol’s effect on the brain. 

Cognitive deficits resulting from these alcohol and drug related neural insults have potentially harmful implications for subsequent academic, occupational, and social functioning extending into adulthood. Therefore, neurocognitive sequelae from heavy drinking and drug use are important to elucidate.

TYPICAL ADOLESCENT BRAIN DEVELOPMENT

Adolescence marks a period of rapid development between childhood and adulthood involving complex social, biological, and psychological changes. The interactions of these multidimensional factors have considerable implications for adolescent development. Included in these alterations are substantial changes in the efficiency and specialization of the adolescent brain, which is accomplished through synaptic refinement and myelination. Synaptic refinement involves reductions in gray matter by eliminating unnecessary neural connections. 

During adolescence, this synaptic pruning occurs primarily in the prefrontal and temporal cortex and in subcortical structures such as the striatum, thalamus, and nucleus accumbens. The adolescent brain also undergoes increased myelination, which allows for improved integrity of white matter fiber tracts and efficiency of neural conductivity. 

Higher-order association areas appear to develop only after lower-order sensorimotor regions fully mature, with frontal lobes being the final areas of the brain to complete development. Along with these neuromaturational changes, it is suggested that increased myelination allows for smoother, more efficient communication between frontal-subcortical brain regions, allowing for better top-down cognitive control in adolescence.

In conjunction with these numerous brain transformations, shifting social influences and peer group affiliation heavily impact adolescent behaviors. This may place youth at a particularly heightened risk for initiating and continuing alcohol and drug use. Specifically, transformations in the prefrontal regions and limbic systems are thought to contribute to increased risk taking and novelty/sensation seeking behaviors. The neuromaturation and neurochemical changes that are present during this period correspond to a range of cognitive, emotional, and behavioral changes, and are hypothesized to contribute to adolescents’ increased propensity for alcohol and drug use.

ADOLESCENT SUBSTANCE USE AND NEUROCOGNITION

The current literature suggests that heavy drinking during adolescence does have a subtle, but significant, deleterious effects on adolescent neurocognitive functioning. Studies have found that adolescent heavy drinkers exhibit decrements in memory, attention and speeded information processing, and executive functioning. In a study comparing alcohol dependent and healthy control adolescents, 

Brown et al. found that drinkers recalled 10% less verbal and nonverbal information than controls, even after three weeks of monitored abstinence. A similar degree of reduction was found on attentional and speeded information processing tasks in abstinent adolescent drinkers. These findings are consistent with literature examining neurocognitive deficits in young heavy drinkers, which found similar decreases on attention and information processing, along with deficits in language competence and academic achievement. Deficits in executive functioning, specifically in future planning, abstract reasoning strategies, and generation of new solutions to problems, have also been found.

While it has often been assumed that marijuana use is not linked to long-term cognitive deficits, recent data suggest that even after four weeks of monitored abstinence, adolescents who regularly smoke marijuana performed poorer on performance tests of learning, cognitive flexibility, visual scanning, error commission, and working memory. Further, the number of lifetime marijuana use episodes was significantly related to overall poorer cognitive functioning, even after controlling for lifetime alcohol use.

We prospectively examined neuropsychological functioning in 26 youths with no histories of alcohol or drug problems, and compared them to 47 youths with histories of heavy adolescent alcohol, marijuana, and stimulant use. Follow-up neuropsychological tests were given to the subjects seven different times across 8 years, on average between the ages of 16 to 24. While there were no significant differences between users and non-users on neurocognitive test scores at the first time point, heavy drinkers performed worse on cognitive tasks at age 24 than light drinkers. 

In particular, those who had a history of alcohol withdrawal symptoms (e.g., orthostatic hypotension, nausea, insomnia, or irritability) were the most likely to have decreases in performance scores, especially on tests of spatial functioning. Overall, heavy drinking during adolescence was linked to a reduction in keeping up with age expectations.

