Pharmacological Treatment of Cannabis Dependence
* Address correspondence to this author at the Department of Medical Biophysics and Nuclear Medicine, Hadassah Medical Organization, Ein Kerem, Jerusalem 91120, Israel; Tel: 972(2)6776705; Fax: 972(2)6421203; [email protected]
Cannabis is the most frequently used illegal psychoactive substance in the world. There is a significant increase in the number of treatment admissions for cannabis use disorders in the past few years, and the majority of cannabis-dependent individuals who enter treatment have difficulty in achieving and maintaining abstinence. Thus, there is increased need for medications that can be used to treat this population. So far, no medication has been shown broadly and consistently effective; none has been approved by any national regulatory authority. Medications studied have included those that alleviate symptoms of cannabis withdrawal (e.g., dysphoric mood, irritability), those that directly affect endogenous cannabinoid receptor function, and those that have shown efficacy in treatment of other drugs of abuse or psychiatric conditions. Buspirone is the only medication to date that has shown efficacy for cannabis dependence in a controlled clinical trial. Results from controlled human laboratory studies and small open-label clinical trials suggest that dronabinol, the COMT inhibitor entacapone, and lithium may warrant further study. Recent pre-clinical studies suggest the potential of fatty acid amide hydrolase (FAAH) inhibitors such as URB597, endocannabinoid-metabolizing enzymes, and nicotinic alpha7 receptor antagonists such as methyllycaconitine (MLA). Controlled clinical trials are needed to evaluate the clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications.
CANNABIS USE DISORDERS
Cannabis is the most frequently used illegal substance in the world [1–3]. Cannabis abuse and cannabis dependence are diagnoses recognized in the United States Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM IV)  and the WHO International Classification of Diseases, Tenth Revision (ICD-10) . In the United States, the number of individuals with disorders associated with cannabis use is twice that of any other illicit drug , with approximately 4 million adults meeting criteria for a life-time diagnosis of cannabis dependence . Relapse rates for cannabis users in treatment are comparable to those found for other drugs of abuse [7–11].
NEUROPHARMACOLOGICAL MECHANISMS OF CANNABIS DEPENDENCE
Exogenous cannabis (and its primary psychoactive component, Δ-9-tetrahydrocannabinol [THC]) acts on the endogenous cannabinoid (endocannabinoid) system in the brain and other body tissues by binding to two different types of cannabinoid receptors on cell membranes: CB1 and CB2 . CB1 receptors are located primarily in pre-synaptic neurons of the CNS and are responsible for the acute psychological and cardiovascular effects of cannabis. CB2 receptors are located largely in the periphery and modulate immune function and inflammatory response.
Endocannabinoids (endogenous ligands at CB receptors) such as anandamide serve as retrograde neuromodulators of synaptic activity. They are released postsynaptically by a variety of stimuli upon demand, travel across the synaptic cleft, and then activate presynaptic CB receptors. A membrane transporter actively takes anandamide into the cell. Anandamide is then broken down by fatty acid amide hydrolase (FAAH) [13–15].
The neuropharmacological mechanism of cannabis dependence may involve interactions of the endocannabinoid system with the dopaminergic and opioid systems. Additionally, CB receptor agonists such as THC act as inhibitors of neurotransmission in acetylcholine, GABA, and glutamatergic pathways. Chronic administration of cannabinoids leads to down-regulation of the CB receptor and receptor function desensitization .
THC like other drugs of abuse, releases DA in the mesocortico-limbic regions of animal brains [17–19]. PET brain imaging studies in healthy human volunteers provide inconsistent evidence for this action in humans. One study showed modest THC-induced dopamine release in the ventral striatum and dorsal putamen using [ 11 C] raclopride . Another study found no significant effect of THC on [ 11 C] raclopride binding, although THC markedly increased psychosis-like symptoms . A subsequent study using the same methodology found significant decreases in frontal and temporal lobe [ 11 C] raclopride binding after THC challenges, but no changes in the striatum, which is also part of the dopamine reward pathway . Decreased frontal lobe binding significantly correlated with catechol-O-methyltransferase (COMT) status. Therefore, medications that target the brain dopamine reward system may have a role in the treatment of cannabis dependence, as they may for other drugs of abuse.
Cannabis intoxication is a syndrome recognized in DSM-IV  and ICD-10 , with both psychological and behavioral (euphoria, relaxation, increased appetite, impaired memory and concentration), and physical (motor incoordination, tachycardia, orthostatic hypotension), manifestations. Intoxication is usually mild and self-limiting, not requiring pharmacological treatment . The most severe effects (anxiety, panic, psychosis) are best treated symptomatically with a benzodiazepine or second-generation (atypical) anti-psychotic medication. No medication is approved specifically for treatment of cannabis intoxication.
Studies with the selective CB1 receptor antagonist/inverse agonist rimonabant suggest that CB1 receptors mediate many of the acute effects of cannabis in humans. In a double-blind, placebo-controlled study of 63 healthy men with a history of cannabis use, single oral doses of rimonabant produced significant dose-dependent blockade of the subjective intoxication and tachycardia caused by smoking an active (2.64% THC) or placebo (double-blind) cannabis cigarette 2 hours later  The 90-mg dose produced about 40% reductions in ratings of “high” “stoned” and “drug effect” (on 100-mm visual-analogue scales) and a 60% reduction in heart rate. Rimonabant alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or its time course. This pattern of findings suggests that the observed attenuation of cannabis effects was specifically due to CB1 receptor blockade, and not to reduction in brain THC concentration or counteracting effects of rimonabant.
CB receptor antagonists such as rimonabant might be useful in treating acute cannabis intoxication, in the way that the mu-opioid receptor (mOR) antagonists naloxone and naltrexone are used to treat opiate intoxication. However, such medications are no longer available for clinical use. Rimonant and similar CB1 receptor antagonists were withdrawn from clinical development and use because of psychiatric side-effects associated with their long-term use .
THE CANNABIS WITHDRAWAL SYNDROME
Both human laboratory and clinical outpatient studies have established the reliability, validity and time course of the cannabis withdrawal syndrome [26, 27] and the cannabis withdrawal syndrome has been proposed for inclusion in DSM-V . Some US studies suggest that about half of patients in treatment have reported symptoms of the cannabis withdrawal syndrome [23, 29–33]. The main symptoms of cannabis withdrawal are anxiety, irritability, depressed mood, restlessness, disturbed sleep, G-I symptoms, and decreased appetite. Most symptoms begin during the first week of abstinence and resolve after a few weeks.
TREATMENT OF CANNABIS WITHDRAWAL SYNDROME
Because symptoms of cannabis withdrawal may serve as negative reinforcement for relapse to cannabis use in individuals trying to abstain [27, 34], pharmacological treatment aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence.
Several studies have tested the effects of medications on cannabis withdrawal [35–37]. These medications are either CB receptor agonists that directly suppress the withdrawal syndrome (analogous to using an opiate to suppress heroin withdrawal) or are designed to indirectly alleviate symptoms of cannabis withdrawal (e.g. dysphoric mood, irritability) by influencing the brain circuits that mediate these symptoms. No medication has regulatory approval for the treatment of cannabis withdrawal. The CB receptor agonist THC has shown efficacy in several human laboratory studies and open-label case series. See Table 1 for description of all pharmacological treatment trials for cannabis dependence.
Pharmacological Trials for Cannabis Dependence
|Haney et al., (2001)
||Randomized Double-blind Placebo-controlled Cross-over
|Haney et al., (2003a)
||Randomized Double-blind Placebo-controlled Cross-over
|* Cornelius et al., (2005)
||Randomized Double-blind Placebo-controlled Cross-over
||Reduced cannabis use
|Haney et al., (2008)
|* Carpenter et al., (2009)
||Randomized Double-blind Placebo-controlled Cross-over
|Haney et al., (2010)
||Baclofen Or Mirtazapine
||30, 60, 90 mg 30mg
||Randomized Double-blind Placebo-controlled Cross-over
|* Cornelius et al., (2010)
||Randomized Double-blind Placebo-controlled Cross-over
|2. Cannabis Agents
Most published studies have been human laboratory studies of short duration (typically 3–4 days), using an inpatient human laboratory model developed at Columbia University (New York, US) . Participants were non-treatment-seeking volunteers who smoked cannabis many times a day. They smoked cannabis (active or placebo) and received oral medication (active or placebo) each day under double-blind conditions. The protocols used a within-subjects crossover design so that each participant received each active and placebo combination of cannabis and medication .
The early laboratory studies evaluated divalproex, an anticonvulsant which is used clinically as a mood stabilizer and to treat epilepsy and migraine headaches  buproprion, which is used clinically as an antidepressant and for smoking cessation; and nefazodone, an antidepressant that blocks post-synaptic 5HT-2a receptors and inhibits pre-synaptic 5HT and NE reuptake . Bupropion is thought to exert its clinical effects by inhibiting reuptake of norepinephrine (NE) and dopamine (DA) and possibly by acting as a nicotine receptor antagonist . Single doses of bupropion sustained-release (300 mg/day for 17 days) and divalproex (1500 mg/day for 29 days) actually worsened, rather than improved, some withdrawal symptoms and had no positive effects [42, 43]. A single dose of nefazodone (450 mg/day) decreased some, but not the majority, of cannabis withdrawal symptoms .
