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Lerner, 2019 Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development.


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Brain Commun; 1. Epub ahead of print 1 January 2019. DOI: 10.1093/braincomms/fcz025.

Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development.

Lerner A, Klein M.



The purpose of this article is to describe dependence and withdrawal phenomena related to CNS drugs discontinuation and to clarify issues related to the evaluation of clinical drug withdrawal and rebound as they relate to safety in new drug development. The article presents current understanding and definitions of drug dependence and withdrawal which are also relevant and important features of addiction, though not the same. Addiction, called substance use disorder in DSM-5, affects an individual’s brain and behaviour, represents uncontrollable drug abuse and inability to stop taking a drug regardless of the harm it causes. Characteristic withdrawal syndromes following abrupt discontinuation of CNS-active drugs from numerous drug classes are described. These include drugs both scheduled and non-scheduled in the Controlled Substances Act, which categorizes drugs in five schedules based on their relative abuse potentials and dependence liabilities and for regulatory purposes. Schedules 1 and 2 contain drugs identified as those with the highest abuse potential and strictest regulations. Less recognized aspects of drug withdrawal, such as rebound and protracted withdrawal syndromes for several drug classes are also addressed. Part I presents relevant definitions and describes clinical withdrawal and dependence phenomena. Part II reviews known withdrawal syndromes for the different drug classes, Part III describes rebound and Part IV describes protracted withdrawal syndromes. To our knowledge, this is the first compilation of withdrawal syndromes for CNS drugs. Part V provides details of evaluation of dependence and withdrawal in the clinical trials for CNS drugs, which includes general design recommendations, and several tools, such as withdrawal questionnaires and multiple scales that are helpful in the systematic evaluation of withdrawal. The limitations of different aspects of this method of dependence and withdrawal evaluation are also discussed.



Free full text https://academic.oup.com/braincomms/article/1/1/fcz025/5588408


Groundbreaking paper presents a unified overview of all psychotropic withdrawal syndromes, prescribed or not, including psychiatric drugs.


From the paper:





In the United States, the significance of drug dependence, especially as it relates to addiction, came to the foreground and captured public attention only in recent decades, following epidemics of drug abuse, dependence and addiction, sweeping the country, resulting in staggering numbers of deaths. Most cases are related not only to opioid drugs, but also to benzodiazepines (BZ), stimulants and street drugs, including heroin, highly potent fentanyl and its analogues, cathinone-like hallucinogens and dissociative substances, and stimulants similar in action to cocaine and methamphetamine (Dowell et al., 2017; Scholl et al., 2018; Colon-Berezin et al., 2019; Kariisa et al., 2019).

Serious and potentially life-threatening adverse events related to drug withdrawal and dependence may result also from other drug classes generally not associated with abuse and not scheduled under the Controlled Substances Act. Withdrawal of antidepressants and other CNS drugs such as BZ and stimulants may lead to dangerous, even life-threatening, withdrawal symptoms and lead to significant public health concerns, such as suicidality (Risse et al., 1990; Valuck et al., 2009; APA, 2013; Fava et al., 2015).

A widespread misunderstanding regarding dependence and withdrawal is that both need to be related to drug abuse and addiction. Also, in general, the occurrence of dependence and withdrawal may be underestimated, and their significance underappreciated, particularly for drugs not known for abuse potential and which are not scheduled substances in the Controlled Substances Act (Newman et al., 2009; Rabinak and Nirenberg, 2010; Reidenberg, 2011; Hudak et al., 2012; Chouinard and Chouinard, 2015; Fava et al., 2015).

Thus, this article has two main goals, one is to provide brief condensed summaries of withdrawal syndromes for the majority of the CNS-active drug groups which are of interest to prescribers, patients and also clinical scientists, this addresses a gap of knowledge usually not readily available in the drug labels.

The second goal is to emphasize the importance of evaluating dependence and withdrawal for all CNS-active drugs and to provide standardized advice how to assess symptoms of drug withdrawal. The information obtained will be used to provide safety data for warnings on drug labels and to inform patients and physicians about possible dependence, withdrawal and rebound related to the drug—and their consequences.

Definitions of dependence and withdrawal

The phrase ‘drug dependence and withdrawal’ most often and traditionally relates to substance abuse. However, at other times it can relate to a broader concept of ‘dependence and withdrawal’, which potentially may encompass all drug classes, because it may be viewed as a function of an organism’s adaptation to the presence of a drug in the body. In this study, we will discuss both approaches.