In summary, adolescence is characterized by dramatic increases in rates of substance use concurrent with ongoing neuromaturation. While neuropsychological studies have shown that adolescent substance use is linked to poorer spatial, inhibitory, and learning and memory functioning, neuroimaging techniques may elucidate the neural mechanisms of these performance deficits

ADOLESCENT SUBSTANCE USE AND BRAIN STRUCTURE

Advances in neuroimaging have made it feasible to closely characterize the brain structure and function of adolescent substance users and to pinpoint the circuitry and regions that may subserve the neuropsychological deficits observed in adolescent substance users.

Hippocampal Volume

Magnetic resonance imaging (MRI) was used to examine structural differences in the hippocampus, an area of the brain crucial to intact memory functioning. Participants were classified as: (1) light to non-drinkers (≤1 drink per month, ≤ 1 lifetime marijuana use episode), (2) heavy drinking adolescents (history of consuming 4/5+ drinks in a day), and (3) heavy marijuana users who also engaged in heavy episodic drinking. 

Manual tracing techniques were employed by reliable raters, and revealed that heavy drinkers had smaller left hippocampal volumes (p<.01), while marijuana+alcohol users had similar volumes as controls. Additionally, greater alcohol abuse/dependence severity was associated with smaller left hippocampal volumes, a finding that supported previous animal models. 

Heavy drinkers showed significantly different patterns of hippocampal asymmetry (p<.05; smaller left than right hippocampal volumes) compared to light-drinking youths, with an asymmetry ratio linked to memory performance. For controls, greater right than left hippocampal asymmetry correlated with better verbal learning (p<.05), but not in user groups (see Figure 1).
Figure 1

Hippocampal volume for adolescents with different substance use patterns. Adolescent users of alcohol, but not alcohol plus marijuana, showed significantly smaller left hippocampal volumes than demographically similar non-users (Medina et al., 2007).

These findings support the hypothesis that heavy alcohol use in adolescence has an adverse influence on the hippocampus, potentially affecting subsequent memory performance. Additionally, marijuana, in combination with alcohol use, could have some neuroprotective effects, but further studies are warranted to examine this hypothesis. 

An alternative explanation is that alcohol and marijuana use may create opposing mechanisms (e.g., neuroinflammation and myelination suppression), so that macromorphometric variables may actually appear normal. Microstructural hippocampal changes related to marijuana use may include increased glial proliferation and white matter density as well as reduced gray matter, resulting in relatively normal hippocampal volumes despite functional pathology. Alternatively, heavy adolescent marijuana use may subtly interfere with synaptic pruning processes, resulting in larger gray matter volumes, particularly in the left hippocampus.

Prefrontal Cortex Volume

During adolescence, the frontal lobe, an area of the brain associated with planning, inhibition, emotion regulation, and integration of novel stimuli, goes through extensive neuromaturation, increasing in efficiency and specialization. In a study comparing prefrontal cortex volumes of adolescent heavy drinkers to non-drinkers and marijuana and alcohol users, prefrontal volumes were smaller in heavy drinkers relative to controls (p=.09) (see Figure 2). This difference was particularly pronounced in females (p<.003), confirming previous studies that examined youth with comorbid drug and psychiatric disorders.
Figure 2

Ventral prefrontal volume in adolescents with minimal and heavy drinking histories; ventral prefrontal region is highlight in white in the figure to the right.

Interestingly, in our preliminary comparison of prefrontal cortex volumes of 16 marijuana-using and 16 control adolescents, few differences were observed. However, among females, marijuana users had a 4%larger posterior and prefrontal cortex volume (p=.06) than non-users, on average. This was associated with poorer verbal memory, suggesting potentially interrupted synaptic pruning in female users. 

Marijuana-using adolescents showed larger global gray matter volumes than controls, with increased marijuana use predicting increased volume (β=.61, p<.01) and poorer verbal and attention performance. These findings also suggest that marijuana use during adolescence may disrupt gray matter pruning processes.

White Matter Volume

White matter maturation during adolescence through young adulthood is important for neuronal transmission between connecting brain regions. A recent study comparing adolescent marijuana users and matched controls indicated no significant differences in white matter volumes. However, marijuana use (β = .42, p < .04) and smaller white matter volume (β = −.34, p < .03) each predicted increased depressive symptoms on the Hamilton Depression Rating Scale. 

