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Medications and Supplements of Concern on Benzodiazepines, During Cessation and After Withdrawal

Alternative Medications to Benzodiazepines

There aren’t any alternatives to benzodiazepines with the same level of efficacy and safety profile in overdose, nor is there a substitute medication to prevent withdrawal from occurring. Barbiturates, like phenobarbital, can be more dangerous than benzodiazepines in overdose, are the most similar drug. This is because both benzodiazepines and barbiturates work on the GABAA receptor in similar ways, and benzodiazepines were created in part to replace the barbiturates, as barbiturate accidental overdoses were often fatal. Patients experiencing benzodiazepine harm usually have sensitized nervous systems and may report adverse reactions to various products they used safely in the past before, like soaps, foods, etc. The same is true for medications. 

It should also be noted that antidepressants and some other psychoactive drugs such as antipsychotics can also cause prescribed physical dependence, may also require a lengthy taper, and thus can create their own withdrawal syndromes upon discontinuation. Studies as recently as 2012 have determined that symptoms upon cessation of SSRIs and benzodiazepines are very similar, indicating that cessation of both of these types of drugs can provoke a potentially severe withdrawal syndrome. Some people can even develop psychotic symptoms after stopping an antipsychotic medication even if they’ve never had psychotic symptoms before.

It is for these reasons that the British National Formulary in their ‘Benzodiazepine Guidance’ from November 2013 state:

The addition of beta-blockers, antidepressants and antipsychotics should be avoided where possible.

Tools such as pharmacogenomic testing may be of some use in determining which medications may or may not be tolerated, however many benzodiazepine-injured patients report having reactions and sensitivities to medications they had no issues with prior to their benzodiazepine harm.

While benzodiazepine withdrawal syndrome might worsen symptoms in someone who had a pre-existing history of anxiety/depression or other psychiatric symptoms, these worsened symptoms are not likely to be permanent. It is important to note that benzodiazepine withdrawal syndrome causes psychiatric symptoms in patients who took benzodiazepines for physical (non-psychiatric) conditions as well—such as tinnitus, muscle spasms, or vertigo, to name a few. Any other drug which decreases the seizure threshold or interacts with GABA neuroreceptors (is GABAergic), and possibly many others, should be approached with caution in someone suffering benzodiazepine withdrawal or with a history of benzodiazepine physical dependence. 

 

Supplements

Beyond prescription pharmaceuticals, there is no evidence that supplements and herbs solve Benzodiazepine Withdrawal Syndrome and Protracted Withdrawal Syndrome issues. There is evidence and anecdotes that certain medications and supplements that are GABAergic have been associated with harm in those experiencing benzodiazepine issues. Dr. C. Heather Ashton, author of the Ashton Manual, has said:

I have always been against supplements which are often just a money-making scam, and most have never been properly tested. Many people take so-called GABA supplements in benzodiazepine withdrawal. This is futile as there is no shortage of GABA in benzo withdrawal: the problem is the down-regulated receptors. I have always advised people withdrawing from benzos not to waste their money on supplements. 

GABA Receptor Downregulation

GABAergic means “pertaining to or affecting the neurotransmitter GABA“. A substance is GABAergic if it produces its effects via interactions with the GABA system, such as by stimulating or blocking neurotransmission. A GABAergic or GABAergic agent is any chemical that modifies the effects of GABA in the body or brain. Some different classes of GABAergic drugs include the following: GABA receptor agonists, GABA receptor antagonists, and GABA reuptake inhibitors. Some examples include gabapentinoids and GABA analogues.

Neuroadaptation occurs with patients on daily prescribed benzodiazepines. This means that their bodies adapt through repeated exposure to a drug, producing long-term changes in the nervous system. Neuroadaptation to the benzodiazepine’s constant presence is the reason for the development of tolerance and a sensitization of the nervous system. 

The continual presence of prescribed benzodiazepine may cause down-regulation of the GABA receptors, meaning that the receptors become fewer. This is believed to be from the homeostatic response of the body to the constant presence of the benzodiazepines. When those who have benzodiazepine neuroadaptation try to stop a benzodiazepine, the nervous system can go into a chronic hyperactive state. The taking of the benzodiazepine has made the body unable to properly utilize GABA.