In the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; APA, 2013) definitions of drug dependence and withdrawal related to substance use disorder are described in the ‘Substance-Related and Addictive Disorders’ section, and are further defined for drugs and substances known to be related to substance use disorders. These substances include opioids, sedatives, hypnotics, anxiolytics, stimulants, cannabis, caffeine, alcohol and tobacco. Of these substances, cannabis is listed in Schedule 1 of the Controlled Substances Act, many opioids and stimulants are listed in Schedule 2; sedatives, hypnotics and anxiolytics are listed in Schedule 3 or 4, whereas caffeine, alcohol and tobacco are not listed in the Controlled Substances Act (United States Congress, 1970).

However, for drugs, in particular CNS active, which are being developed and evaluated by FDA, we will be using another definition, more appropriate for this function, namely, part (i) of the dependence definition cited by the American Society of Addiction Medicine (ASAM). The recent ASAM definitions of dependence, addiction, tolerance and withdrawal gained support by the American Academy of Pain Medicine and the American Pain Society in 2001, and have since then been updated (Ries et al., 2014).

  • Physical dependence—used in three different ways: (i) physical dependence is a state of adaptation that is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, reducing blood level of the drug and/or administration of an antagonist; (ii) psychological dependence is a subjective sense of need for a specific psychoactive substance, either for its positive effects or to avoid negative effects associated with its abstinence; and (iii) one category of psychoactive substance use disorder in previous editions of the Diagnostic and Statistical Manual of Mental Disorders, but not in the DSM-5, published in 2013.

  • Addiction is characterized by inability to consistently abstain, impairment in behavioural control, craving, diminished recognition of significant problems with one’s behaviours and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.

  • Tolerance—a state of adaptation in which exposure to a drug over time results in diminution of one or more of the drug’s physiologic effects.

  • Withdrawal syndrome—the onset of a predictable constellation of signs and symptoms following the abrupt discontinuation of, or rapid reduction in, the dose of a psychoactive substance.

These definitions are important for distinguishing between dependence and addiction or substance use disorder.


To further clarify the concept of dependence it can be said that an individual can be addicted to the drug of abuse, or merely develop dependence to the drug of abuse without being addicted. For drugs not associated with abuse potential, an individual may still develop dependence; but again, this would not be classified as an addiction.

The phenomena of dependence are related to withdrawal, tolerance and rebound. Ashton (1991) described the relation of withdrawal, rebound and tolerance using the example of BZ. The excerpt below is somewhat lengthy for the citation, but it describes withdrawal phenomena, their sequence and physiological background so well that the authors decided to provide it here in full.


Any chronically used drug gradually engenders a series of homeostatic responses which tend to restore normal function despite the presence of the drug. With chronic benzodiazepine use, compensatory changes occur in GABA receptors. Such changes consist of decreased sensitivity of these receptors to GABA, probably as a result of alterations in affinity state and decreased density (Cowen and Nutt, 1982; Nutt and Malizia, 2001).

In addition, there are changes in the secondary systems controlled by GABA, so that the output of excitatory neurotransmitters tends to be restored, and/or the sensitivity of their receptors increases. The whole complex of primary and secondary changes eventually results in benzodiazepine tolerance.

The development of pharmacodynamic tolerance sets the scene for the withdrawal syndrome. Cessation of the drug exposes all the adaptations which have accrued to counteract its presence, releasing a rebound of unopposed activity involving many neurotransmitters and their receptors and many brain systems. Clinically this state is manifested as the withdrawal syndrome, consisting of effects that are largely the opposite of these originally induced by the drug.


Evaluation of dependence and withdrawal is an integral part of FDA’s evaluation of new drugs.

The development of dependence is a general feature of drug effects on the human body which frequently cannot be predicted a priori. Thus, it is important to evaluate thoroughly new drugs for development of dependence, withdrawal and rebound symptoms, as well for development of abuse potential (FDA Abuse Guidance 2017; FDA and Center for Drug Evaluation and Research, 2017).