Further, marijuana use interacted with white matter volume to predict depression scores on the Beck Depression Inventory (BDI). White matter volume was negatively associated with depressive symptoms on the BDI, such that less white matter volume was associated with more depressive symptoms in adolescent marijuana users only (β = −.59, p < .03). Although between-group differences were not found in overall white matter volume, it seems plausible that marijuana use may cause or be linked to subtle alterations in white matter tracts that are responsible for mood regulation and depressive symptoms.

Quality of White Matter

Chronic alcoholic adults show clear abnormalities in brain white matter volume as well as microstructural alterations in white matter tissue organization. Typically, less white matter suggests dissipation of myelin-coated axons. Diffusion tensor imaging (DTI) characterizes the integrity of water matter by examining the diffusion of water molecules in white matter tissue. 

Therefore, DTI provides information on the organization of localized white matter fiber tracts. Two commonly used scalar measurements are fractional anisotropy (FA), which reflects white matter coherence by providing an estimate of the directionally dependent movement of water molecules, and mean diffusivity (MD), an index of the overall displacement of water molecules.

In a preliminary analysis, we looked at the effects of both binge drinking alone and with combined marijuana use on white matter integrity. Forty-two participants (ages 16–19) were identified as controls (n= 14), binge drinkers (≥ 4 drinks on an occasion for females, ≥ 5 drinks on an occasion for males; n= 14), or binge drink+marijuana users (n= 14). Adolescent participants received DTI with whole brain coverage. 

Diffusion weighted data were collected on a 3-Tesla GE magnetic resonance scanner (repetition time=12000 ms; echo time=93.4 ms; 36 × 3.0 mm thick axial slices; voxel resolution 1.875 × 1.875 × 3.0 mm3 , b-value = 2000 s/mm2). Diffusion-weighted images were acquired in 15 directions, in addition to a normalization image (b=0) with no diffusion encoding. Four volumes were acquired and averaged for each direction and the b = 0 volume. FA (or MD) maps from each participant were submitted to Tract-Based Spatial Statistics (TBSS), which facilitated voxelwise between-group comparisons.

Significant group differences were found in eight white matter regions, including frontal association fibers such as frontal-occipital and superior longitudinal fasciculi. Bingers and binge+marijuana users displayed lower FA than controls (ps ≤ .016). Interestingly, bingers demonstrated significantly lower FA than the binge+marijuana group (ps .014 to .043). 

No significant MD differences were found in the 8 clusters identified by the FA analyses. Our findings suggest poorer white matter integrity in adolescents with histories of binge drinking than non-drinkers. However, teens with concomitant binge drinking and marijuana use showed a lesser degree of reduced fiber tract coherence than those engaging in binge drinking alone.

These findings are largely consistent with our previous structural imaging studies that found small yet significant effects of marijuana use on adolescent brain structure and function, and stronger associations between alcohol use and tissue status. In a study that looked specifically at adolescents with alcohol use disorders, we found reduced white matter microstructural integrity compared to demographically matched youths without alcohol use disorders. 

Significantly lower FA was found in the splenium of the corpus callosum, and trends for lower FA were also found in the rest of the corpus callosum, suggesting possible alcohol-related white matter alterations. The callosal fibers are a massive collection of white matter tissue that connect the left and right hemispheres of the brain, and are important for efficient transfer of information. 

Microstructural changes in the corpus callosum may underlie neurocognitive changes associated with alcohol use during adolescent brain maturation. Notably, decreased white-matter integrity was significantly related to longer duration of heavy alcohol use, greater number of past alcohol withdrawal symptoms, and recent consumption of large amounts of alcohol.

Overall, our findings of reduced FA suggest possible myelination alterations in brain regions developing during adolescence, and underscore the impact of the effects of alcohol on white matter maturation during adolescence. Our more recent findings indicate that even subtle binge drinking behaviors can have a substantial impact on tissue development, as adolescents with both alcohol use disorders as well as less frequent or new-onset binge drinking habits were found to have altered white matter integrity. Future studies will follow these cohorts over the adolescent years to see if changes in substance use are followed by changes in indices of white matter quality.