So far, the only medication successful in suppression of withdrawal symptoms in the laboratory was a single dose of 10mg/day oral synthetic THC (dronabinol) . Oral THC was also more effective than placebo in an outpatient study in which oral THC was given to 8 adult, daily cannabis users who were not seeking treatment in a 40-day, within-subject design study . Participants received daily doses of placebo, 30 mg (10 mg/tid), or 90 mg (30 mg/tid) oral THC during three 5-day periods of abstinence from cannabis use, separated by 7–9-day periods of cannabis smoking as usual. Comparison of measures of withdrawal symptoms across conditions indicated a dose-dependent reduction of withdrawal discomfort by THC. Minimal adverse effects were associated with either THC dose. This demonstration of dose-response effect replicates and extends prior findings of the pharmacological specificity of the cannabis withdrawal syndrome .
More recently, the Columbia group has evaluated medications in a more complicated human laboratory design that models both withdrawal and relapse. Regular cannabis users were maintained on each medication condition for 7 inpatient days. Each medication phase was separated by an outpatient washout phase. During the first three inpatient days, placebo cannabis was available for self-administration (withdrawal). For the next 4 days, active cannabis was available for self-administration. Participants paid for self-administered cannabis using study earnings.
The first such study evaluated lofexidine, an agonist at the alpha2-adrenergic receptor that is used to treat opiate withdrawal . Lofexidine was tested both alone and in combination with THC . Eight non-treatment-seeking male regular cannabis users were maintained on each of four medication conditions double-blind: placebo, THC (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day). THC reversed the anorexia and weight loss associated with cannabis withdrawal, and decreased some withdrawal symptoms, but increased sleep onset latency, and did not decrease the resumption of cannabis use when active cannabis was available. Lofexidine, which was sedating, worsened withdrawal-related anorexia and did not robustly attenuate mood symptoms associated with withdrawal, but improved sleep and decreased cannabis relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased cannabis withdrawal, craving, and relapse in daily cannabis smokers relative to either medication alone.
The second such study evaluated baclofen, a GABA B receptor agonist and antispasmodic medication that reduces mood symptoms in heroin withdrawal , and mirtazapine, an antidepressant that enhances noradrenergic and serotonergic transmission and decreases withdrawal symptoms in alcohol-dependent patients , especially agitation and insomnia . In this study, separate groups received baclofen (60, 90 mg/day) for 16 days (n=10) or mirtazapine (30 mg/day) for 14 days (n=11)  Medication administration began when subjects were outpatients prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active cannabis (baclofen group : 3.3% THC; mirtazapine: 6.2% THC). For the next 3 days, participants could self-administer placebo cannabis (withdrawal phase), followed by 4 days in which they could self-administer active cannabis (relapse phase). During active cannabis smoking, baclofen dose-dependently decreased craving for tobacco and cannabis, but had little effect on mood during abstinence and did not decrease relapse. Mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease cannabis relapse. Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine show promise for the treatment of cannabis withdrawal.
TREATMENT OF CANNABIS DEPENDENCE
3.1. Agonist Approach
One strategy to treat drug dependence is long-term treatment with the same agonist drug or with a cross-tolerant drug to suppress withdrawal and drug craving. This approach is successfully used in the treatment of tobacco (nicotine) dependence (nicotine itself) and opiate dependence (methadone, buprenorphine). It is being studied for treatment of cannabis dependence using synthetic THC which is legally marketed in many countries as an oral medication for appetite stimulation and suppression of nausea and vomiting due to chemotherapy. Questions of medication abuse and diversion must be addressed, as with opiate agonist substitution treatment.
Use of oral synthetic THC in outpatients was reported in a study that showed the potential benefit, as well as questions that arise from the use of this medication in cannabis-abusing populations . Controlled clinical trials of oral THC are currently underway (www.clinicaltrials.gov).
3.2. Antagonist Approach
The antagonist approach uses long-term treatment with a CB1 antagonist to prevent patients from experiencing the pleasurable reinforcing effects of cannabis use, resulting in extinction of drug-seeking and drug-taking behavior. This approach has been used successfully with the mOR antagonist naltrexone in the treatment of opiate dependence . It could be implemented should a CB1 receptor antagonist again become available for human use.
A recent randomized, double blind, parallel group study investigated whether subacute (2-week) treatment with the CB1 receptor antagonist rimonabant (40 mg daily) attenuated the effects of smoked cannabis in 42 healthy men with a history of cannabis use . The repeated daily rimonabant doses attenuated the acute cardiovascular effects of a cannabis cigarette (2.78% THC) to a similar degree as a single 90-mg dose; repeated 40-mg doses attenuated subjective effects after 8 but not 15 days (possibly because of smaller sample size and lower statistical power at day 15). Rimonabant did not significantly affect THC pharmacokinetics, suggesting that the observed effects were due to receptor blockade and not reduced THC levels in the brain.
3.3. Other Approaches
Alternative pharmacotherapy approaches may arise from improved understanding of the neuropharmacology of cannabis use disorders, including the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence . These findings suggest that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters anandamide and 2-arachidonoylglycerol (2-AG) might alleviate cannabis withdrawal and dependence. One such agent, the FAAH inhibitor URB597, selectively increased anandamide levels in the brain of rodents and primates. Preclinical studies showed that URB597 produced analgesic, anxiolytic-like, and antidepressant-like effects in rodents, which were not accompanied by overt signs of abuse liability. This evidence suggests that FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal .
3.3.a. Opiate Antagonist Naltrexone
Because animal studies show that mOR antagonists block effects of THC, several human laboratory studies have investigated whether the mOR antagonist naltrexone can reduce the subjective effects of cannabinoids in humans. In cannabis users, pretreatment with high doses of naltrexone (50–200 mg) failed to attenuate or enhanced the subjective effects of THC [56, 57] or smoked cannabis . However, a lower, more mOR-selective dose of naltrexone (12 mg) decreased the intoxicating effects of 20 mg, but not 40 mg, of THC . A recent placebo-controlled study in 29 heavy cannabis smokers found that opioid-receptor blockade by naltrexone (12, 25, 50, or 100 mg daily) enhanced the subjective and cardiovascular effects of cannabis . This pattern of human experimental findings is not completely consistent, but suggests that clinically used doses of naltrexone would not be effective as treatment for cannabis dependence, and might actually increase the abuse liability of cannabis.
3.3.b. Dopamine Agents
Catechol-O-Methyl Transferase (COMT) Inhibitor– Entacapone
Dopamine (DA) is a major neurotransmitter in the brain’s meso-cortico-limbic reward pathway, believed to be a common pathway involved in drug-seeking for all drugs of abuse [61–63] DA deficiency in this reward pathway plays a major role in drug compulsion and craving . Catechol-O-methyl transferase (COMT) is an enzyme that inactivates catecholamine neurotransmitters and plays a pivotal role in regulating homeostatic levels of DA neurotransmitter in the inter-synaptic cleft. COMT inhibitors would increase synaptic DA activity, perhaps counteracting the DA deficiency considered to play a role in drug compulsion and craving. The gene for COMT is located on chromosome 22q11.21 There is some evidence that carriers of the valine158 allele of the COMT gene, who should have increased brain dopamine turnover, are at increased risk for psychotic symptoms and development of schizophrenia if they use cannabis by the age of 18 . However, these findings were not replicated in a later study .
As mentioned earlier, THC, like other drugs of abuse, releases DA in the meso-cortico-limbic regions of animal brains. PET brain imaging studies in healthy volunteers so far seems to suggest that THC administration results in modest dopamine release in some human brain regions, but the role of this action in the rewarding effects of THC remains unclear. Therefore, the place in treatment of medications that target the brain dopamine reward system also remains unclear.
Entacapone is a COMT inhibitor approved for the treatment of Parkinson’s disease, in a recent study entacapone (up to 2000 mg/day) was given to 36 patients with cannabis dependence (DSM-IV) in an open-label trial for 12 weeks, continued for 12 months in interested individuals. Entacapone both short-term and long-term significantly decreased craving for cannabis in 52.7% of the patients, but no information was reported on patients’ cannabis use. Entacapone was well tolerated and there was no serious adverse event .
3.3.c. Glutamate- N-acetylcysteine (NAC)
The neurotransmitter glutamate has emerged as a potential target in the treatment of addictions, such as cocaine, nicotine, and cannabis dependence. In animal studies, N-acetylcysteine (NAC) reverses drug-induced down-regulation of the cystine-glutamate exchanger, which restores normal regulation of glutamate release, reducing compulsive drug-seeking behaviors . Consistent with this evidence, preliminary studies have demonstrated significant reductions in cocaine craving  and cigarette use  during NAC treatment.