This nervous system reaction can occur on the benzodiazepines, in tolerance withdrawal, when stopping benzodiazepines, or after being completely withdrawn. While the nervous system is in a hyperactive state of tolerance, toxicity, withdrawal, or protracted withdrawal, patients anecdotally report having reactions to certain substances, even if they previously tolerated them, and setbacks from these reactions.

 

Setbacks and Reactions to Substances 

Setback refers to the return of a withdrawal syndrome after improvement or healing. Reaction describes an increase or recurrence of withdrawal symptoms after exposure to a substance. For an example consider a patient who experienced protracted withdrawal syndrome for 2 years post taper. They healed and returned to normal functioning.The patient, after a stressful day, consumed a GABA supplement hoping to relax. Within a few days all of their protracted withdrawal symptoms returned, rendering them bedridden and unable to work again for another 2 years. 

Usually, setbacks occur after environmental stresses, according to Dr. Heather Ashton in her 2011 supplement to The Ashton Manual, which can include GABAergic and other substances. Reactions and setbacks can vary from short-lived and mild to severe and long-lasting. 

The potential reason(s) for these “reactions” and “setbacks”, as described by Dr. Heather Ashton:

One mechanism which might be involved in long-term (and possibly permanent) effects of benzodiazepines is an alteration in the activity of benzodiazepine receptors in brain GABA neurones. These receptors down-regulate (become fewer) as tolerance to benzodiazepines develop with chronic use. Such down-regulation is a homeostatic response of the body to the constant presence of the drugs. Since benzodiazepines themselves enhance the actions of GABA, extra benzodiazepine receptors are no longer needed, so many are, in effect, discarded. These down-regulated receptors are absorbed into neurones where, over time, they undergo various changes including alterations in gene expression. When these receptors are slowly reinstated after drug withdrawal, they may return in a slightly altered form. They may not be quite so efficient as before in increasing the actions of GABA, the natural ‘calming’ neurotransmitter. As a result, the brain may be generally less sensitive to GABA and the individual is left with heightened central nervous system excitability and increased sensitivity to stress. Molecular biologists point out that changes in gene expression can be very slow, or even unable, to reverse..

It is not unusual to experience recurrence of apparent benzodiazepine withdrawal symptoms years after a successful withdrawal and a return to normal health. This pattern of symptoms is unique to the individual, depending on his physical and psychological makeup, and no doubt on the innate density of his/her benzodiazepine receptors and the balance of his endozepines. The experience of benzodiazepine withdrawal is deeply etched into the mind and memory of those who have been through it. Like all memories, it is actually physically present in the strength and connections of their neural synapses. These recurrent symptoms are all signs of GABA underactivity with its accompanying increased output of excitatory neurotransmitters, resulting in a hyperactive, hypersensitive central nervous system. The mechanism of action is exactly the same as that of benzodiazepine withdrawal, which is why the symptoms are the same.

It is not clear why many people report experiencing adverse effects from new drugs or drugs they have tolerated before taking benzodiazepines. The drugs involved are so disparate – from skin ointments to eye drops to local anaesthetics to antidepressants, steroids and many others – that it is difficult to attribute these reactions to metabolic effects, allergies or other known effects. Presumably the general hypersensitivity of the nervous system magnifies the reaction to any foreign substances, but no clear explanation has yet emerged. An exception is quinolone antibiotics, which displace benzodiazepines from their binding sites and should not be taken by patients on, or recently on, benzodiazepines.

Neurotoxicity

Another explanation for reactions and setbacks might be found by researching neurotoxicity. Neurotoxicity is the capacity of chemical, biological or physical agents to cause adverse functional or structural damage in the nervous system. People with chronic neurotoxic syndromes (sometimes called protracted withdrawal) often experience chemical sensitivity, even to chemicals they were never sensitive to prior to the exposure to the neurotoxin. Common symptoms of neurotoxicity can include problems with memory, concentration, learning, mental processing speed, sleep, thinking, language, as well as anxiety, depression, confusion, personality changes, fatigue, and numbness of the hands and feet. Many types of nervous system disorders can be caused by neurotoxicity, including numerous neurologic and psychiatric disorders, as well as chemical sensitivity. Some experts compare head injuries to neurotoxicity, as the resulting inflammation and neurotransmitter dysfunction is similar. 

