Cannabis use during youth enhances sensitivity to cocaine from the first exposure


Cannabis use makes young brains more sensitive to the first exposure to cocaine, according to a new study on rodents led by scientists at Columbia University and the University of Cagliari in Italy.

By monitoring the brains of both adolescent and adult rats after giving them synthetic psychoactive cannabinoids followed by cocaine, the research team identified key molecular and epigenetic changes that occurred in the brains of adolescents — but not adults.

This discovery reveals a new interplay between the two drugs that had never previously been directly observed in biological detail.

These findings, reported this week in the Proceedings of the National Academy of Sciences, provide new understanding of how the abuse of cannabis during teenage years may enhance the first experience with cocaine and lead to continued use among vulnerable individuals.

“We know from human epidemiological studies that individuals who abuse cocaine have a history of early cannabis use, and that a person’s initial response to a drug can have a large impact on whether they continue to use it.

But many questions remain on how early cannabis exposure affects the brain,” said epidemiologist Denise Kandel, PhD, who is a professor of Sociomedical Sciences in Psychiatry at Columbia’s Vagelos College of Physicians and Surgeons and co-senior author of today’s paper.

“Our study in rats is the first to map the detailed molecular and epigenetic mechanisms by which cocaine interacts with brains already exposed to cannabinoids, providing much-needed clarity to the biological mechanisms that may increase the risk for drug abuse and addiction,” added co-author and Nobel laureate Eric Kandel, MD, codirector of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and Senior Investigator of the Howard Hughes Medical Institute.

Previous research had revealed key differences in how cannabis and cocaine affect brain chemistry. “Studies on the addictive properties of cocaine have traditionally focused on the mesolimbic dopaminergic pathway, a brain system that underlies our motivation to pursue pleasurable experiences,” said Philippe Melas, PhD, who was an associate research scientist in Eric Kandel’s lab at Columbia’s Zuckerman Institute and is the paper’s co-senior author.

“While cannabis enhances mesolimbic dopaminergic activity similarly to cocaine, it also affects an entirely different neurochemical system that is widespread in the brain called the endocannabinoid system. This system is essential for brain development — a process that is still ongoing in adolescence.”

Besides the dopaminergic system, both cannabis and cocaine appear to share some additional features. Recent studies have suggested that the development of cocaine craving is dependent on the brain’s glutamatergic system.

This system uses glutamate, a brain molecule that acts as a synaptic transmitter in the brain, enhancing the transmission of signals between the brain’s neurons.

According to previous research, as well as findings presented in today’s new study, using cannabis during adolescence may also affect this glutamatergic signaling process.

To delve deeper into a potential link between the two drugs, Dr. Melas and the husband-and-wife team of Drs. Eric and Denise Kandel partnered with Paola Fadda, PhD, Maria Scherma, PhD, and Walter Fratta, PhD, researchers in the Department of Biomedical Sciences, at the University of Cagliari in Italy.

The group examined the behavioral, molecular and epigenetic changes that occur when both adolescent and adult rats are first exposed to WIN, a synthetic cannabinoid with psychoactive properties similar to those of THC found in cannabis, and then are subsequently exposed to cocaine.

“We found that adolescent rats that had been pre-exposed to WIN had an enhanced reaction to their initial exposure to cocaine. Notably, we observed this effect in adolescent but not in adult rats,” said Dr. Melas, who is now a junior researcher in the Department of Clinical Neuroscience at the Karolinska Institutet in Sweden.

Upon further examination, the team found that, when preceded by a history of psychoactive cannabinoid use in adolescence, exposure to cocaine sets off a battery of unique molecular reactions in the rat brain.

These reactions included not only changes in the aforementioned glutamate receptors but also key epigenetic modifications.

Epigenetic modifications are distinct, in that they affect the way genes are switched on or off but do not affect the sequence of the genes themselves.

The Columbia team had previously found similar epigenetic mechanisms in adult animals in response to nicotine and alcohol in the brain’s reward center, known as the nucleus accumbens.

In the present study, however, the epigenetic effects of cannabinoids were found to be specific to adolescents and to target the brain’s prefrontal cortex.

The prefrontal cortex, which plays a role in various executive functions, including long-term planning and self-control, is one of the last regions of the brain to reach maturity, a fact that has long been linked to adolescents’ propensity for risky behavior.

Moreover, aberrant prefrontal cortex activity is often observed in patients suffering from addiction. Efforts to enhance the function of the prefrontal cortex are currently being evaluated in the treatment of addiction through the use of brain stimulation and other methodologies.

“Our findings suggest that exposure to psychoactive cannabinoids during adolescence primes the animals’ prefrontal cortex, so that it responds differently to cocaine compared to animals who had been given cocaine without having previously experienced cannabis,” said Dr. Melas.