A recent open-label study gave NAC (1,200 mg) twice daily for 4 weeks to 24 cannabis-dependent males and females who were interested in reducing their cannabis use . Treatment with NAC was well tolerated and associated with significant decreases in self-report measures of cannabis use and craving, but no change in semi-quantitative urine cannabinoid levels.
3.3.d. Norepinephrine Reuptake Inhibitor- Atomoxetine
Cannabis users demonstrate time and dose-dependent impairments in attention, memory, executive function and response inhibition that resemble deficits in patients with attention deficit hyperactivity disorder (ADHD) and share morbidity with this disorder . A recent study  evaluated atomoxetine, an ADHD medication with low abuse potential, in an 11-week open-label study of thirteen treatment-seeking, cannabis-dependent patients (25, 40, 80mg/day). For the eight participants who completed the study, there was a trend towards reduction in cannabis use and increase in percent days of abstinence. The majority of patients experienced gastrointestinal adverse events.
A more recent double-blind, placebo-controlled 12-week study of atomoxetine (25–100 mg/day escalating doses) in 38 cannabis-dependent outpatients with concurrent ADHD found no significant change in cannabis use, although there was some improvement in ADHD symptoms .
3.3.e. Anxiolytic- Buspirone
Buspirone shares some of the properties of the benzodiazepines and the neuroleptics; it is a 5-HT (1A) receptor agonist  and a D2 receptor antagonist . A preliminary 12-week, open-label study in 10 cannabis-dependent men found that buspirone (maximum 60 mg per day) in a 12-week open-label trial significantly reduced frequency and duration of cannabis craving and use and reduced irritability and depression . A following 12-week controlled clinical trial compared buspirone (maximum 60mg/day) vs. placebo, together with motivational interviewing, in 23 cannabis-dependent participants . Among the 24 participants who completed the trial, those randomized to buspirone had a greater percentage of cannabis-negative urine samples (95% CI:7–63%, p<0.05) and a trend towards achieving the first cannabis-negative urine sample sooner than those participants treated with placebo. These findings support the promise of buspirone as a treatment for cannabis dependence.
3.3.f. Mood Stabilizers
Lithium is a mood stabilizer used primarily in the treatment of bipolar disorder (depression and mania), both acutely and chronically. A preclinical study showing that lithium attenuated cannabis withdrawal in rats  prompted two small open-label clinical studies. In the first study, lithium (600 to 900 mg/day), administered to 9 adults for 6 days, reduced withdrawal symptoms in 4 of the 9 participants . However, cannabis was admittedly smoked during this period by one of these 4 participants and cannabis abstinence was not verified in the others. In the second study, 20 cannabis-dependent participants received lithium (500 mg 2x/day) for 7 days in an inpatient detoxification facility . Twelve participants completed the 7-day inpatient detoxification. Self-reported cannabis abstinence at post-treatment follow-up sessions was 64% (Day 10), 65% (Day 24), and 41% (Day 90). Participants self-reported cannabis abstinence on 88% of days post-treatment. Five participants reported continuous abstinence that was corroborated with urine toxicology tests on Day 90. These results provide limited support for a double-blind trial of lithium as treatment for cannabis dependence.
A small 6-week controlled clinical trial in 25 cannabis-dependent outpatients also receiving weekly relapse prevention psychotherapy found that divalproex (1500–2000 mg daily, to achieve plasma concentrations of 50–120 ng/mL) did not reduce cannabis use more than placebo and was poorly tolerated by participants .
A 13-week controlled clinical trial comparing nefazodone (300mg/day), bupropion-sustained release (150mg/day), or placebo, plus weekly, individual coping skills therapy in 106 cannabis-dependent outpatients found no significant medication effects on cannabis use or cannabis withdrawal symptoms . These results suggest that nefazodone and bupropion-sustained release are not effective in treating cannabis dependence.
TREATMENT OF PATIENTS WITH COMORBID CANNABIS DEPENDENCE AND DEPRESSION
Cannabis users frequently have co-morbid mood symptoms, especially depression [84, 85]. The prevalence of depression in this population suggested that anti-depressant medication might promote abstinence in this population.
Two studies evaluated the selective serotonin reuptake inhibitor (SSRI) anti-depressant medication fluoxetine in this population. A post hoc analysis of 13 cannabis-using patients among a larger sample of alcohol-abusing, depressed adolescents treated with fluoxetine (20–40 mg daily) showed reduction in cannabis and alcohol dependence and depressive symptoms . Five-year follow-up of 10 patients showed that cannabis and alcohol dependence were reduced and academic ability improved, but clinical depression remained problematic. A later 12-week, controlled clinical trial in 70 adolescents and young adults with comorbid major depression and cannabis use disorder found fluoxetine (20 mg daily) no better than placebo in treating either the depressive symptoms or the cannabis- related symptoms . The lack of a significant between-group difference in symptoms may reflect limited medication efficacy, a ceiling effect because of the efficacy of the concurrent psychosocial treatment (cognitive behavioral/motivational enhancement psychotherapy), or low statistical power from small sample size.
4. NEW PRE-CLINICAL DEVELOPMENTS
Several recent studies in animals have used compounds that affect the endocannabinoid system and offer promising leads for future therapeutic agents. First, the benzoflavone moiety from methanol extracts of passiflora incarnate Linneaus reversed the effects of THC in mice . Second, nicotinic alpha7 receptor antagonists such as methyllycaconitine (MLA) antagonized the discriminative effects of cannabinoids at doses that did not produce depressant or toxic effects . Finally, inhibitors of endocannabinoid- metabolizing enzymes reduced rimonabant-induced precipitated withdrawal responses in THC- dependent mice . These results suggest several potential therapeutic agents that warrant further study.
Results from controlled human laboratory studies suggest that CB1 receptor antagonists, should they again become available for clinical use, might be effective treatment for cannabis intoxication and that oral THC (perhaps combined with an α-adrenergic agonist such as lofexidine) might be effective treatment for cannabis withdrawal. For the treatment of cannabis dependence, there is little data to guide the clinician, as few controlled clinical trials have been conducted. Only buspirone has shown efficacy in such a trial, while atomoxetine, bupropion, divalproex, and nefazadone have not. A few small open-label clinical trials suggest that the COMT inhibitor entacapone, dronabinol, and lithium may warrant further study, although this recommendation is tempered by the weakness of evidence from open-label studies. In contrast, available evidence from human laboratory studies suggests that the mu-opioid receptor antagonist naltrexone may increase the abuse liability of cannabis and therefore should not be used for treatment. Recent pre-clinical studies suggest the potential of FAAH inhibitors such as URB597 for the treatment of cannabis withdrawal and of endocannabinoid-metabolizing enzymes andnicotinic alpha7 receptor antagonists such as methyllycaconitine (MLA) for treatment of cannabis dependence.
In response to the continuing public health problem that they pose, the National Institute on Drug Abuse launched in 2004 a research program to develop medications for treating cannabis use disorders (CUDs)  which hopefully will bear fruit in the future.
Dr. Weinstein is supported by the National Institute for Psychobiology in Israel that is funded by the Charles E. Smith Foundation. Dr. Gorelick is supported by the US National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health.
1. United Nations Office on Drugs and Crime (ONODC) World Drug Report 2010. United Nations Office on Drugs and Crime. http://unp.un.org.