 

Potentially Dangerous Substances List

The following is a list of supplements, medications, etc. which one may wish to avoid during a taper, benzodiazepine cessation, during protracted withdrawal and even after healing, due to the potential for interference with recovery. The list is not all-inclusive. The lists are solely provided for information purposes and not medical advice. 

Please also note that some of the drugs and/or supplements listed may have their own withdrawal complications and require a taper. 

Acorus
A petroleum ether extract of Acorus calamus rhizomes enhanced the GABA-induced chloride current through GABA(A) receptors.

ADHD Medications
These include stimulants such as Ritalin, Adderall and the like. These drugs may lower the seizure threshold and also increase anxiety.

Alcohol
Alcohol is an indirect GABA agonist.

Antibiotics: Non-Fluoroquinolone
Per The Ashton Manual, antibiotics for some reason, sometimes seem to aggravate withdrawal symptoms. There are some studies indicating that penicillins are GABA receptor antagonists. Many antibiotics have a structure that mimics GABA.

Anticonvulsants (Some)
Some anticonvulsants have GABAergic activity or a similar mechanism of action to benzodiazepines. 

Antipsychotics (Some)
These have been known to cause severe and potentially permanent adverse effects, such as movement disorders known as Tardive Dyskinesia, akathisia and the development of psychosis even in people without a history of psychotic disorders. Some anticonvulsants have GABAergic activity or a similar mechanism of action to benzodiazepines. 

Aspartame/Artificial Sugars
Aspartame (α-aspartyl-l-phenylalanine-o-methyl ester), an artificial sweetener, has been linked to behavioral and cognitive problems. Possible neurophysiological symptoms include learning problems, headache, seizure, migraines, irritable moods, anxiety, depression, and insomnia. 

Ashwagandha
Ashwagandha is thought to be GABA-mimetic and to interact with sedatives such as Klonopin. Some benzo abusers take ashwagandha to make their benzos more potent. Exhilarin also contains holy basil (similar to Kava Kava or Pentobarbital), bacopa (interacts with benzos), amla fruit and essential basil oil (can lower seizure threshholds).

Baclofen
Baclofen reduces the strength of excitatory (glutamate) and inhibitory (GABA) transmission in the amygdala by a presynaptic mechanism

Bái Sháo/Paeonia Lactiflora Pall
/Radix Paeoniae Alba/ White Peony

Bind to GABA receptors.

Caffeine
Caffeine directly interacts with GABA synapses.

Cannabis (Marijuana, CBD oil, THC)
Cannabinoids impact the GABA receptors. CBD and others can impact cytochrome P450, a family of liver enzymes. See: CBD-Drug Interactions: The Role of Cytochrome P450. The cannabinoid CB1 receptor is involved in the anxiolytic, sedative and amnesic actions of benzodiazepines. Prolonged Cannabinoid Exposure Alters GABA(A) Receptor Mediated Synaptic Function in Cultured Hippocampal Neurons.  The major central endocannabinoid directly acts at GABAAreceptors. In all its forms, cannabis works with the brain’s GABA pathways just as benzos do. Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD.

Chamomile
Chamomile is widely regarded as a mild tranquilizer and sleep-inducer. Sedative effects may be due to the flavonoid, apigenin that binds to benzodiazepine receptors in the brain. Studies in preclinical models have shown anticonvulsant and CNS depressant effects respectively.

China Root/Hoelen/Pachymic Acid/Poria
A study provided evidence for the hypnotic effects as pachymic acid enhanced pentobarbital-induced sleeping behaviors via GABAA-ergic mechanisms in rodents

Corticosteroids (all forms)
Glucocorticoids exert an opposing rapid regulation of glutamate and GABA synaptic input.

Corydalis
GABA antagonist.