Brain Blood Flow

Understanding cerebral blood flow (CBF) is important since inadequate blood flow can damage brain tissue. CBF can also influence the blood oxygen dependent signal interpreted in functional magnetic resonance imaging (fMRI). Moreover, chronic alcoholics have been shown to have reduced blood flow into the brain. In a study examining CBF in alcohol dependent young women (n=8), we found decreases as compared to female light drinkers (n=8) using perfusion-weighted magnetic resonance imaging. 

In these 18–25 year-olds, decreases were seen in six prefrontal and parietal regions (η2 = .47 to .83), and there were no regions in which perfusion was greater for alcohol dependent participants compared to controls. These findings may help clarify the metabolic changes behind differences in functional brain activity seen in adolescents with histories of alcohol misuse.

ADOLESCENT SUBSTANCE USE AND BRAIN FUNCTIONING

In addition to alterations in brain structure, recent findings have suggested decrements in brain functioning associated with adolescent substance use. Functional magnetic resonance imaging (fMRI) investigates neural activity of the brain by measuring changes in blood oxygen level dependent (BOLD) signal, which indicates areas of increased activation in response to a mental task or stimulus. This technique is noninvasive and does not require injections or radioactive materials, making it a safe and appropriate technique for examining adolescent brain functioning.

Spatial Working Memory

Numerous studies involving adult alcoholics suggest neural disruption while executing cognitive tasks; however, it is unclear to what extent drinking must progress, and at what age, before abnormalities manifest. Our group found that adolescents who drank heavily for one to two years showed abnormalities in brain response on cognitive tasks measuring spatial working memory (SWM) as compared to light drinkers. 

While both the heavy and light drinkers performed similarly on the task, heavy drinkers exhibited increased activation in the parietal lobe, with decreased activation in the occipital and cerebellar regions, compared to light drinkers. Additionally, youth with more hangover experiences and greater alcohol consumption showed greater abnormalities. These results suggest that after as little as one to two years of heavy drinking, adolescents may exhibit subtle neural reorganization that includes compensation, highlighting the potential early influence of drinking on neurocognitive functioning during the escalation of alcohol use disorders.

In another study by our lab, young adults who had engaged in four to five years of heavy drinking showed poorer performance on the same SWM task during fMRI, in addition to decreased activation in parietal and frontal regions. Together, these results suggest that the adolescent brain may be able to compensate for subtle neural abnormalities associated with drinking; however, repeated heavy drinking episodes may interfere with the brain’s ability to make up for alcohol-related deficiencies in neural functioning.

Additional studies from our laboratory (e.g.,compared young adult marijuana users (ages 16–18) after one month of abstinence to matched controls on the same SWM task described in the previous studies. Although there were no differences in task performance between the marijuana users and controls, the marijuana users exhibited increased activation in parietal, temporal, and frontal (including insula) brain regions. 

The marijuana users also showed less activation in cerebellum and occipital cortices than controls. Findings remained significant after controlling for alcohol and other drug use, and also suggest compensatory and possibly inefficient SWM-related neural response associated with marijuana use.

Verbal Encoding

Decrements in verbal encoding abilities have also been observed in binge drinking adolescents during fMRI tasks involving recall of learned word pairs. Compared to nondrinkers, bingers showed less response in right superior frontal and bilateral posterior parietal cortices, with more response in occipital cortex, during the verbal encoding task. 

This suggests less utilization of working memory systems during encoding for bingers compared to nondrinkers on tasks of encoding. In addition, drinkers encoded marginally fewer words than nondrinkers (p=.07), and had no differential activation to novel stimuli. Together, these results suggest slightly poorer initial verbal learning, disadvantaged verbal processing, and decelerated learning for adolescents who engage in binge drinking compared to abstinent adolescents.