2. Substance Abuse and Mental Health Services Administration. Rockville, MD: 2010. Results from the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings. (Office of Applied Studies, NSDUH Series H-38A, HHS Publication No. SMA 10-4856 Findings). [Google Scholar]
3. European Monitoring Centre for Drug and Drug addiction (EMCDDA) Conference proceedings: Identifying Europe’s information needs for effective drug policy EM-CDDA, Lisbon, December 2009; Luxembourg: 2009. Publications Office of the European Union ISBN 978-92-9168-409-0 www.emcdda.europa.eu. [Google Scholar]
4. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. [Google Scholar] Artigas F, Nutt DJ, Shelton R. Mechanism of action of antidepressants. Psychopharmacol Bull. 2002; 36 Suppl 2:123–132. [PubMed] [Google Scholar]
5. World Health Organization (WHO) Geneva: WHO; 2007. International Classification of Diseases, Tenth Revision (ICD-10) – Clinical Modification. [Google Scholar]
6. Stinson FS, Ruan WJ, Pickering R, Grant BF. Cannabis use disorders in the USA: prevalence, correlates and co-morbidity. Psycholl Med. 2006; 36 :1447–1460. [PubMed] [Google Scholar]
7. Copeland J, Swift W, Roffman R, Stephens RS. A randomized controlled trial of brief cognitive– behavioral interventions for cannabis use disorder. J Subste Abuse Treat. 2001; 21 :55–64. [PubMed] [Google Scholar]
8. Kadden RM, Litt MD, Kabela-Cormier E, Petry NM. Abstinence rates following behavioral treatments for marijuana dependence. Addict Behav. 2007; 32 :1220–1236. [PMC free article] [PubMed] [Google Scholar]
9. Stephens RS, Roffman RA, Simpson EE. Treating adult marijuana dependence: a test of the relapse prevention model. J Consult Clin Psychol. 1994; 62 :92–99. [PubMed] [Google Scholar]
10. Stephens RS, Roffman RA, Curtin L. Extended versus brief treatment for marijuana use. J Consult Clin Psychol. 2000; 68 :898–908. [PubMed] [Google Scholar]
11. Moore BA, Budney AJ. Relapse in outpatient treatment for marijuana dependence. J Subst Abuse Treat. 2003; 25 :85–89. [PubMed] [Google Scholar]
12. Pertwee RG. Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addict Biol. 2008; 13 :147–159. [PubMed] [Google Scholar]
14. Mechoulam R. Marijuana, Chemistry, Pharmacology, Metabolism and Clinical Effects. New York: Academic Press; 1973. [Google Scholar]
15. Sarel S, Mechoulam R, Agranat I. Trends in Medicinal Chemistry. Oxford, UK: Blackwell Publ.; 1991. [Google Scholar]
16. Montoya ID, Vocci F. Novel medications to treat addictive disorders. Curr Psychiat Rep. 2008; 10 (5):392–398. [PMC free article] [PubMed] [Google Scholar]
17. Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL. Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleusaccumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacol (Berl) 1990; 102 :156–162. [PubMed] [Google Scholar]
18. Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997; 276 :2048–2050. [PubMed] [Google Scholar]
19. Fadda P, Scherma M, Spano MS, Salis P, Melis V, Fattore L, Fratta W. Cannabinoid self-administration increases dopamine release in the nucleus accumbens. Neuroreport. 2006; 17 :1629–1632. [PubMed] [Google Scholar]
20. Bossong MG, van Berckel BNM, Boellaard R, Zuurman L, Schuit RC, Windhurst AD, van Gerven JMA, Ramsey NF, Lammertsma AA, Kah RS. Δ9-Tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacol. 2009; 34 :759–766. [PubMed] [Google Scholar]
21. Stokes PRA, Mehta MA, Curran HV, Breen G, Grasby PM. Can recreational doses of THC produce significant dopamine release in the humn striatum? Neuroimage. 2009; 48 :186–190. [PubMed] [Google Scholar]
22. Stokes PRA, Egerton A, Watson B, Reid A, Breen G, Lingford-Hughes A, Nutt DJ, Mehta MA. Sinificant decreases in frontal and temporal [11C]- raclopride binding after THC challenge. Neuroimage. 2010; 52 :1521–1527. [PubMed] [Google Scholar]
23. Jaffe JH. Drug addiction and drug abuse. In: Gilman AG, Goodman LS, Murad F, editors. The Pharmacological Basis of Therapeutics. 7th Edition. USA: Macmillan; 1985. [Google Scholar]
24. Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arc Gen Psychiat. 2001; 58 (4):322–328. [PubMed] [Google Scholar]
25. LeFoll B, Gorelick DA, Goldberg S. The future of endocannabinoid-oriented clinical research after CB1 antagonists. Psychopharmacol. 2009; 205 (1):171–174. [PMC free article] [PubMed] [Google Scholar]
26. Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiat. 2004; 161 (11):1967–1977. [PubMed] [Google Scholar]
27. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiat. 2006; 19 :233–238. [PubMed] [Google Scholar]
29. Budney AJ, Radonovich KJ, Higgins ST, Wong CJ. Adults seeking treatment for marijuana dependence: a comparison with cocaine-dependent treatment seekers. Exp Clin Psychopharmacol. 1998; 6 (4):419–426. [PubMed] [Google Scholar]
30. Budney AJ, Moore BA, Vandrey RA, Hughes JR. Onset, magnitude, and duration of abstinence effects following heavy marijuana use. Drug Alc Dep. 2002; 66 :S23. [Google Scholar]
31. Budney AJ, Hughes JR, Moore BA, Novy PL. Marijuana abstinence effects in mariujana smokers maintained in thein home environment. Arc Gen Psychiat. 2001; 58 :917–924. [PubMed] [Google Scholar]
32. Stephens RS, Roffman RA, Simpson EE. Treating adult marijuana dependence: a test of the relapse prevention model. J Consult Clin Psychol. 1994; 62 :92–99. [PubMed] [Google Scholar]
33. Stephens RS, Roffman RA, Curtin L. Extended versus brief treatment for marijuana use. J Consult Clin Psychol. 2000; 68 :898–908. [PubMed] [Google Scholar]
34. Levin KH, Copersino ML, Heishman SJ, Liu F, Kelly DL, Boggs DL, Gorelick DA. Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers. Drug and Alc Dep. 2010; 111 :120–127. [PMC free article] [PubMed] [Google Scholar]
35. Hart CL. Increasing treatment options for cannabis dependence: a review of potential pharmacotherapies. Drug Alc Dep. 2005; 80 :147–159. [PubMed] [Google Scholar]
36. Nordstrom BR, Levin FR. Treatment of cannabis use disorders: a review of the literature. Am J Add. 2007; 16 (5):331–342. [PubMed] [Google Scholar]
37. Benyamina A, Lecacheux M, Blecha L, Reynaud M, Lukasiewcz M. Pharmacotherapy and psychotherapy in cannabis withdrawal and dependence. Expt Rev in Neurotherapy. 2008; 8 (3):479–491. [PubMed] [Google Scholar]
38. Vandrey R, Haney M. Pharmacotherapy for cannabis dependence: how close are we? CNS Drugs. 2009; 23 (7):543–553. [PMC free article] [PubMed] [Google Scholar]
39. Löscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002; 16 :669–694. [PubMed] [Google Scholar]
40. Artigas F, Nutt DJ, Shelton R. Mechanism of action of antidepressants. Psychopharmacol Bull. 2002; 36 Suppl 2:123–132. [PubMed] [Google Scholar]
41. Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT. Review of the pharmacology and clinical profile of bupropion, an anti-depressant and tobacco use cessation agent. CNS Drug Rev. 2006; 12 :178–207. [PMC free article] [PubMed] [Google Scholar]
42. Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW. Bupropion SR worsens mood during marijuana withdrawal in humans. Psychopharmacol. 2001; 155 :171–179. [PubMed] [Google Scholar]
43. Haney M, Hart CL, Vosburg SK, et al. Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacol. 2004; 29 :158–170. [PubMed] [Google Scholar]
44. Haney M, Hart CL, Ward AS, Foltin RW. Nefazodone decreased anxiety during marijuana withdrawal in humans. Psychopharmacol (Berl) 2003; 165 :157–165. [PubMed] [Google Scholar]
45. Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alc Dep. 2007; 86 (1):22–29. [PubMed] [Google Scholar]
46. Levi MS, Borne RF. A review of chemical agents in the pharmacotherapy of addiction. Curr Medic Chem. 2002; 9 :1807–1818. [PubMed] [Google Scholar]
47. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacol. 2008; 197 :157–168. [PMC free article] [PubMed] [Google Scholar]
48. Akhondzadeh S, Ahmadi-Abhari SA, Assadi SM, Shabestari OL, Kashani AR, Farzanehgan ZM. Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiate withdrawal. J Clin Pharmacol Therap. 2000; 25 :347–353. [PubMed] [Google Scholar]
49. Liappas J, Paparrigopoulos T, Tzavellas E, Rabavilas A. Mirtazapine and venlafaxine in the management of collateral psychopathology during alcohol detoxification. Prog Neuropsychopharmacol. 2005; 29 :55–60. [PubMed] [Google Scholar]
50. Yoon SJ, Pae CU, Kim DJ, Namkoong K, Lee E, Oh DY, Lee YS, Shin DH, Jeong YC, Kim JH, Choi SB, Hwang IB, Shin YC, Cho SN, Lee HK, Lee CT. Mirtazapine for patients with alcohol dependence and comorbid depressive disorders: a multicentre, open label study. Prog Neuropsychopharmacol. 2006; 30 :1196–1201. [PubMed] [Google Scholar]