Dioscorea/Wild Yam 
Dioscorea enters and physically blocks the ion channels normally associated with GABA.

Epinephrine
This is adrenaline and is often found in local anesthetics. Some local anesthetics do not contain epinephrine; ask your doctor. Lidocaine with epinephrine is commonly used for dental procedures. To avoid this, many dental patients will request carbocaine plain/without epinephrine. Lidocaine inhibits GABA(A) currents.

Estrogen
Estrogen regulates GABA in rats.

Exhilarin
Exhilarin is thought to be GABA-mimetic and to interact with sedatives such as Klonopin. Some benzo abusers take ashwagandha to make their benzos more potent. Exhilarin also contains holy basil (similar to Kava Kava or Pentobarbital), bacopa (interacts with benzos), amla fruit and essential basil oil (can lower seizure threshholds).

Fluoroquinolone Antibiotics
These antagonize the GABAA receptor and have recently been updated with Black Box warnings by the FDA regarding risks “due to potentially permanent, disabling side effects occurring together,” such as nerve damage, Myasthenia Gravis, and others. It is important to note as well that the fluoroquinolones actually displace benzodiazepines from their binding sites on GABA-receptors. This class of antibiotics can precipitate acute withdrawal in people taking or tapering from benzodiazepines. It may be necessary to take antibiotics during benzodiazepine withdrawal, but, if possible, the fluoroquinolones should be entirely avoided. Fluoroquinolones should be contraindicated with chronic benzodiazepine exposure in nearly every scenario.

GABA supplements
The problem in benzodiazepine neuroadaptation and withdrawal is not one of a lack of GABA, but one of a lack of receptors to properly utilize GABA. These supplements are not typically useful in general as they don’t cross the blood-brain barrier. 

Gabapentin/Lyrica/Neurontin/Pregabalin
These drugs are commonly used even though they have not been proven effective for benzodiazepine cessation. A clinical trial for “GabapentinTreatment of Benzodiazepine Dependence” began in 2013. It was terminated, without results, in 2018. All of these drugs require their own slow taper and have their own severe withdrawal syndromes with corresponding patient support groups.

Ganoderma/Reishi Mushroom
Ganoderma lucidum potentiates pentobarbital-induced sleep via a GABAergic mechanism.

LDN or Low- Dose Naltrexone 
Naltrexone and its active metabolite 6-β-naltrexol are competitive antagonists at μ-opioid and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. Standard therapeutic doses of naltrexone blocks these receptors, which does two things; it prevents inhibition of GABA receptors (normally, signaling through the GABA receptors inhibits the activity of neurons; many drugs inhibit GABA and thus “free up” neuronal activation; preventing inhibition of GABA allows GABA’s normal inhibition activity to take place) and it blocks dopamine release.

Jujube Fruit/Ziziphus Jujuba
The results of a study showed that GABA is present in jujube fruit, in a relatively high amount, as measured by the present method.

Kava/Piper Methysticum 
Kava, like many of these herbs, has a multi-faceted and complicated mode of action. Some research suggests that it may be a positive allosteric modulator of the GABA receptor, like benzos.

Lemon Balm/Melissa Officinalis
Prevents the breakdown of GABA by being a potent inhibitor of the enzyme GABA transaminase.

L-Theanine
L-Theanine is found in a lot of calming supplements like Zen Mind Progesterone medicines and creams. It increases GABA.

Magnesium
This mineral binds to GABA receptors. 

Magnolia
Magnolia may have anxiolytic-like effects and that these effects may be mediated by GABAergic transmission with the increase of Cl(-) channel opening.

Melatonin 
Melatonin increased levels of GABA in an animal study.

Monosodium Glutamate (MSG)  and Other Preservatives
Two-step biotransformation of monosodium glutamate to GABA. 

Nasal Decongestants
Decongestants increase adrenaline which may increase anxiety.

NSAIDs
During the preparation of DRG neurons harvested from Sprague-Dawley rats, the whole-cell recording technique was used to record the effect of NSAIDs on GABA-activated inward currents, and the expression levels of the TMEM16A and TMEM16B subunits were revealed.