The evaluation of human dependence and withdrawal is important for regulatory reasons, as it relates to 21U.S.C. 811 and 812 (United States Code, Title 21—FOOD AND DRUGS; U.S. Government, 2006😞 a drug that is a controlled substance, needs to be monitored for abuse and misuse and new data that relate to abuse and dependence liability resulting from abuse needs to be assessed.

The assessment of dependence and withdrawal is also necessary as a potential warning for physicians and patients and should be provided in the drug label to inform if the drug can be abruptly withdrawn at the end of treatment or must be slowly tapered to avoid potentially dangerous even life-threatening adverse events after abrupt withdrawal. It is also important to inform subjects abusing the drug about health consequences of the development of dependence and of drug withdrawal.

Drug dependence and withdrawal

We present here withdrawal-related phenomena which can be identified for many different drug groups; this list is based largely on a description of clinical aspects of withdrawal emerging after discontinuation of selective serotonin reuptake inhibitors (SSRIs; Chouinard and Chouinard, 2015). These withdrawal phenomena include:

  • New symptoms (acute withdrawal symptoms): Newly emerging signs and symptoms which occur almost immediately after abrupt drug discontinuation or sometimes even after the dose decrease. These symptoms are related to the disruption of neuroregulatory changes (neuroadaptation) established during drug administration.

  • Rebound: Recurrence of symptoms of the treated disorder in patients, more severe than before the treatment.

  • Protracted withdrawal syndrome: Usually appears long past the timeframe of acute withdrawal symptoms, may last for weeks and months, and sometimes may present as a newly emerging disorder.

  • Relapse. Return of signs and symptoms of the disease after a remission due to natural causes or termination of treatment; it occurs as a phenomenon in the natural history of the disorder. Relapse is not an aspect of dependence; however, it is mentioned here because it occurs during the timeframe of acute withdrawal and needs to be differentiated from the withdrawal.

  • Symptoms of delayed drug toxicity: May be over-imposed on acute withdrawal symptoms and sometimes are difficult to differentiate from them.



Edited by Altostrata

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

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Thanks Alto!


"Evaluation of dependence and withdrawal is an integral part of FDA’s evaluation of new drugs."


Would have been nice if they had actually done this evaluation on SSRIs before setting us all on this nightmare path and ruining millions of lives. Ah well. One can dream.

Started on Prozac and Xanax in 1992 for PTSD after an assault. One drug led to more, the usual story. Got sicker and sicker, but believed I needed the drugs for my "underlying disease". Long story...lost everything. Life savings, home, physical and mental health, relationships, friendships, ability to work, everything. Amitryptiline, Prozac, bupropion, buspirone, flurazepam, diazepam, alprazolam, Paxil, citalopram, lamotrigine, gabapentin...probably more I've forgotten. 

Started multidrug taper in Feb 2010.  Doing a very slow microtaper, down to low doses now and feeling SO much better, getting my old personality and my brain back! Able to work full time, have a full social life, and cope with stress better than ever. Not perfect, but much better. After 23 lost years. Big Pharma has a lot to answer for. And "medicine for profit" is just not a great idea.


Feb 15 2010:  300 mg Neurontin  200 Lamictal   10 Celexa      0.65 Xanax   and 5 mg Ambien 

Feb 10 2014:   62 Lamictal    1.1 Celexa         0.135 Xanax    1.8 Valium

Feb 10 2015:   50 Lamictal      0.875 Celexa    0.11 Xanax      1.5 Valium

Feb 15 2016:   47.5 Lamictal   0.75 Celexa      0.0875 Xanax    1.42 Valium    

2/12/20             12                       0.045               0.007                   1 

May 2021            7                       0.01                  0.0037                1

Feb 2022            6                      0!!!                     0.00167               0.98                2.5 mg Ambien

Oct 2022       4.5 mg Lamictal    (off Celexa, off Xanax)   0.95 Valium    Ambien, 1/4 to 1/2 of a 5 mg tablet 


I'm not a doctor. Any advice I give is just my civilian opinion.

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  • 2 weeks later...

The categorizations they came up with look eerily similar to what I came up with in this thread barely 1 week before you posted this alto. I have never seen or heard about this paper before. Spooky.




Dx: complex PTSD

Discontinuation/taper history: sertraline, trazodone, prazosin, mirtazapine, diazepam

Took 200mg quetiapine for 0.5 years and 150mg for 1.5 years until 01/2020. Now microtapering daily at an overall rate of 12.5mg/month.

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