51. Haney M, Hart CL, Vosburg SK, Comer SD, Collins S, Reed SC, Cooper Z, Foltin RW. Effects of baclofen and mirtazapine on a laboratory model of marijuana withdrawal and relapse. Psychopharmacol. 2010; 211 :233–244. [PMC free article] [PubMed] [Google Scholar]
52. Levin FR, Kleber HD. Use of dronabinol for cannabis dependence: two case reports and review. Am J Add. 2008; 17 :161–164. [PMC free article] [PubMed] [Google Scholar]
53. Comer SD, Sullivan MA, Yu E, Rothenberg JL, Kleber HD, Kampman K, Dackis C, O’Brien CP. Injectable, Sustained-Release Naltrexone for the Treatment of Opioid Dependence A Randomized, Placebo-Controlled Trial. ArcGen Psychiat. 2006; 63 :210–218. [PMC free article] [PubMed] [Google Scholar]
54. Huestis MA, Boyd SJ, Heishman SJ, Preston KL, Bonnet D, Le Fur G, Gorelick DA. Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users. Psychopharmacol (Berl) 2007; 194 (4):505–515. [PMC free article] [PubMed] [Google Scholar]
55. Clapper JR, Mangieri RA, Piomelli D. The endocannabinoid system as a target for the treatment of cannabis dependence. Neuropharmacol. 2009; 56 Suppl 1:235–243. [PMC free article] [PubMed] [Google Scholar]
56. Wachtel SR, de Wit H. Naltrexone does not block the subjective effects of oral Delta(9)- tetrahydrocannabinol in humans. Drug Alc Dep. 2000; 59 :251–260. [PubMed] [Google Scholar]
57. Haney M, Bisaga A, Foltin RW. Interaction between naltrexone and oral THC in heavy marijuana smokers. Psychopharmacol. 2003; 166 :77–85. [PubMed] [Google Scholar]
58. Greenwald MK, Stitzer ML. Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Drug Alc Dep. 2000; 59 :261–275. [PubMed] [Google Scholar]
59. Haney M. Opioid antagonism of cannabinoid effects: differences between marijuana smokers and nonmarijuana smokers. Neuropsychopharmacol. 2007; 32 :1391–1403. [PubMed] [Google Scholar]
60. Cooper ZD, Haney M. Opioid antagonism enhances marijuana’s effects in heavy marijuana smokers. Psychopharmacol (Berl) 2010; 211 (2):141–148. [PMC free article] [PubMed] [Google Scholar]
61. Koob GF. Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci. 1992; 13 :177–184. [PubMed] [Google Scholar]
62. Di Chiara G, North RA. Neurobiology of opiate abuse. Trends Pharmacol Sci. 1992; 13 :185–193. [PubMed] [Google Scholar]
63. Wise RA. Neurobiology of addiction. Curr op Neurobiol. 1996; 6 :243–251. [PubMed] [Google Scholar]
64. Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Angrist B, Gatley SJ, Logan J, Ding YS, Pappas N. Association of Methylphenidate-induced craving with changes in right striatoorbitofrontal metabolism in cocaine abusers: implications in addiction. Am J Psychiat. 1999; 156 (1):19–26. [PubMed] [Google Scholar]
65. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiat. 2005; 57 (10):1117–1127. [PubMed] [Google Scholar]
66. Zammit S, Spurlock G, Williams H, Norton N, Williams N, O’Donovan MC, Owen MJ. Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interaction with tobacco and cannabis use. Brit J Psychiat. 2007; 191 :402–407. [PubMed] [Google Scholar]
67. Shafa R. COMT- Inhibitors may be a Promising Tool in Treatment of Marijuana Addiction Trials. A J Addict. 2009; 18 :322. [Google Scholar]
68. Kau KS, Madayag A, Mantsch JR, et al. Blunted cystine-glutamate antiporter function in the nucleus accumbens promotes cocaine induced drug seeking. Neuroscience. 2008; 155 :530–537. [PMC free article] [PubMed] [Google Scholar]
69. LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K, Saladin M, McRae A, Brady K. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addictn. 2006; 15 :105–110. [PMC free article] [PubMed] [Google Scholar]
70. Knackstedt LA, LaRowe S, Mardikian P, et al. The role of cystineglutamate exchange in nicotine dependence in rats and humans. Biol Psychiat. 2009; 65 :841–845. [PMC free article] [PubMed] [Google Scholar]
71. Gray KM, Watson NL, Carpenter MJ, Larowe SD. Nacetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Add. 2010; 19 (2):187–189. [PMC free article] [PubMed] [Google Scholar]
72. Wilens TE. Attention Deficit Hyperactivity Disorder and Substance Use Disorders. AJ Psychiat. 2006; 163 :2059–2063. [PubMed] [Google Scholar]
73. Tirado CF, Goldmanm M, Lynch K, Kampman KM, Obrien CP. Atomoxetine for treatment of marijuana dependence: a report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study. Drug Alc Dep. 2008; 94 :254–257. [PMC free article] [PubMed] [Google Scholar]
74. McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, White KG, Brady KT. A Placebo-Controlled Trial of Atomoxetine in Marijuana-Dependent Individuals with Attention Deficit Hyperactivity Disorder. Am J Add. 2010; 19 (6):481–489. [PMC free article] [PubMed] [Google Scholar]
75. Blier P, Bergeron R, de Montigny C. Selective activation of post-synaptic 5-HT1A receptors induces rapid antidepressant response. Neuropsychopharmacol. 1997; 16 (5):333–338. [PubMed] [Google Scholar]
76. Gobert A, Rivet JM, Cistarelli L, Melon C, Millan MJ. Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin1A receptors and blockade of alpha2-adrenergic receptors underlie its actions. Neuroscience. 1999; 93 (4):1251–1262. [PubMed] [Google Scholar]
77. McRae AL, Brady KT, Carter RE. Buspirone for Treatment of Marijuana Dependence: A Pilot Study. Am J Add. 2006; 15 :404. [PubMed] [Google Scholar]
78. McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, Wahlquist AE, Simpson SA, Brady KT. A placebo-controlled trial of buspirone for the treatment of marijuana dependence. Drug Alc Dep. 2009; 105 (1–2):132–138. [PMC free article] [PubMed] [Google Scholar]
79. Cui SS, Bowen RC, Gu GB, Hannesson DK, Yu PH, Zhang X. Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation. J Neurosci. 2001; 21 :9867–9876. [PMC free article] [PubMed] [Google Scholar]
80. Bowen R, McIlwrick J, Baetz M, Zhang X. Lithium and marijuana withdrawal. Can J Psychiat. 2005; 50 :240–241. [PubMed] [Google Scholar]
81. Winstock AR, Lea T, Copeland J. Lithium carbonate in the management of cannabis withdrawal in humans: an open-label study. J Psychopharmacol. 2009; 23 :84–93. [PubMed] [Google Scholar]
82. Levin FR, McDowell D, Evans SM, Nunes E, Akerele E, Donovan S, Vosburg SK. Pharmacotherapy for marijuana dependence: a double-blind, placebo-controlled pilot study of divalproex sodium. Am J Add. 2004; 13 :21–32. [PubMed] [Google Scholar]
83. Carpenter KM, McDowell D, Brooks DJ, Cheng WY, Levin FR. A preliminary trial: double-blind comparison of nefazodone, bupropion-SR, and placebo in the treatment of cannabis dependence. Am J Add. 2009; 18 (1):53–64. [PMC free article] [PubMed] [Google Scholar]
84. Petronis KR, Samuels JF, Moscicki EK, Anthony JC. An epidemiologic investigation of potential risk factors for suicide attempts. Soc Psychiat Psychiat Epidem. 1990; 25 :193–199. [PubMed] [Google Scholar]
85. Rowe MG, Fleming MF, Barry KL, Manwell LB, Kropp S. Correlates of depression in primary care. Journal of Family Practice. 1995; 41 :551–558. [PubMed] [Google Scholar] Sarel S, Mechoulam R, Agranat I. Trends in Medicinal Chemistry. Oxford, UK: Blackwell Publ.; 1991. [Google Scholar]
86. Cornelius JR, Clark DB, Bukstein OG, Bimaher B, Salloum IM, Brown SA. Acute phase and five year follow up study of fluoxetine in adolescents with major depression and comorbid substance abuse disorder: a review. Add Behavs. 2005; 30 :1824–1833. [PubMed] [Google Scholar]
87. Cornelius JR, Buksteinb OG, Douaihy AB, Clark DB, Chung TA, Daley DC, Wood DS, Brown SJ. Double-blind fluoxetine trial in comorbid MDD–CUD youth and young adults. Drug Alc Dep. 2010; 112 :39–45. [PMC free article] [PubMed] [Google Scholar]
88. Dhawan K, Kumar S, Sharma A. Reversal of cannabinoids (delta9-THC) by the benzoflavone moiety from methanol extract of Passiflora incarnata Linneaus in mice: a possible therapy for cannabinoid addiction. Jf Pharm Pharmacol. 2002; 54 (6):875–881. [PubMed] [Google Scholar]
89. Solinas M, Scherma M, Fattore L, Stroik J, Wertheim C, Tanda G, Fratta W, Goldberg SR. Nicotinic alpha 7 receptors as a new target for treatment of cannabis abuse. J Neurosci. 2007; 27 (21):5615–5620. [PMC free article] [PubMed] [Google Scholar]
90. Schlosburg JE, Carlson BL, Ramesh D, Abdullah RA, Long JZ, Cravatt BF, Lichtman AH. Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J. 2009; 11 (2):342–352. [PMC free article] [PubMed] [Google Scholar]
Does CBD Interact With Fluoxetine (Prozac)?
Fluoxetine (Prozac), is a common prescription SSRI medication used in the treatment of anxiety and depression.
There’s a moderate risk of CBD interacting with fluoxetine.