Further studies in our laboratory comparing verbal encoding abilities between adolescents reporting marijuana use and matched controls have found no differences on task performance. Yet, marijuana users evidence more frontal and less temporal activation compared to matched controls. Although both groups performed similarly on the fMRI task, adolescent marijuana users have shown poorer performance on sensitive measures administered as part of an extensive neuropsychological test battery (e.g., California Verbal Learning Test-II, Wechsler Memory Scale-III Story Memory), particularly on initial learning trials. Taken together, changes in brain activation in adolescent marijuana users on a verbal encoding task may be indicative of less allocation of attentional resources toward encoding the novel material.

Inhibition

In addition to decrements in spatial working memory and verbal encoding, modestly decreased ability to inhibit behaviors has been found in binge drinking adolescents. A pilot study from our group found greater BOLD response relative to controls in the frontal areas and less activation in the cerebellar areas during a go/no-go task of response inhibition administered during fMRI, despite similar task performance. 

On response selection (“go”) trials, drinkers exhibited less BOLD response than controls in the mid-cingulate, subcortical, and temporal areas. Better task accuracy was linked to more frontal response during these trials among controls, but not among drinkers (p<.025). These findings suggest that even infrequent exposure to large doses of alcohol may influence inhibitory processing. As with all cross-sectional studies described, follow-up evaluations will help elucidate the temporal relationship between inhibition and alcohol use.

We also looked at response inhibition in marijuana users after 28 days of monitored abstinence, as compared to matched controls. Participants were excluded for any neurological problems or Axis I diagnoses other than cannabis abuse or dependence. The study used the same go/no-go task described above, and although marijuana users performed similarly as controls, they exhibited increased activation on inhibition (“no-go”) trials in right dorsolateral prefrontal cortex, bilateral medial frontal cortex, bilateral inferior and superior parietal lobules, and right occipital gyri. 

On “go” trials, marijuana users had increased activation in right prefrontal, insular, and parietal cortices (p<.05, clusters >943 µl). More response during “no-go” trials related to worse neuropsychological performance (e.g., impulsivity, complex attention, cognitive flexibility, planning). Neuropsychological indicators of impulsivity were in turn linked to more medial temporal and less anterior cingulate response in marijuana users (p<.05). 

Differences remained even after controlling for lifetime and recent alcohol use. This suggests that marijuana users have increased brain processing effort during an inhibition task despite showing intact task performance, even after 28 days of abstinence. Such increased neural processing effort to achieve inhibition may predate the onset of regular use, or result from it.

Cue Reactivity

Adolescent response to alcohol advertising is of concern, as they are exposed to alcohol-related ads on a daily basis in many countries. We have observed that heavy drinking youth show greater brain activation while viewing alcohol advertisements than they do to non-alcohol beverage ads. This substantially greater brain activation to alcoholic beverage pictures was observed throughout the brain, particularly in the prefrontal area, nucleus accumbens, hypothalamus, posterior cingulate, and temporal lobe, and was prominent in the left hemisphere, limbic, and visual cortices. 

This suggests that reward, visual attention limbic, appetitive, and episodic memory systems were preferentially invoked in response to alcohol ads relative to non-alcohol ads in heavy drinking teens. Only the inferior frontal gyrus showed more activation in light drinkers during the task, potentially indicating a negative valence to these alcohol stimuli in non-drinking teens. Overall, light drinkers showed more response to non-alcoholic beverage pictures. These findings extend previous studies in adults, and link alcohol advertisement exposure in youth to activation in reward, desire, positive emotion, and episodic recall brain areas.

Predicting Relapse

Relapse is a common clinical problem in individuals with substance dependence. Previous studies have implicated a multifactorial process underlying relapse; however, the contribution of specific neural substrates had yet to be examined. We looked at whether results from functional imaging shortly after drug cessation could predict relapse in stimulant dependent individuals. The goals were to evaluate the neurobiology of decision-making dysfunction in stimulant dependent subjects, and to determine if functional imaging could be used as a tool to predict relapse.

Participants included treatment seeking methamphetamine dependent adult males (N=46). All individuals underwent fMRI three to four weeks after cessation of substance use. Of the 40 subjects who were followed a median of 370 days, 18 relapsed and 22 did not. The main outcome measure was BOLD activation during a simple two-choice prediction task. During the prediction task, a house was presented, flanked by a person on its left and right. 