These results in rats offer important clues to the biological mechanisms that may underlie the way that different classes of drugs can reinforce each other in humans.

The results also support the notion that cannabis abuse during adolescence can enhance a person’s initial positive experience with a different drug, such as cocaine, which in turn can have an effect on whether that person chooses to continue, or expand, their initial use of cocaine.

“This study suggests that teenagers who use cannabis may have a favorable initial reaction to cocaine, which will increase their likelihood of engaging in its repeated use so that they eventually become addicted, especially if they carry additional environmental or genetic vulnerabilities,” said Dr. Denise Kandel.

Most research involving rodents and addiction has traditionally focused on adult animals. It has also largely been limited to studying one substance of abuse at a time, without taking into consideration a history of drug exposure in adolescence.

“These and other experiments are key to understanding the molecular changes to the brain that occur during drug use,” said Dr. Eric Kandel, who is also University Professor and Kavli Professor of Brain Science at Columbia. “This knowledge will be crucial for developing effective treatments that curb addiction by targeting the disease’s underlying mechanisms.”

This paper is titled “Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular and epigenetic response to cocaine.” Additional contributors include Johanna S. Qvist, Arun Asok, PhD, Shao-shan C. Huang, PhD, Paolo Masia, PhD, Matteo Deidda, PhD, Ya B. Wei, PhD and Rajesh K. Soni, PhD.

Funding: This research was supported by the Howard Hughes Medical Institute, Cohen Veterans Bioscience, the Swedish Research Council (Dnr 350-2012-6535), the Royal Physiographic Society in Lund (Sweden), the Sweden-America Foundation, the National Institute of Mental Health (F32MH114306) and the Department of Biomedical Sciences Project in Italy (RICDIP_2012_Fratta_01).

A limited number of preclinical studies indicate that CBD could have therapeutic properties on cocaine and METH addiction and some preliminary data suggest that CBD may be beneficial in cocaine-crack addiction in humans.

CBD has shown promising results in reducing the inflammation and seizures induced by cocaine [51,52] and in several preclinical models of addiction to amphetamine [38], cocaine [38,54,59] and METH [56,61,98].

Importantly, a brief treatment of CBD induces a long-lasting prevention of reinstatement of cocaine and METH seeking behaviours. However, in other studies, CBD treatment had a minimal effect on cocaine reinstatement [54,57].

These controversial results indicate that the efficacy of CBD may be dependent on a range of factors, including the dose and schedule of administration of this compound (i.e., acute or repeated; before, co-administered with, or after the psychostimulant drug), the type of substance of abuse under study (cocaine, amphetamine or METH), the paradigm used to evaluate psychostimulant addiction (ICSS, self-administration, conditioned place preference or behavioural sensitization) and the process studied (acquisition, extinction, reinstatement or reconsolidation).

In the self-administration paradigm, CBD showed higher efficacy to block the reinstatement than the acquisition or maintenance of self-administration [54]. Furthermore, in the CPP paradigm, CBD was more effective to accelerate extinction [38] or to impair reconsolidation [60] than to block the acquisition or expression of the place conditioning induced by cocaine or amphetamines [38].

In addition, context-induced reinstatement of cocaine seeking was prevented by CBD [59] while this compound did not affect priming-induced reinstatement [54]. These results may reflect a predominant role of CBD in attenuating drug-related memory, without altering the reinforcing or rewarding properties of cocaine.

The evidence of CBD’s role in regulating emotional memory is further supported by the blockade of stress-induced reinstatement of cocaine seeking [59]. CBD was also able to block priming-induced reinstatement of METH seeking but this effect was observed only with high doses [58] or icv administration [61,98].

In comparison to other drugs of abuse, CBD seems to have a relatively weaker efficacy in disrupting the rewarding and reinstating effects of psychostimulant drugs. For example, on the ICSS paradigm, CBD did not alter the effects of cocaine with an effective dose to inhibit the effects of morphine [36].

Similarly, CBD prevented cue-induced reinstatement of heroin [72], but not cocaine self-administration [57].

Drug addiction is characterized by the compulsive desire to use drugs and a loss of control over consumption. For this reason, in the preclinical field, the effects of CBD need to be evaluated in experimental models of drug-escalation, which translate more readily to drug abusers searching treatment, who have initiated and progressed their drug use until developing a compulsive pattern of consumption.

Future preclinical studies should evaluate the effects of CBD on priming- and stress-induced reinstatement of cocaine CPP as well as on the negative consequences of withdrawal after repeated exposure to cocaine and METH.