According to the CDC, roughly 13% of the population takes antidepressant medications. Another survey found that nearly 14% of the population takes CBD .
Unsurprisingly, there are a lot of people who take both CBD (cannabidiol) and SSRIs at the same time.
Is this combination safe? Are there any dangers to be aware of? We’ll explore the potential risks and interactions when combining CBD with fluoxetine (Prozac).
Table of Contents
- Does CBD Interact With Fluoxetine (Prozac)?
- Precautions While Taking Fluoxetine
Does CBD Interact With Fluoxetine (Prozac)?
There is a moderate risk of increased side effects when using CBD with antidepressants such as fluoxetine (Prozac) .
The chances of users experiencing a serious interaction are low. However, some of the rare but possible side effects are severe — including seizures and serotonin syndrome.
There are two main ways CBD can interact with fluoxetine.
Interaction 1: Slowed Elimination (Metabolic Inhibition)
CBD strongly interacts with other drugs metabolized by CYP2C19 and moderately interacts with drugs metabolized by CYP2D6 .
Most SSRIs, including fluoxetine, are also metabolized by CYP2D6 . Fluoxetine is a moderate inhibitor of drugs metabolized by CYP2D6 but a strong inhibitor of drugs metabolized by CYP2C19.
Since CBD and fluoxetine compete for metabolism in the liver, serum levels of both compounds can elevate. This slows fluoxetine’s metabolization, which, in turn, increases the possibility of side effects.
Adverse effects from mixing CBD with fluoxetine include nausea, diarrhea, and headaches.
Interaction 2: Increased Effect (Agonistic Interaction)
Simultaneously taking two substances with similar actions results in an agonistic interaction. CBD and fluoxetine may compound each other’s actions as they are both used to treat depression, anxiety, and panic disorders.
This interaction can result in serious side effects.
Therefore, before taking CBD and fluoxetine together, you must consult with your physician first. They may want to reduce your dose of Prozac or advise you to separate your dose of SSRIs and CBD by about 2-hours to minimize your risk.
Other Names for Fluoxetine
Fluoxetine is a generic drug marketed under many different brand names. All of the following medicines share the same risk and potential for interaction with CBD.
Some of the other names for fluoxetine are:
Fluoxetine (Prozac) is classified as an SSRI drug. CBD and SSRIs interact and share the same risks.
- Fluvoxamine (Luvox, Faverin, Fluvoxin, Boxamine, Fluvator)
- Paroxetine (Aropax, Paxil, Pexeva, Seroxat, Sereupin, Brisdelle)
- Sertraline (Zoloft, Lustral, Actiser, Dazolin, Depsert, Insert, Mares)
- Citalopram (Celexa, Cipramil, C-pram, Celepra, Celica, Cipam, Citalent, Citalomine)
- Escitalopram (Lexapro, Alwel, Anipram, Rhopram S, Talo, Szetalo, Stalopam, S Celepra)
- Dapoxetine (Priligy, Dasutra, Duralast, Kutub, Dapox, Ejalong, Prilyxet, Xydap)
Is It Safe to Take CBD & Fluoxetine (Prozac) Together?
Safety concerns with the co-administration of CBD and fluoxetine (Prozac) are still a topic of debate. Few studies exist on potential drug interactions between these two substances.
CBD and fluoxetine, when taken together, may lead to some undesirable side effects such as dizziness, drowsiness, difficulty in concentrating, and confusion. Older individuals may experience impairment in motor coordination along with judgment and thinking.
A lower dosage of fluoxetine, when taken with CBD, may have fewer side effects than higher dosages. However, it’s best to avoid the co-administration of CBD and fluoxetine.
Consult your doctor before you combine CBD with any other medication, including fluoxetine.
Is CBD a Viable Alternative to Fluoxetine (Prozac)?
CBD could be a natural alternative in treating depression, substituting fluoxetine due to its similar effects, but it depends on what fluoxetine is prescribed for . If it’s for anything other than mild depression, CBD is unlikely to help. It appears to be better tolerated than routine psychiatric medications .
According to the WHO, there have been no reports of a lethal overdose with CBD, and it has an exceedingly low potential for abuse or dependency .
CBD has a low overall risk of side effects with short-term use compared to most antipsychotics. However, further research is needed to evaluate possible long-term dangers and damages.
However, do not stop taking fluoxetine or adjust the dose as it can lead to withdrawal symptoms. Always consult your physician first before switching between drugs or supplementing prescribed antidepressants with CBD.
What Is Fluoxetine (Prozac)?
Fluoxetine (Prozac) is a prescription-only medication belonging to the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. It is a generic drug with trade names such as Prozac, Rapiflux, Sarafem, Barazac, and Selfemra.
It’s the drug of choice in treating obsessive-compulsive disorders, panic disorders, social phobias, eating disorders, premenstrual dysphoric disorder, and post-traumatic stress disorder.
These drugs also treat anxiety and bipolar disorders, body dysmorphic disorder, compulsive buying, kleptomania, and premature ejaculation.
It’s for use in children seven years or older only and is available in dosages of 10 mg, 20 mg, 40 mg, and 90 mg capsules.
||Prozac, Rapiflux, Sarafem, Barazac, Selfemra, etc
||Selective Serotonin Reuptake Inhibitor (SSRI)
||Metabolized by CYP2C19 and CYP2D6
|Interaction with CBD
||Metabolic Inhibitor and Agonistic Interaction
|Risk of interaction
What Does Fluoxetine Do?
Fluoxetine (Prozac), belonging to the SSRI class of drugs, blocks serotonin’s reabsorption (reuptake) into neurons.
This leads to increased levels of serotonin in the brain. SSRIs mainly affect serotonin, not other neurotransmitters. Serotonin, famously known as the happy hormone, stabilizes our mood, feelings of well-being, and happiness.
Side Effects of Fluoxetine
- Altered appetite and weight
- Abnormal dreams
- Flu-like syndrome
The following are serious side effects that need immediate medical attention. Call your healthcare provider right away if you have any of these symptoms.
- Allergic reactions and rash
- Abnormal bleeding
- Potential for cognitive and motor impairment
- Suicidal thoughts and behaviors in children, adolescents, and young adults under twenty-five years of age
- Serotonin syndrome (change in mental status, overactive reflexes, fever)
Precautions While Taking Fluoxetine
Besides side effects, there are other things to be aware of if you’re using fluoxetine.
Concomitant Use With Alcohol
Do not mix CBD or fluoxetine with alcohol. The adverse effects of both substances may be fatal when taken with alcohol.
Use With Other Medication
Do not use fluoxetine if you have previously used monoamine oxidases (MAO) inhibitors such as phenelzine and tranylcypromine. It may lead to a condition known as serotonin syndrome, which is life-threatening.
Other drugs that increase serotonin levels include tricyclic antidepressants (TCA), triptans, amphetamine, methamphetamine, MDMA, buspirone, and serotonin-norepinephrine reuptake inhibitors.
Patients using blood-thinning medications should also avoid fluoxetine.
Opioids like pethidine, tramadol, dextromethorphan, and tapentadol will increase serotonergic activity. Fentanyl and methadone have similar effects but to a lesser degree.
A combination of opioids and fluoxetine may increase the risk of serotonin toxicity. Fluoxetine also blocks the metabolism of opioids leading to reduced analgesic effects .
Use In Pregnancy
Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (Pregnancy Category C). It is not for use in breastfeeding women as fluoxetine is excreted in breast milk.
Dose adjustments are required in patients with liver cirrhosis; these patients need lower or less frequent dosing. Unlike other drugs, dose adjustment for fluoxetine is not necessary for patients with impaired renal functions.
Do not stop fluoxetine without talking to your healthcare provider. Stopping the drug suddenly may cause serious withdrawal symptoms such as anxiety, irritability, high or low mood, feeling restless, or changes in sleep habits. Other symptoms include headache, sweating, nausea, dizziness, electric shock-like sensations, shaking, and confusion.
Key Takeaways: Is It Safe to Take Fluoxetine (Prozac) With CBD?
CBD is a natural, relatively nontoxic chemical with antidepressant action. There is a moderate risk if you use CBD and fluoxetine (Prozac) together.
Adverse effects of co-administration include dizziness, drowsiness, difficulty in concentrating, and confusion.
Always consult with your healthcare provider to ensure that CBD does not interact with any medication you are currently taking.
How I Used CBD and Research to Get off SSRI’s and avoid Serotonin Withdrawal Syndrome
We already covered the first great “weaning” I had to do with benzos (Xanax, Ativan, Valium) at our CBD for benzo withdrawal article.
Next, in lockstep, the doctors decided SSRI’s would be the best course of treatment for my rolling anxiety.
It nearly killed me.
More accurately, I suddenly didn’t want to live any longer.
It seems to be the go-to remedy for women entering a rough perimenopause as I did.
According to the doctor, it takes a few weeks to start working (not true. see CBD and SSRI’s to learn how they initially increase anxiety/depression).
About two weeks in, I was a mess.
Total flatline response.