The participant decided on which side of the house a car would appear. Each trial was self-paced to maximize self-determined action, thus the subject determined the number of trials by the latency to select a response. Immediately following the subject’s response, the car was presented for 300 ms on the far left or right side. The screen provided the feedback whether the prediction was correct. 

Unbeknownst to the participant, the computer determined the response based on the participant’s selection. Three error rate block types included a high chance level (20% of responses were “correct”), a 50% chance-level, and a low (80% of responses were “correct”) chance level. The task captures the key elements of decision-making: the probability of an outcome associated with an option, the positive or negative consequence, and the magnitude of the consequence.

The fMRI activation patterns in right insular, posterior cingulate, and temporal cortex correctly predicted 20 out of 22 subjects who did not relapse, and 17 out of 18 subjects who did. A Cox regression analysis revealed that the combination of right middle frontal gyrus, middle temporal gyrus, and posterior cingulate activation best predicted the time to relapse. In total, this is the first investigation to show that fMRI can be used to predict relapse in substance dependent individuals. 

It is likely that relapse corresponds with less activation in structures that are critical for decision-making, and thus poor decision-making sets the stage for relapse. The insular cortex may act through the interoceptive system to influence ability to differentiate between good versus poor choices, while the inferior parietal lobule may play a role in poor assessment of decision-making situations and subsequent reliance on habitual behavior. 

Overall, substance dependent adults show brain patterns that can be used to predict whether and when relapse may occur. Future studies are needed to determine if this is true for adolescents, and whether brain activation patterns can be used to evaluate an individuals’ readiness for treatment completion or treatment response.

Summary

Overall, changes in brain functioning in adolescents differ by substance use pattern. Research has shown that heavy drinking during adolescence can lead to decreased performance on cognitive tasks of memory, attention, spatial skills, and executive functioning. These behavioral ramifications of heavy alcohol use may emerge as a consequence of the reduced volume of important brain structures (e.g., hippocampus), compromised quality of white matter, and abnormalities in activation during cognitive tasks. 

Studies have also shown that marijuana use during adolescence can result in decreases in cognitive functioning, particularly learning and sequencing scores. In integrating and interpreting the results of adolescent marijuana studies from our laboratory, it is important to note that the groups are generally equivalent on task performance, and therefore the underlying brain responses in controls and users can be largely assumed to represent activity to the same mental action. Corresponding marijuana-related changes in cognition may be related to increases in gray matter tissue volume, decreases in white matter microstructural integrity, and increases in neuronal activation during cognitive tasks.

In sum, we can reasonably rule out recent use as accounting for the observed differences between substance groups, given that participants in some studies have been abstinent one month or greater. Substance using adolescents have been found to differ from non-users on neuropsychological performance, brain tissue volume, white matter integrity, and functional brain response. Longitudinal studies are essential to fully understand how alcohol and marijuana use affect adolescent neurodevelopment.

METHODOLOGICAL CONSIDERATIONS

The cross-sectional nature of the majority of studies examining adolescent neurocognitive functioning makes it difficult to determine the influence of alcohol and drug use on adolescent neurocognition. Therefore, ongoing longitudinal neuroimaging studies are essential to ascertain the degree to which substance intake is linked temporally to adverse changes on indices of brain integrity, or whether neural abnormalities reflect pre-existing patterns. In cross-sectional or longitudinal work, several methodological features are critical to evaluate the potential influence of adolescent substance use on neurocognition. These issues pertain to ensuring participant compliance, accurately assessing potential confounds, and maximizing participant follow-up.

Adolescent compliance as a research participant can be maximized by attending to rapport, building trust, and ensuring privacy of self-report data to the extent that is ethical and feasible to the setting. For behavioral tasks within or outside of imaging, it is critical to ensure participants comprehend task instructions, are fully trained on fMRI tasks, and then are given reminders just prior to task administration. Motion during scan acquisition is detrimental to the quality of imaging data, and is often worse in younger adolescents than older teens or adults. 