Some of these issues are currently being researched in the authors’ laboratory. Further studying of the mechanisms of action underlying CBD’s therapeutic potential for psychostimulant addiction will be also necessary. The reversion of psychostimulant-induced alterations in the DA mesolimbic system and the minimization of inflammatory injury promoted by cocaine or METH seem to be important mechanisms.

Moreover, the protracted behavioural effects of CBD suggest that this compound has a long-term impact on synaptic plasticity, which is mediated by the endocannabinoid system [141] and altered by addictive drugs [142].

According to Gerdeman et al. [53], the endocannabinoid-mediated synaptic plasticity “may act specifically within drug-paired environments to maintain cocaine-directed behavioural responses”. Figure 2 shows the hypothetical mechanisms (based on the results of preclinical studies) involved in the effects of CBD on cocaine/METH addiction.

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Figure 2
Hypothetical mechanisms involved in the effects of CBD on cocaine/METH addiction. The involvement of these processes is supported by the results of preclinical studies. VTA: ventral tegmental area; DA: dopamine; NAcc: nucleus accumbens; DA D2: dopamine D2 receptors; CB1R; cannabinoid receptors type 1; Hipp: hippocampus; CB2R; cannabinoid receptors type 2; vmPFC: ventromedial prefrontal cortex; m-OR: mu opioid receptors; d-OR: delta opioid receptors; 5-HT: serotonin; 5-HT1AR: type 1A serotonin receptors; 7-nAChR: nicotinic acethylcholine receptors type 7; GSK3: glycogen synthase kinase-3; Akt: protein kinase B; mTORC1: mammalian target of rapamycin complex 1; MAPK, mitogen-activated protein kinase; ERK1/2: Extracellular signal-regulated kinases type 1 and type 2; BDNF: brain derived neurotrophic factor; TrkB: Tropomyosin receptor kinase B; Amyg: amygdala; mPFC: medial prefrontal cortex; IL: interleukine; TNF- α: tumor necrosis factor alpha; PPARg: Peroxisome proliferator-activated receptor gamma.

The FDA has approved a purified form of CBD (Epidiolex) to treat rare, severe forms of epilepsy. However, there are no other FDA-approved drug products that contain CBD for the treatment of any other diseases.

The cause of this lies in the FDA’s priority to protect and promote public health and, consequently, this Agency is committed to science-based decision-making. The FDA recognizes CBD’s potential benefits, but also maintains that questions remain regarding its safety, including the potential for liver injury (identified during the review of the marketing application for Epidiolex).

Currently, CBD is the subject of substantial clinical research on its potential medical uses, including the treatment of addiction to drugs of abuse, but there remain many open questions that need to be considered before CBD may be more widely available.

For example, what is the maximal dose of CBD that is safe to consume daily?

How does CBD’s safety depend on the method of administration?

What are the risks of long-term exposure?

Are there drug interactions?

How does CBD impact special populations (such as adolescents or pregnant women) and people with chronic diseases?

In addition to the safety issues, the effectiveness of CBD for treating addiction to psychostimulant drugs has not yet been proven. The paucity of preclinical findings and the lack of results derived from clinical trials greatly hinder the FDA’s approval of CBD to treat addiction to cocaine or METH.

From the case of Epidiolex, the FDA only supports a drug’s approval after careful review of the evidence obtained in scientifically valid research and the conclusion that CBD is safe and effective for its intended use. Thus, a priority of research is to demonstrate the usefulness of CBD as a novel pharmacotherapy for psychostimula

nt dependence in clinical trials. These future clinical trials should include randomised controlled samples of individuals with the diagnosis of cocaine or METH dependence (without or with comorbid neuropsychiatric conditions) to investigate the specific effects of CBD on these disorders, the specific mechanism of action of CBD and the safe and ideal therapeutic doses of this compound.

Biological measures must also be included in these clinical trials in order to correlate the therapeutic effects of CBD to changes in neurotransmitters, intracellular signalling, neuroinflammatory markers, and structural and functional cerebral changes [120]. It is needed to obtain clinical evidence for the safety and effectiveness of CBD through adequate and well-controlled clinical trials for the translation of CBD in the treatment of psychostimulant abuse and addiction.

In conclusion, there is currently limited evidence of the potential therapeutic benefits of CBD for cocaine and METH use disorders and commonly related adverse symptoms.

A clear limitation of the literature is the paucity of human research and the lack of clinical trials. Given the absence of abuse liability of CBD and its general tolerability, this compound appears to be a promising candidate for pharmacotherapy of psychostimulant drug-use disorders. Further preclinical studies and future clinical trials are clearly necessary to fully evaluate the potential of CBD as an intervention for cocaine and METH addictive disorders.

The validation of the safety and efficacy of CBD in reducing craving and relapse in preclinical and clinical trials will be necessary for the translation of research findings into clinical settings.

Zuckerman Institute


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