Opiates
FDA black box warning interaction for opiates and benzodiazepines.  Increased risk of respiratory depression when combined with other drugs. This combination can lead to death.
Exogenous opioids attach to mu receptors, reducing the amount of GABA released. 

Oregano Oil
Oregano Oil is thought to be involved in the GABAergic system. This recorded interview is an account given by a caregiver to someone with benzodiazepine harmed patient who experienced a severe setback from Oregano oil applied directly to the skin. Note that oregano oil can be found in food.

Passionflower/Passiflora Incarnata
According to animal studies, a high potency passionflower extract has an anxiolytic effect comparable to diazepam.

Penicillin
Penicillin  probably exerts its proconvulsant effect by inhibiting GABA-gated chloride ion influx. However, it appears not to act through the BZ receptor of the GABA/BZ receptor complex.

Phenibut (beta-phenyl-gamma-aminobutyric acid HCl)
Phenibut
acts as a GABA-mimetic, primarily at GABA(B) and, to some extent, at GABA(A) receptors. Phenibut (beta-phenyl-gamma-aminobutyric acid HCl)

Picamilon
One study in animals showed that picamilon permeated the blood–brain barrier  and then is hydrolyzed into GABA and niacin. The released GABA in theory would activate GABA receptors potentially producing an anxiolytic response.

Polygala
Polygala acts as a GABA(A) agonist.

Progesterone
Progesterone modulates GABA(A).

Pseudoephedrine
This and other stimulating additives in over-the-counter cough and congestion remedies may cause increased anxiety.

Pueraria
Effected GABA(A) in rats.

Quinine
Antimalarial drugs inhibit GABA(a).

Soma/Carisoprodol 
Soma/carisoprodol is a muscle relaxant. However, a metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties.

Saffron Extract/Safranal
Saffron Extract has anticonvulsant properties. It has been shown to act as an agonist at GABA(A) receptors.

Salvia Officinalis 
The Salvia officinalis extract replaced 50% of specific ligand binding to GABA(A) and GABA(B) receptor.

Schisandra
Up-regulates the expression of GABA(A)

Scullcap (Scutellaria spp.)
Scullcap has been used traditionally as an anxiolytic and sedative. It has a number of flavones that have been reported to selectively bind with high affinity to central benzodiazepine receptor sites.

SSRIs/SNRIs
Some other medications typically used in anxiety disorders—such as SSRIs and SNRIs for example—can be stimulating to the central nervous system, and people with a history of benzodiazepine physical dependence, withdrawal and central nervous system damage may be more sensitive to their adverse effects. These other medications may cause further hyperexcitability in the already sensitized nervous system of a person harmed by benzodiazepines. Antidepressant sensitivity is more common in younger people and females, and the increase in anxiety caused by an antidepressant can result in a higher risk of suicide. For these reasons, initiating antidepressant therapy in someone suffering from benzodiazepine withdrawal or damage, and those who are benzodiazepine-sensitized or with a sensitive constitution in general should be approached with extreme caution, if attempted at all.

Testosterone
Testosterone impacts GABA+ levels in the posterior-cingulate in unmedicated depressed women during reproductive life.

Valerian
(Valeriana spp.) is widely used as an herbal sedative. Its exact method of action is still unknown, although it affects the GABA system. It contains a wide range of constituents, including alkaloids, valeric acid (which is similar in structure to both GABA and GHB), valerenic acid (which may bind to serotonin receptors), and even GABA itself. Additionally, valerian has been shown to stimulate an enzyme called glutamate decarboxylase (GAD) which creates GABA from glutamate in the brain.

Wellbutrin/Bupropion
This medication is often prescribed as a smoking cessation aid or antidepressant. It is not approved for anxiety or depression with anxiety as a comorbidity and can worsen anxiety. This medication can also lower the seizure threshold. Manufacturer’s guidelines warn: “You should not take Wellbutrin if you have seizures, an eating disorder, or if you have suddenly stopped using alcohol, seizure medication, or sedatives.” Serious adverse effects of this medication may include “suicidal thoughts, anxiety, agitation, seizure, mania, high blood pressure, and liver damage”.