Adolescent head motion can be minimized by the following steps: discuss the importance and rationale for keeping the head still multiple times before and at the scan appointment; model and practice how to say “yes” and “no” when communicating with the research subject from the scanner; model and practice techniques for relaxing and ensuring subjects are in a position suitable for long-term comfort (e.g., legs are not crossed) before scanning begins; maximize participant comfort by using soft cushions around the head and under the knees; and many studies, especially those with younger participants, find practicing scanning in a less expensive mock scanner results in improved participant comfort and more reliable data during data acquisition.

Accurately measuring and accounting for confounds frequently present in adolescent substance-using populations is essential for elucidating the true effect of substance use on adolescent neurocognitive functioning. Common confounds in this population include head injury, depression, ADHD, conduct disorder, prenatal exposure to neurotoxins, family history-related effects, and polysubstance involvement. Conversely, excluding subjects for the aforementioned confounds may impede the generalizability of results. The tradeoff between minimizing confounds and having meaningful, ecologically valid results is an important study design decision, especially given the high cost of fMRI sessions.

Accurately measuring abstinence is another important consideration in substance-related research protocols. If abstinence is required for participation (and compensation) in a study, the dynamics of self-report could change. While biological data may help confirm self-report, these measures are imperfect and do not pinpoint the quantity of specific timing of substance intake. Regarding abstinence from cannabis, obtaining serial quantitative THC metabolite levels, normalized to creatinine, is the best approach for guarding against new use episodes.

Tracking participants over time is a critical part of many clinical issues when interested in the degree to which a variable (e.g., alcohol or marijuana use) might result in neural changes. Although some statistical approaches can help manage attrition, effective tracking procedures are more desirable to ensure study integrity. To maximize participant follow-up, frequent contact with participants must be maintained. 

Having a well-trained, friendly staff experienced with the population also helps retain participants and parents, and ensures that all participants fully understand the tasks and expectations during the study. Collecting comprehensive contact information can help track adolescents over time in case they should relocate. Additionally, follow-up measures and procedures should be as similar as possible to baseline, except to mitigate learning and practice effects. 

For imaging studies, field map unwarping of EPIs (e.g., fMRI and DTI) should also be considered, as this technique appears to produce more consistent localization of activations. Finally, as technical problems are common, back up plans for each piece of equipment used in the neuroimaging session should be in place.

CONCLUSIONS

Current research suggests that substance use in adolescence leads to abnormalities in brain functioning, including poorer neurocognitive performance, white matter quality, changes in brain volume, and abnormal neuronal activation patterns. fMRI studies have illuminated enhanced cue response in adolescent drinkers, and have shown the potential to predict treatment outcomes in stimulant dependent adults.

A few questions still remain, such as whether heavy substance use during adolescence causes cognitive impairments and changes in neurodevelopment, if and when are critical periods of heightened vulnerability to such effects, and if observed abnormalities remit with reduced use. We have the capability to design studies in which we restrict or control for nicotine and most other drug use, but few adolescent drug users do not also use alcohol. 

It is also important to understand if results generalize to youth with psychiatric problems, other substance use histories, and low socioeconomic status, and to further explore implications for changes in brain activation for learning and behavioral control, along with mood and psychiatric illness. Harder parametric tasks that include conditions on which behavior does differ between groups would help us better understand the cognitive domains we have observed differences on. 

Lastly, we need to better understand the biochemical changes that may mediate macrostructural, microstructural, and functional neuronal changes in response to substance use, such as cannabinoid receptor activity changes. Multimodal approaches to neuroimaging may help us disentangle such questions (e.g., PET, spectroscopy).

Our group is currently conducting longitudinal studies of adolescent substance users as well as youth at risk for substance problems due to family history or early conduct disorder (minimal use at the time of the first imaging session). Follow-up scan data, already underway, will elucidate if substance use during the follow-up interval predicts changes in brain functioning. 

These investigations will ascertain if: (1) substance (alcohol and marijuana, predominantly, given sample characteristics) use during adolescence seems to cause detrimental changes in neurodevelopment, or if (2) substance use does not account for the differences, the previously observed differences would likely represent pre-existing markers of risk for heavy substance use during adolescence.