No appetite. lost 10 pounds in 1 week. My stomach was a wreck.
Then I started to feel nothing.
No taste. No feeling. Just flat affect. (the technical term).
Negative thoughts crept up and even suicidal thoughts.
I ended up in the ER after I couldn’t sleep for 3 days straight.
The ER doctor there prescribed an anti-nausea drug (did I mention my gut was wrecked??) which has a strong warning against taking with SSRI’s.
Psychotic break, please.
As I mentioned in my story here, this was the lowest point of my life and I really was negotiating with “someone” as to whether I wanted to stay on this Earth any longer.
I had to stop the SSRI’s.
Apparently, I’m in good company if you check out the stats at the CBD versus SSRI’s page or CBD versus anxiety medications here.
They generally work for about 30% of patients until the body builds tolerance.
We’re going to really look at how CBD affects the same serotonin pathways but without tolerance below!
More importantly, we’ll address the real star of the show..BDNF! Our brain’s fertilizer!
Coming off of the benzos was brutal but this would turn out to be worse.
SSRIs don’t have the clinical addiction connection with dopamine but that doesn’t mean they’re easier to come off of.
You shouldn’t drop them cold turkey.
The focus of this article is how CBD might help with the process.
Research is shedding light on the pathways shared by both but in very different ways.
We’ll look at the following topics:
- A quick introduction to the pathways of SSRIs and how CBD affects them
- Can CBD help with SSRI withdrawal
- Can CBD be taken with SSRI’s
- Can CBD replace SSRI’s
- My process using CBD to replace SSRI
- Best CBD for SSRI withdrawal and replacement
Lots to cover and as with all our articles, we’re going to lean heavily on NIH research.
Let’s get started.
First, a lay of the land.
A quick introduction to the pathways of SSRIs and how CBD affects them
It’s important to get some background on what SSRI’s do in the body.
Our focus here is on anxiety (since that’s our current run of investigation) but SSRIs are actually more relevant for depression.
Either way, they affect the same pathway.
Serotonin is a powerful workhorse neurotransmitter in the brain.
In fact, 70% of our serotonin is actually made in the gut (see CBD and gut biome here).
SSRI’s primary lever is to boost the amount of serotonin available to neurons.
It turns out that the real effect of serotonin on the pathways of anxiety and depression deal with neurogenesis.
That’s why it takes so long to work.
Neurogenesis is the process of rebuilding and replenishing neurons.
Learn all about it at our CBD and neurogenesis article.
In fact, you can’t deplete serotonin or its precursor (tryptophan) and cause healthy people to suddenly display anxiety and depression:
Tryptophan depletion studies in never-depressed individuals are variable, with no or little overall effect on lowering of mood
Read that back over again. It’s really important.
Where they see an effect is in healthy people with a family member that has depression or people with past depression issues.
There appear to be other systems that influence this.
In fact, the gut microbiome’s role is coming to light:
Influence of gut microbiota on behavior is becoming increasingly evident
As we stated above, serotonin’s real effect on anxiety and depression appears to be in its ability to rebuild or repair specific brain areas under duress.
Many things can cause damage to these brain areas in the anxiety circuit:
- Chronic inflammation
- Chronic stress
- Infection at specific times of brain development
- THC (yes, CBD’s cousin in cannabis)
- Gut bacteria dysregulation and gut permeability
- Immune system response to weakened gut barrier
The last one is critically important.
Early trauma or infection (even in utero -especially third trimester) can downregulate serotonin later in life (along with many other key pathways like GABA).
We have a monster review on it here.
Regardless of the cause, brain loss can feed into the pathway for anxiety and depression.
A good synopsis of it is here:
Pathological anxiety and chronic stress are associated with structural degeneration and impaired functioning of the hippocampus and the prefrontal cortex (PFC), which may account for the increased risk of developing neuropsychiatric disorders, including depression and dementia,”
So back to SSRI and serotonin.
A study looked at sertraline, an SSRI commonly used (brand name is Zoloft).
Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor
Why is this important for SSRI’s which boost serotonin?
Similarly, we discuss the possibility that adult hippocampal neurogenesis mediates antidepressant effects via the ventral (in rodents; anterior in humans) hippocampus’ influence on the HPA axis, and mechanisms by which antidepressants may reverse chronic stress-induced 5-HT and neurogenic changes.
To decipher a bit…
5-HT is our serotonin pathway.
Neurogenesis (building and repairing brain tissue) in the hippocampus appears to be very important for longer-term anxiety and depression.
So. that’s the primary lever by which SSRI’s might affect anxiety and depression (till they don’t due to tolerance).
Of course, serotonin levels alone can also have an effect.
IF you have reduced serotonin levels.
There’s no good way to test for this so it’s a guess by the doctor.
Usually, they infer. anxiety or depression = low serotonin.
Here’s the important take away:
Chronic treatment with fluoxetine and imipramine induced anxiolytic-like effects in the novelty suppressed feeding test in control mice but not in animals that were submitted to x-ray-irradiation of the SGZ (SGZ-x-irradiation), a procedure that blunts neurogenesis by killing cells undergoing proliferation.
We’ll translate because this is the smoking gun of our whole discussion.
Long term administration of an SSRI (fluoxetine is Prozac) reduced anxiety in mice.
However, when the area of the hippocampus where neurogenesis was essentially turned off (via radiation), the anti-anxiety effects went away!
What about CBD and this serotonin pathway?
Turns out that CBD directly affects and serotonin function but without the nasty side effects.
The eCB-induced modulation of stress-related behaviors appears to be mediated, at least in part, through the regulation of the serotoninergic system
eCB is short for the endocannabinoid system in which CBD operates in.
More importantly, CBD directly bolsters the endocannabinoid system which is involved across the entire anxiety circuit. not just serotonin.
A great study on CBD and public speaking for people with social anxiety reflected this change in stress response:
Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech
It even reduces the physiological responses (heart rate, blood pressure, skin conductance) to stress:
this result suggests that CBD also protects the patients from their subjective physiological abnormalities induced by the SPST
This is important because remember that chronic stress and inflammation is what can do damage to brain areas such as the hippocampus which leads to long term anxiety and depressive states.
The long term stress is chemically displayed by cortisol.
The very thing – the “plasticity” or ability to change – of the hippocampus is what also makes it vulnerable to stress hormones like cortisol:
Imaging studies of the human hippocampus have suggested a negative relationship between cortisol levels and hippocampal volume.
As for cortisol, our stress hormone:
The present results suggest that CBD interferes with cortisol secretion.
Finally, as we saw with the mice and radiated hippocampus above, what about CBD and neurogenesis?:
More recently, a study conducted with transgenic mice (GFAP-TK mice) showed that the anxiolytic effect of chronic CBD administration (14 days) in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signaling
Voila! (my mother’s French so I get the pass).
This statement just means that CBD’s “long term” effect on anxiety are due to the same neurogenesis in the hippocampus that SSRI’s affect.
We’ve covered all these topics in detail but felt it was important to at least look at the shared pathways.
The interesting factor is that CBD doesn’t just boost serotonin levels regardless of baseline.
It supports the endocannabinoid system which balances serotonin levels.
You see this all over the research such as:
Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain
We have to translate that. it’s too important.
Essentially, they injured mice and which depleted serotonin and increased pain sensitivity and anxiety.
CBD reverses these effects and primary through the serotonin pathway!
The key work is “modulate”. Not boost like SSRIs.
Let’s get to more specific questions that originally brought us here.
Can CBD help with SSRI withdrawal
So. they don’t officially call it SSRI withdrawal.
They don’t officially say it’s “addictive”.
Personally, I can tell you it’s was one of the hardest things to come off of. ever!
Even rougher than the benzos (see CBD and benzo withdrawal) and they have a black box warning on the package!
Since SSRI’s don’t directly juice the dopamine system in the usual suspect region of the nucleus accumbens, they’re not classed as technically “addictive” or habit-forming.
They also don’t create euphoria (pleasure) or have the technical term of “hedonic”.
For this reason, problems with coming off of SSRI’s are grouped under the term Serotonin Discontinuation Syndrome.
George Orwell would be proud (and probably medicated).
Here’s the deal. serotonin is a master neurotransmitter in the nervous system (and gut).
Yes, it governs gut function, sleep, and sex drive but it’s real tour de force is on mood.
Sometimes called the “feel good” neurotransmitter, it can loosely be associated with feeling. right, grounded, whole. “Good in our own skin”.
Yes, those sound like cheesy catchphrases from a 60’s Woodstock song but nevertheless, this speaks to how widespread serotonin’s effect in the brain.
Many neurotransmitters are one-trick ponies.
GABA slows things down. Glutamate speeds them up. Cortisol is a stress response.
Serotonin is a blanket of activity across the brain.
This is obvious from the crazy catch-all of side effects from SSRI’s found here:
It’s an impressive list of bodily functions gone awry.
I can personally attest to a few of them including suicidal thoughts and total flat affect.
Check out some of the research on SSRI’s and suicidal or homicidal thoughts:
With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y
By the way, CBD does not show any of these effects which aren’t surprising given the role of the endocannabinoid system and neurotransmitters.
The keyword there is “modulates”. Not increases. Not reduces.
The endocannabinoid system is shown to balance the key system in the body:
- Nervous system – neurotransmitters such as serotonin and GABA
- Endocrine system – hormones such as cortisol and histamine
- Immune system – such as inflammatory agents which can damage brain areas
So. given the many pies that serotonin has its finger in, what do you think will happen when you take it away!
Unlike the benzos, at least the doctor warned me in advance not to stop it cold turkey.
I was prescribed Lexapro for rolling panic attacks and 24-7 anxiety (from perimenopause hormone drop and serum sickness from oral typhoid vaccine. story here).
After everything we learned, a high dose of CBD (300 – 600 mg) in the beginning would have been ideal.
I would wean that down to 300 mg for the long term effect of neurogenesis (see how many mg of CBD for anxiety here) which research shows on a bell curve. peaking about 300 mg.
I personally, take 150 mg in the morning and 150 mg before bed.
Before, my anxiety would race at night and interfere with my sleep.
It’s best to hold the CBD oil under your tongue for up to 60 seconds (see how to increase CBD by 4xs here).
Ideally, you want to take it after a meal so more can get into the bloodstream.
It’s important to take CBD at least 4 hours away from any medication including SSRIs.
They both can use the same pathway in the liver (p450) for processing which might boost or reduce levels of the SSRI in the bloodstream.
Work with a naturopath.
Remember how we said that CBD “modulates” serotonin function.
Here’s the critical piece of that study:
Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity.
Rather than just increase serotonin available in the brain and body, CBD worked through the endocannabinoid system to affect receptor sensitivity.
- Too much serotonin is bad (See Serotonin syndrome below).
- Too little serotonin (function) is bad (anxiety, depression, and a host of mood disorders).
The most important word in that statement is “normalize”.
Balance is our goal.
There’s interesting research on how CBD does this by influencing our brain’s own conversion of tryptophan to serotonin:
these cannabinoids in the modulation of serotonergic signaling by their capacity to increase the availability of circulating tryptophan, the precursor necessary for the biosynthesis of the neurotransmitter 5-hydroxytryptamine (5-HT; serotonin)
It’s fascinating and could be a key between inflammation/infection and mood disorders.
The closest direct study we have for withdrawal is brand new with opioid withdrawal.
It’s even more difficult than SSRI withdrawal since the dopamine and naturally occurring opioid systems in the brain are hit hard!
The results from a double-blind study:
Acute CBD administration, in contrast to placebo, significantly reduced both craving and anxiety induced by the presentation of salient drug cues compared with neutral cues.
Big review on CBD and opioid withdrawal here.
More interestingly to us is the long term effect it had:
CBD also showed significant protracted effects on these measures 7 days after the final short-term (3-day) CBD exposure.
We’re not sure why this isn’t on every broadcast across the country given the opioid (and soon to be benzo) epidemic.
SSRI’s are different in that it’s more a function of serotonin balancing but the opioid study is a powerful example.
Here’s an interesting point.
SSRI’s eventually build tolerance.
This is a technical term for the brain’s reaction to boosting serotonin by making less serotonin itself to offset the outside influence.
The brain will literally reduce the number and sensitivity of serotonin receptors.
That’s why doctors will change SSRI’s after a period of time or increase dosages.
Eventually, the SSRI will be ineffectual aside from long term neurogenesis effects we mentioned above.
Of course, if you still have the chronic stress, inflammation, or immune response, the damage to the hippocampus continues unabated.
Here’s the issue.
When you come off the SSRI. even slowly. you’ll definitely have a reduced baseline serotonin level even if you didn’t actually have one before.
A great book called Never Enough by Judith Gisel explains this reaction in the brain very poignantly. A must-read!
Let’s look at another question we see regularly.
Can CBD help with Serotonin Syndrome
First of all, serotonin syndrome is a very serious, life-threatening condition.
Essentially, it’s the result of too much serotonin.
A general explanation and list of symptoms is below but seek medical help immediately if present:
It can start with shivering and diarrhea.
More severe symptoms can follow. Even deadly outcomes.
One note. a common approach to treating Serotonin syndrome in the medical field is the administration of benzos which have their own issues.
Short term, they may be fine but addiction issues can crop up pretty quickly.
In terms of CBD for Serotonin syndrome, we have to be careful since they both use the same P450 pathway in the liver.
Anything that taxes this metabolism pathway can increase levels of SSRI’s.
Some people actually use CBD to reduce the dosages of SSRIs due to this effect.
Usually, your doctor will recommend reducing the SSRI right away (work with your doctor) if they suspect Serotonin Syndrome.
You can check the half-life of the various SSRI’s here at our CBD versus SSRI’s articles.
Here’s the issue.
The common practice for Serotonin syndrome is to stop the SSRI.
This may then lead to SSRI Withdrawal Syndrome which we described above.
Work with your doctor on this. It can be very serious and very fast.
Learn all about the SSRI Syndrome treatment commonly prescribed here:
Just a head’s up. watch out for opioids and SSRI’s combined as there’s a known additive effect between the two of them.
More on that here:
Can CBD be taken with SSRI’s
There isn’t specific research yet on SSRI and CBD taken at the same time.
Yes, we want to take it at least 4 hours apart if taking together. We explained that in our CBD and medications here.
CBD uses the same liver pathway (P450) as most SSRI’s so it may cause their levels to increase in the bloodstream.
There are some reports on Reddit boards where people can reduce their SSRI levels or stop completely (slowly of course) due to CBD’s effect.
This is what we know.
SSRI’s boost serotonin in one direction. up up up and away (until the brain catches up and offsets the increase).
CBD works in the endocannabinoid system to balance serotonin function.
In theory, CBD should help to exercise a check and balance on serotonin functioning.
CBD can boost serotonin when levels are low. (see CBD and serotonin here).
It doesn’t have the side effect profile of SSRI’s (Serotonin Syndrome) even at much higher levels (tested up to 1500 mg in studies).
This points to the fact that it doesn’t boost in one direction.
We want to see hard research on it but you’re not going to get that from pharmaceutical companies where billion-dollar markets are jeopardized.
We can only look at shared pathways at this point.
Again, at least 4 hours apart.
See below for CBD levels to help offset this drop-off.
Can CBD replace SSRI’s
Based on the shared pathways for both (serotonin), replacing SSRI’s with CBD might be an option.
Ideally, you start with CBD before getting entangled in SSRI’s but that’s another article on our health care delivery system!
Make sure to work with your naturopath and know that it is strongly advised not to stop SSRI’s quickly.
A quick review of how I replaced Lexapro:
- Gradually reduced Lexapro dose over 30 days with pill cutter
- Tested CBD for 50mg first day to test; opposite time from SSRI
- Quickly increased to 300mg daily (3 x 100mg after meals)
After this period, I reduced CBD to 100mg daily but some people see much longer periods for serotonin pathways to find grounding.
One note..estrogen and testosterone drive serotonin and there’s no bandaiding the loss of these! See estrogen and mental health as an example.
Best CBD for SSRI withdrawal and replacement
In our experience based on both research of the market and personal trial and error, there are a few considerations in choosing the best CBD for SSRI withdrawal and replacement.
First, the basics:
- Organically grown in the US
- CO2 processed (much cleaner end result)
- 3rd party tested
- No THC (see THC versus CBD for anxiety)
- No pesticides
- No solvents (speaks to the CO2 processing above)
- No bacteria
- No mold
- No heavy metals
Those are minimum requirements and we actually test IndigoNaturals twice to this effect.
Secondly, we need a sufficient level of CBD.
The ideal sweet spot for neurogenesis (which is the basis for SSRI’s effect) in the brain is 300 mg per research.
Beyond that, we still have a dose-dependent effect on anxiety but the neurogenesis effect actually decreases.
For this reason, a good 90% of the junk on the market isn’t going to work.
A 1-ounce bottle with 300 mg is a complete rip-off.
We went through that same process when we originally started.
That’s why we have 2000 and really 6000 mg bottles of CBD.
I personally use the 6000 mg bottle with 1 dropper in the morning and once at night.
One dropper is about 200 mg (6000 divided by 30).
Finally, all the research is on CBD by itself.
Not CBD full-spectrum, hemp oil, or anything else.
For 40-60% of the population, histamine responses to all that plant material are going the wrong direction for anxiety due to serotonin withdrawal.
Histamine is a powerful excitatory chemical in the brain and directly opposes GABA.
It’s simple….we based crafting of IndigoNaturals on research.
Just look at any of our articles (such as CBD and general anxiety disorder or CBD and depression as an example).
We don’t mess around because we’ve suffered ourselves.
We’re out of that now and we want others to understand what’s happening and get relief.
If you’ve been there, you’ll understand why.
One final piece. the real effect of SSRI’s (downstream) may be something you’ve never heard of called BDNF.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.